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WO2025149667A1 - Antibody drug conjugates and uses thereof - Google Patents

Antibody drug conjugates and uses thereof

Info

Publication number
WO2025149667A1
WO2025149667A1 PCT/EP2025/050621 EP2025050621W WO2025149667A1 WO 2025149667 A1 WO2025149667 A1 WO 2025149667A1 EP 2025050621 W EP2025050621 W EP 2025050621W WO 2025149667 A1 WO2025149667 A1 WO 2025149667A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
seq
amino acid
acid sequence
set forth
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/050621
Other languages
French (fr)
Inventor
Paul Jackson
Leigh Zawel
George PROCOPIOU
Fu LI
Chi-Ting Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pheon Therapeutics Ltd
Original Assignee
Pheon Therapeutics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pheon Therapeutics Ltd filed Critical Pheon Therapeutics Ltd
Publication of WO2025149667A1 publication Critical patent/WO2025149667A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment

Definitions

  • the disclosure generally relates to antibody-drug conjugates that bind tumor-associated antigens (TAA) and methods of use thereof.
  • TAA tumor-associated antigens
  • chemotherapeutic agents While numerous chemotherapeutic agents have been developed, many often demonstrate unacceptable toxicity and or lack of specificity for cancer cells over non-cancerous tissues. To avoid the non-specific cytotoxic effects of chemotherapeutic agents, targeted antibody therapy has revolutionized cancer treatment with several monoclonal antibodies demonstrating clinical potential. Because antibodies against tumor-associated antigens (TAA) often lack therapeutic activities, they have been conjugated to cytotoxic agents in order to combine the effectiveness of chemotherapy with the targeting of antibodies. In principle, selective delivery of cytotoxic agents to specific tumor tissues by antibody binding should reduce the systemic toxicity of traditional small-molecule chemotherapeutics.
  • TAA tumor-associated antigens
  • XAA is valine-alanine.
  • XAA is an amino acid sequence having 3 amino acid moieties. In some embodiments, XAA is selected from alanine-alanine-alanine, glutamic acid-valine-citrulline, and valine-lysine-glycine. In some embodiments, XAA is an amino acid sequence having 4 amino acid moieties. In some embodiments, XAA is selected from glycine-glycine- phenylalanine-glycine, glutamic acid-aspartic acid-phenylalanine-tryptophan, glycine- phenylalanine-leucine-glycine, and alanine-leucine-alanine-leucine.
  • LA is -[CH2CH2O] P -(CH2)2-C(O)-XAA-.
  • L has the formula:
  • n is an integer from 4 to 8. In some embodiments, n is 4. In some embodiments, n is 8.
  • the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
  • PTK7 protein tyrosine kinase 7
  • HER2 epidermal growth factor receptor 2
  • VH heavy chain variable region
  • a VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1051-1085).
  • the antibody or antigen binding fragment thereof comprises:
  • a VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 622-629).
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises:
  • a heavy chain variable region comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789, and (ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
  • VH heavy chain variable region
  • the antibody or binding fragment thereof comprises:
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3 (any one of SEQ ID NOs: 793-811 or 1086-1107).
  • the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (SEQ ID NOs: 793-811 or 1086-1107).
  • the antibody or binding fragment thereof comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
  • the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Table 3B (SEQ ID NOs: 1086-1107).
  • the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4 (any one of SEQ ID NOs: 812-841 or 1108-1111).
  • the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4 (any one of SEQ ID NOs: 1108-1111).
  • the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108- 1111).
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 824.
  • the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
  • DAR drug-to-antibody ratio
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody drug conjugate of formula (I); and a pharmaceutically acceptable carrier.
  • the disclosure provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of an antibody drug conjugate of formula (I), or a pharmaceutical composition of the disclosure.
  • the cancer is acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, triple-negative breast cancer (TNBC), bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing’s tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma,
  • TNBC
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • Ab comprises an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B;
  • the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
  • the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
  • the antibody or binding fragment thereof comprises:
  • a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 2A-2C (any one of SEQ ID NOs: 1-393 or 1002-1050), and (ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 2A-2C (any one of SEQ ID NOs: 394- 786 or 1051-1085).
  • the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
  • PTK7 protein tyrosine kinase 7
  • HER2 epidermal growth factor receptor 2
  • the antibody or binding fragment thereof comprises:
  • VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 2C (any one of SEQ ID NOs: 1002-1050);
  • the antibody or binding fragment thereof comprises:
  • VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236);
  • VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629).
  • the antibody or binding fragment thereof comprises:
  • a VH comprising three HCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
  • a VL comprising three LCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
  • the antibody or binding fragment thereof comprises:
  • VH comprising three HCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
  • a VL comprising three LCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
  • the antibody or binding fragment thereof comprises:
  • VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229);
  • VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622).
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • the antibody or binding fragment thereof comprises a scFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
  • the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
  • the antibody or binding fragment thereof comprises a scFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
  • the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
  • the antibody or binding fragment thereof comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
  • the antibody or binding fragment thereof comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108- 1111).
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
  • the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 824.
  • the drug moiety is selected from
  • Ab comprises an antibody or antigen binding fragment thereof that binds a TAA as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; n is an integer from 1 to 20; and
  • the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
  • VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and (ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1051-1085).
  • VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 229-236;
  • a VH comprising three HCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in SEQ ID NO: 787 (HCDR1), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
  • the antibody or binding fragment thereof comprises:
  • VH comprising three HCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
  • a VL comprising three LCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
  • the antibody or binding fragment thereof comprises:
  • the antibody or binding fragment thereof comprises:
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • VH heavy chain variable region
  • the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
  • the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
  • the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
  • the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
  • the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
  • the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
  • DAR drug-to-antibody ratio
  • n is an integer from 1 to 10, 2 to 8, or 4 to 8, optionally n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, optionally n is 4 or 8, optionally n is 4, optionally n is 8.
  • the disclosure provides an antibody-drug conjugate having any one of formula 1030-1064 or 1101-1118, wherein Ab is an antibody that binds (e.g., specifically binds) to a TAA as disclosed in Table 1, or binding fragment thereof.
  • the tumor-associated antigen is protein tyrosine kinase 7 (PTK7).
  • the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
  • the disclosure provides an antibody-drug conjugate of any one of embodiments (I)-(XVII).
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B; n is 1;
  • L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
  • VL light chain variable region
  • L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
  • VL light chain variable region
  • (C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1108-1111.
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • VL light chain variable region
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • VH heavy chain variable region
  • VL light chain variable region
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • Ab is an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B ; n is 4;
  • VH heavy chain variable region
  • (C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
  • Ab is an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B ; n is 4;
  • VH heavy chain variable region
  • VL light chain variable region
  • Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
  • VH heavy chain variable region
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • L-D has the formula:
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • L-D has the formula: wherein the antibody or binding fragment thereof comprises:
  • VL light chain variable region
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • VL light chain variable region
  • Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1; n is 8;
  • L-D has the formula:
  • VH heavy chain variable region
  • (C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1; n is 8;
  • VH heavy chain variable region
  • VL light chain variable region
  • (C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1108-1111.
  • the disclosure provides an antibody-drug conjugate having formula (I):
  • L-D has the formula:
  • antibody or binding fragment thereof comprises:
  • L-D has the formula: wherein the antibody or binding fragment thereof comprises:
  • Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8; L-D has the formula: wherein the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • isostere refers to a group or molecule whose chemical and/or physical properties are similar to those of another group or molecule.
  • a “bioisostere” is a type of isostere and refers to a group or molecule whose biological properties are similar to those of another group or molecule.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the terms “prevent,” “preventing,” and/or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition.
  • the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g. , a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g. , increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • cocrystal refers to a molecular complex derived from a number of cocrystal formers known in the art.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients.
  • the use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.
  • a “prodrug” refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g. , two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4- hydroxyproline, hydroxy lysine, desmosine, isodesmosine, 3- methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters).
  • Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups.
  • Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • any compound that can be converted in vivo to provide the bioactive agent is a prodrug within the scope of the disclosure.
  • Various forms of prodrugs are well known in the art.
  • pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991).
  • prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. , organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g., dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the disclosure.
  • target the drug action e.g. , organ or tumor-targeting, lymphocyte targeting
  • aqueous solubility of a drug e.g., i.v. preparations and eyedrops
  • topical drug delivery e.g., dermal and ocular drug delivery
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1-10)alkyl or C1-10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range, e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C
  • Alkylhetaryl refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylheterocycloalkyl refers to an -(alkyl) heterocyclic radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
  • alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (/'. ⁇ ?. , (C2-io)alkenyl or C2-10 alkenyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R
  • alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (where t is 1 or 2), -OC(O)-R a , - N(R a )
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (z.e. , (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range - e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbomyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (where t is 1 or 2), -S(O) t R a - (where t is 1 or 2), -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a
  • Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.
  • Cycloalkyl-heteroaryl refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
  • alkoxy refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (z.e., - ⁇ -(substituted alkyl)).
  • the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, acylsulfonamido, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - S(O) t R a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2
  • a (Ci-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O- C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
  • substituents which independently are: alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (where t is 1 or 2), -OC(O)-R a , -
  • the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O) t R a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N, -C(O)N
  • Amino or “amine” refers to a -N(R a )2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl
  • alkyl refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - S(O) t R a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given - e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, acylsulfonamido, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , - S(O) t R a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR
  • Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.
  • the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SIU, -S(O) t R a - (where t is 1 or 2), -OC(O)-R a ,
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • “Hydroxamate” refers to the -C(O)NR a OR a moiety, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon can be specified by either (R) or (5).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (5).
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (/?)- or an (5)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (/?)- or (5)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (5)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (5)-isomeric form is 80%.
  • the enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • an enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw- Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).
  • an enantiomerically enriched preparation of the (k)-cnant iomcr means a preparation of the compound having greater than 50% by weight of the (k)-cnantiomcr relative to the (/?)-cnantiomcr, such as at least 75% by weight, or such as at least 80% by weight.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization.
  • Solvate refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups,
  • “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).
  • “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).
  • “Sulfonyl” refers to groups that include -S(C>2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -8(6)2)- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).
  • a sulfonamide group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • an antigen refers to the molecular structure or to any molecule or linear molecular fragment derived from the processing of the native antigen being recognized by an antibody or by T cell receptors.
  • an antigen can be a virus or virus- derived molecule, a bacteria or bacteria-derived molecule, a protein or protein fragment, a molecule such as a toxin, a chemical, a drug, or any other structure recognized by the immune system as being foreign and eliciting an immune response.
  • tumor-associated antigen herein describes a large family of antigens that includes antigens derived from genes overexpressed in tumors, differentiation antigens, and cancer germline/cancer testis antigens.
  • Antigens derived from genes overexpressed in tumors comprise a class of normal self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a results of their malignant profile.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.
  • Antibodies may be murine, human, humanized, chimeric, or derived from other species.
  • An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York).
  • a target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody.
  • An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen-binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • the hypervariable region generally encompasses amino acid residues from about amino acid residues 24-34 (LCDR1; “L” denotes light chain), 50-56 (LCDR2) and 89-97 (LCDR3) in the light chain variable region and around about 31-35 (HCDR1; “H” denotes heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region; Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and/or those residues forming a hypervariable loop (e.g.
  • nanobody single-domain antibody (sdAb)”, “variable domain of a heavy chain-only antibody (VHH),” or “single domain-based VHH,” as used herein are used interchangeably and refer to single-domain heavy chain-only antibody derived from the Camelidae family.
  • a nanobody is an antibody fragment derived from the Camelidae heavy-chain only IgG antibody.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a variable heavy domain (VH) connected to a variable light domain (VL) in the same polypeptide chain (VH-VL).
  • VH variable heavy domain
  • VL variable light domain
  • linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • chimeric antibody refers to a recombinant antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized HuMab mice (see, e.g., Nils Lonberg et al., 1994, Nature 368:856-859, WO 98/24884, WO 94/25585, WO 93/1227, WO 92/22645, WO 92/03918 and WO 01/09187 regarding HuMab mice), xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSETM technology) or Trianni mice (see, e.g., WO 2013/063391, WO 2017/035252 and WO 2017/136734).
  • immunized HuMab mice see, e.g., Nils Lonberg et al.,
  • humanized antibody refers to an antibody that has been engineered to comprise one or more human framework regions in the variable region together with non- human (e.g., mouse, rat, or hamster) complementarity-determining regions (CDRs) of the heavy and/or light chain.
  • CDRs complementarity-determining regions
  • a humanized antibody comprises sequences that are entirely human except for the CDR regions.
  • Humanized antibodies are typically less immunogenic to humans, relative to non-humanized antibodies, and thus offer therapeutic benefits in certain situations.
  • suitable techniques for their generation See for example, Hwang, W. Y. K., et al., Methods 36:35, 2005; Queen et al., Proc.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121-1123).
  • CDR complementarity determining region
  • each variable heavy region is a disclosure of the vhCDRs (e.g., vhCDRl, vhCDR2 and vhCDR3) and the disclosure of each variable light region is a disclosure of the vlCDRs (e.g., vlCDRl, vlCDR2 and vlCDR3).
  • the CDRs of an antibody can be determined according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132- 136 and Lefranc M-P et al, (1999) Nucleic Acids Res 27: 209-212. Unless stated otherwise herein, references to residue numbers in the variable domain of antibodies means residue numbering by the IMGT numbering system.
  • a “blocking” antibody or an “antagonist” antibody is one which inhibits or reduces biological activity of the antigen it binds. Certain blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.
  • An “epitope” is a term of art that indicates the site or sites of interaction between an antibody and its antigen(s). As described by (Janeway, C, Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3- 8. New York, Garland Publishing, Inc.): “An antibody generally recognizes only a small region on the surface of a large molecule such as a protein... Certain epitopes are likely to be composed of amino acids from different parts of the antigen polypeptide chain that have been brought together by protein folding.
  • Antigenic determinants of this kind are known as conformational or discontinuous epitopes because the structure recognized is composed of segments of the protein that are discontinuous in the amino acid sequence of the antigen but are brought together in the three-dimensional structure.
  • an epitope composed of a single segment of polypeptide chain is termed a continuous or linear epitope” (Janeway, C. Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3-8. New York, Garland Publishing, Inc.).
  • an epitope/paratope residue can be characterized as a residue having a non-zero change in buried surface area (BSA) due to interaction with the cognate antibody/antigen.
  • BSA buried surface area
  • epitope/paratope can be characterized through function, e.g., by competition binding with other Abs.
  • the epitope/paratope can also be defined more generically as comprising amino acid residues for which substitution by another amino acid will alter the characteristics of the interaction between the Ab and Ag (e.g., alanine scanning).
  • an “antibody that binds to the same epitope” as a reference antibody refers to an antibody that contacts an overlapping set of amino acid residues of the antigen as compared to the reference antibody or blocks binding of the reference antibody to its antigen in a competition assay by 50% or more.
  • the amino acid residues of an antibody that contact an antigen can be determined, for example, by determining the crystal structure of the antibody in complex with the antigen or by performing hydrogen/deuterium exchange. In some embodiments, residues of an antibody that are within 5 A the antigen are considered to contact the antigen.
  • an antibody that binds to the same epitope as a reference antibody blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • “Fv” consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody.
  • “Single-chain Fv” also abbreviated as “sFv” or “ScFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain.
  • the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding.
  • an “isolated antibody” when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non- proteinaceous solutes.
  • an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) approaches.
  • electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatographic e.g., ion exchange or reverse phase HPLC
  • the antibody will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art.
  • a molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances.
  • an antibody that specifically or preferentially binds to a TAA epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other TAA epitopes or non-TAA epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety, or epitope) which specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.
  • Specific binding or “preferential binding” includes a compound, e.g., a protein, a nucleic acid, an antibody, and the like, which recognizes and binds to a specific molecule, but does not substantially recognize or bind other molecules in a sample.
  • an antibody which recognizes and binds to its cognate antigen in a sample, but does not substantially recognize or bind other molecules in the sample, specifically binds to that cognate antigen.
  • the specified binding moiety e.g., an antibody or an antigen-binding portion thereof
  • the term “specific binding” or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of 10 4 M or lower, alternatively 10 s M or lower, alternatively 10 6 M or lower, alternatively 10 7 M or lower, alternatively 10 s M or lower, alternatively 10 9 M or lower, alternatively 10’ 10 M or lower, alternatively 10 1 1 M or lower, alternatively 10 12 M or lower or a Kd in the range of 10 4 M to 10 6 M or 10 6 M to 10 10 M or 10 7 M to 10 9 M.
  • solid-phase ELISA immunoassay immunoprecipitation
  • immunoprecipitation BIAcoreTM (GE Healthcare, Piscataway, NJ)
  • fluorescence-activated cell sorting FACS
  • OctetTM FormeBio, Inc., Menlo Park, CA
  • Western blot analysis are among many assays that may be used to identify an antibody that specifically reacts with an antigen or a receptor, or ligand binding portion thereof, that specifically binds with a cognate ligand or binding partner.
  • a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background, even more specifically, an antibody is said to “specifically bind” an antigen when the equilibrium dissociation constant (KD) value is less or equal to 1 pM, such as less or equal to 100 nM, less or equal to 10 nM, less or equal to 100 pM, less or equal to 10 pM, or less or equal to 1 pM.
  • KD equilibrium dissociation constant
  • affinity means the strength of the binding of an antibody to an epitope.
  • the affinity of an antibody is given by the dissociation constant Kd, defined as [Ab]x[Ag]/[Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen.
  • Kd dissociation constant
  • Ka affinity constant
  • the term “compete”, as used herein with regard to an antibody means that binding of a first antibody, or an antigen-binding portion thereof, to an antigen reduces the subsequent binding of the same antigen by a second antibody or an antigen-binding portion thereof.
  • the binding a first antibody creates steric hindrance, conformational change, or binding to a common epitope (or portion thereof), such that the binding of the second antibody to the same antigen is reduced.
  • Standard competition assays may be used to determine whether two antibodies compete with each other.
  • IC50 is intended to refer to the effective concentration of antibody of the present invention needed to neutralize 50% of the bioactivity of IL-23 on human lymphoma DB cells in the bioassay described in Example 5: Inhibition of STAT3 activation in human DB cell Assay.
  • EC50 with respect to an agent and a particular activity (e.g., binding to a cell, inhibition of enzymatic activity, activation or inhibition of an immune cell), refers to the efficient concentration of the agent which produces 50% of its maximum response or effect with respect to such activity.
  • EC 100 with respect to an agent and a particular activity refers to the efficient concentration of the agent which produces its substantially maximum response with respect to such activity.
  • the disclosure provides antibodies and antigen binding fragment thereof useful within the antibody-drug conjugates (ADCs) and other compounds and/or conjugates described herein.
  • the antibody and/or binding fragment thereof binds to an antigen (e.g., specifically binds to an antigen), as listed in Tables 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B below.
  • Tumor-associated antigens are a large family of antigens that includes antigens derived from genes overexpressed in tumors, differentiation antigens, and cancer germline/cancer testis antigens.
  • Antigens derived from genes overexpressed in tumors comprise a class of normal self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a result of their malignant profile.
  • the proteins which are usually overexpressed e.g., EGFR, hTERT, p53, carbonic anhydrase IX
  • TAA are major targets for cancer therapies.
  • Antibody- based agents targeting cancer biomarkers include monoclonal antibodies (MoAbs), radiolabeled MoAbs, bispecific T cell engagers (BiTEs), and antibody-drug conjugates (ADCs).
  • Antibodies targeting CD 19, CD20, CD22, CD30, CD33, CD38, CD79B, SLAMF7, and HER2 are in clinical applications for hematological malignancies.
  • CD 123, CLL-1, B cell maturation antigen, and CD 138 are targets for cancer immunotherapeutic agents.
  • Immune checkpoint inhibitors (ICIs) against PD- 1 , PD-L 1 , and CTLA-4 have led to the revolution of cancer immunotherapy.
  • ICIs targeting IDO, LAG3, TIM-3, TIGIT, SIGLECs, VISTA and CD47 are being explored.
  • Small molecule inhibitors (SMIs) against tyrosine kinase oncoproteins such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, EGFR, ALK, HER2, PTK7, VEGFR, FGFR, MEK, and MET have fundamentally changed the landscape of cancer therapy.
  • SMIs against BCL-2, IDHs, BRAF, PI3 kinase, mTOR, PARP, and CDKs have become the mainstay in the treatment of a variety of cancer types.
  • the tumor-associated antigen is protein tyrosine kinase 7 (PTK7).
  • the tumor-associated antigen is HER2. Protein tyrosine kinase 7 (PTK7)
  • the antibody or binding fragment thereof comprises a heavy chain variable region (VH) that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 229.
  • VH heavy chain variable region
  • the antibody or binding fragment thereof comprises a VH that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 229, and a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 622.
  • the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 622-629.
  • the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of SEQ ID NO: 622.
  • Table 3B Anti-PTK7 single-chain variable fragment (scFv). Heavy chain variable regions are italicized and antibody light chain variable regions are underscored. Linkers are bolded.
  • the binding fragment thereof is a single-chain variable fragment (scFv) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
  • scFv single-chain variable fragment
  • the binding fragment thereof is a single-chain variable fragments (scFv) comprising an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
  • scFv single-chain variable fragments
  • the binding fragment thereof is a single-chain variable fragments (scFv) comprising an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1086-1107.
  • scFv single-chain variable fragments
  • Table 4A Exemplary nanobody sequences.
  • Table 4B Anti-PTK7 nanobodies sequences.
  • the binding fragment thereof is a nanobody that comprises an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 824.
  • the antibody or binding fragment thereof is a nanobody that comprises or consists of an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 812-841.
  • the antibody or binding fragment thereof is a nanobody that comprises or consists of an amino acid sequence that is 100% identical to an amino acid sequence of SEQ ID NO: 824.
  • the antibody or binding fragment thereof comprises a heavy chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1-393 or 1002-1050.
  • the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085.
  • the antibody or binding fragment thereof comprises:
  • VH complementarity determining region three
  • VL light chain variable region
  • VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085.
  • LCDR1 VL complementarity determining region one
  • the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1051-1085.
  • the antibody or binding fragment thereof comprises:
  • LCDR2 VL complementarity determining region two
  • the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 622-629.
  • VH complementarity determining region three
  • VL light chain variable region
  • LCDR3 VL complementarity determining region three
  • the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 622.
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • LCDR2 VL complementarity determining region two
  • LCDR3 VL complementarity determining region three
  • the antibody or binding fragment thereof comprises:
  • VH heavy chain variable region
  • LCDR3 VL complementarity determining region three
  • the VL comprises or consists of an amino acid sequence of SEQ ID NO: 622.
  • the antibody or binding fragment thereof is a scFv that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
  • VH heavy chain variable region
  • HCDR1 VH complementarity determining region one
  • HCDR2 VH complementarity determining region two
  • VH complementarity determining region three comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions
  • VL light chain variable region
  • LCDR3 VL complementarity determining region three
  • scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
  • the antibody or binding fragment thereof is a scFv that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1086- 1107.
  • HCDR1 VH complementarity determining region one
  • LCDR1 VL complementarity determining region one
  • LCDR2 VL complementarity determining region two
  • LCDR3 VL complementarity determining region three
  • scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1086-1107.
  • VH heavy chain variable region
  • the antibody or binding fragment thereof is encoded by a DNA polynucleotide sequence.
  • introduction of the DNA into a competent mammalian cell will result in the production of the polypeptide comprising the antibody or binding fragment thereof.
  • Exemplary methods of antibody production by these means are disclosed in U.S. Patent Nos. 8,008,449, 10,934,571 and 11,339,215.
  • an antibody, or binding fragment thereof that binds to the same epitope as any of the antibodies or antigen binding fragment thereof described herein.
  • antibody competition assay can be assessed by surface plasmon resonance (SPR) or bio-layer interferometry (BLI).
  • amino acids with acidic side chains e.g., aspartic acid, glutamic acid
  • basic side chains e.g., lysine, arginine, histidine
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan
  • aromatic side chains e.g., phenylalanine, tryptophan, histidine, tyrosine
  • aliphatic side chains e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine
  • amide e.g., asparagine, glutamine
  • beta- branched side chains e.g., asparagine
  • the antibody, or binding fragment thereof, of the invention has an affinity (KD) value of or less than about 350 nM, about 325 nM, about 323.10 nM, about 300 nM, about 286.44 nM, about 275 nM, about 250 nM, about 232.13 nM, about 225 nM, about 219.13 nM, about 200 nM, about 195.54 nM, about 175 nM, about 158 nM, about 150 nM, about 125 nM, or about 100 nM.
  • KD affinity
  • the SPR measurement is conducted using a BIACORE® T100 or T200 instrument.
  • a standard assay condition for surface plasmon resonance can be based on antibody immobilization of approximately 100-500 Response Units (RU) of IgG on the SPR chip.
  • Purified target proteins are diluted in buffer to a range of final concentrations and injected at a requisite flow rate (e.g., 10-100 pl/min)to allow the calculation of Ka.
  • Dissociation is allowed to proceed to establish off-rate, followed by 3 M MgCh (or 20 mM NaOH) for regeneration of the chip surface.
  • Sensorgrams are then analyzed using a kinetics evaluation software package.
  • the binding affinity (KD) value is measured using solutionbased kinetic exclusion assay (KinExATM).
  • KinExATM solutionbased kinetic exclusion assay
  • the KinExA measurement is conducted using a KinExATM 3200 instrument (Sapidyne).
  • the Kinetic Exclusion Assay (KinExATM) is a general purpose immunoassay platform (basically a flow spectrofluorimeter) that is capable of measuring equilibrium dissociation constants, and association and dissociation rate constants for TAA/antibody interactions. Since KinExATM is performed after equilibrium has been obtained it is an advantageous technique to use for measuring the KD of high affinity interactions where the off-rate of the interaction may be very slow.
  • the KinExATM methodology can be conducted generally as described in Drake et al., (2004) Analytical Biochem. 328, 35-43.
  • the TAA is a human antigen, cyno antigen, or mouse antigen.
  • an antibody should bind to the tartet with high affinity. It is desirable that the antibody have binding affinities (KD) to the human antigen in low nanomolar range, such as about 40 nM or lower.
  • the target is a human TAA and the KD value is about 40 nM, about 45 nM or about 50 nM.
  • the antigen is a cyno TAA and the KD value is about 62 nM, about 64 nM, about 66 nm, about 68 nM, or about 70 nM.
  • the drug moiety is a small molecule having a molecular weight preferably less than about 5 kDa, more preferably less than about 4 kDa, more preferably less than about 3 kDa, most preferably less than about 1.5 kDa or less than about 1 kDa.
  • the drug moiety has an ICso of about less than about 1 nM.
  • the small molecule therapeutic agents used in this disclosure include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, ceil cycle progression inhibitors, PI3K/m-TOR/AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperones inhibitors, HDAC inhibitors, PARP inhibitors, nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, Wnt Hedgehog signaling pathway inhibitors and RNA polymerase inhibitors.
  • cytotoxic compounds e.g., broad spectrum
  • angiogenesis inhibitors e.g., ceil cycle progression inhibitors
  • PI3K/m-TOR/AKT pathway inhibitors PI3K/m-TOR/AKT pathway inhibitors
  • MAPK signaling pathway inhibitors e.g., kinase inhibitors
  • kinase inhibitors kinase inhibitors
  • protein chaperones inhibitors e.g., HDAC inhibitors
  • Broad spectrum cytotoxins include, but are not limited to, DNA-binding, intercalating or alkylating drugs, microtubule stabilizing and destabilizing agents, platinum compounds, topoisomerase inhibitors (including topoisomerase I and topoisomerase II inhibitors) and protein synthesis inhibitors.
  • Exemplary DNA-binding, intercalation or alkylating drugs include, but are not limited to, CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin, nemorubicin and its derivatives, PNU- 159682), bisnapththalimide compounds such as elinafide (LU79553).and its analogs, alkylating agents, such as calicheamicins, dactinomycins, mitomycins, pyrrolobenzodiazepines, indolinobenzodiazepines and the like.
  • anthracyclines doxorubicin, epirubicin, idarubicin, daunorubicin, nemorubicin and its derivatives
  • bisnapththalimide compounds such as elinafide (LU79553).and its analogs
  • alkylating agents such as calicheamicins, dactinomycins
  • Exemplary CC-1065 analogs include, but are not limited to, duocarmycin SA, duocarmycin A, duocarmycin CI , duocarmycin C2, duocarmycin B 1, duocarmycin B2, duocarmvcin D, DU- 86, KW-2189. adozeiesin, bizelesin, carzeiesin. seco-adozelesin, and related analogs and prodrug forms, examples of which are described in U.S. Patent Nos. 5,475,092; 5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316. Doxorubicin and its analogs include those described in U.S. Patent No.
  • Calicheamicins include, e.g., enediynes, e.g., esperamicin, and those described in U.S. Patent Nos. 5,714,586 and 5,739, 116.
  • Duocarmycins include those described in U.S. Patent Nos. 5,070,092; 5, 101,038; 5, 187, 186; 6,548,530; 6,660,742; and 7,553,816 B2; and Li et al., Tel Letts., 50:2932 - 2935 (2009).
  • topoisomerase inhibitors include, but are not limited to, camptothecin, camptothecin derivatives, camptothecin analogs and non-natural camptothecins, such as, for example, exatecan, Dxd, Sn-38 (7-ethyl-10- hydroxy-camptothecin), CPT-1 1 (irinotecan), GI-147211C, topotecan, 9-aminocamptothecin, 7-hydroxymethyl camptothecin, 7-aminomethyl camptothecin, 10-hydroxy camptothecin, (20S)-camptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, diflomotecan, belotecan, lurtotecan and S39625, and any analogues thereof.
  • camptothecin camptothecin derivatives
  • camptothecin analogs such as, for example, exatecan, Dxd
  • Non-limiting examples of other topoisomerase inhibitors e.g. topoisomerase I and/or topoisomerase II
  • topoisomerase I and/or topoisomerase II include those described in WO 2020/00880 and WO 2021/148501.
  • Nonlimiting examples of other camptothecin compounds that can be used in the present disclosure include those described in J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23 :554 (1980); J. Med. Chem, 30: 1774 (1987).
  • the drug moiety is exatecan and/or an analogue thereof.
  • the drug moiety is Dxd and/or an analogue thereof.
  • Non-limiting examples of pyrrolobenzodiazepines (PBD) and analogs thereof include, but are not limited to, those described in Denny, Exp. Opin. Ther. Patents., 10(4):459- 474 (2000), Antonow and Thurston, Chem Rev., 2815-2864 (2010), Min et al., ACS Omega 5:25798-25809 (2020), and Hartley Exp. Opin. Biol. Therapy 7:931-943 (2020).
  • microtubule stabilizing and destabilizing agents include, but are not limited to, taxane compounds, such as paclitaxel, docetaxel, tesetaxel and carbazitaxel; maytansinoids, auristatins and analogs thereof, vinca alkaloid derivatives, epothilones and cryptophycins.
  • Exemplary maytansinoids or maytansinoid analogs include, but are not limited to maytansinoi and maytansinol analogs, maytansine or DM-i and DM-4 are those described in U.S. Patent Nos. 5,208,020; 5,416,064; 6,333.410, 6,441, 163; 6,716,821; RE39, 151 and 7,276,497.
  • the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. 52: 127-131), maytansinoids or maytansinoid analogs.
  • auristatins include, but are not limited to, auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F, auristatin F phenylenediamine (AFP), auristatin F hydroxylpropylamide (AF FTP A), monomethyl auristatin F hydroxylpropylamide (MMAF HP A), and dolastatin.
  • auristatin E also known as a derivative of dolastatin-10
  • AEB auristatin EB
  • AEFP auristatin EFP
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • AFP auristatin F phenylenediamine
  • AF FTP A auristatin F hydroxylpropyl
  • Non-limiting examples of cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021, the disclosures of each of which are incorporated herein by reference in their entireties.
  • Non-limiting examples of other classes of compounds or compounds with these or other cytotoxic modes of action may be selected, including, e.g., mitomycin C, mitomycin A, daunorubicin, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, aminopterin, bleomycin, l-(chloromethyl)-2, 3 -dihydro- lH-benzo[e]indol-5-ol, pyrridinobenzodiazepines (PDD), pyrrolobenzodiazepine (PBD) and polyamide and dimers thereof.
  • mitomycin C mitomycin A
  • daunorubicin doxorubicin
  • morpholino-doxorubicin morpholino-doxorubicin
  • cyanomorpholino-doxorubicin aminopterin
  • bleomycin l-(chloromethyl)-2
  • Non-limiting examples of other suitable cytotoxic agents include puromycins, topotecan, rhizoxin, echinomycin, combretastatin, netropsin, estramustine, cryptophysins, cemadotin, discodermolide, eleutherobin, and mitoxantrone.
  • Angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors, VEGF inhibitors, PIGF inhibitors, VGFR inhibitors, PDGFR inhibitors, MetAP2 inhibitors.
  • Exemplary VGFR and PDGFR inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent) and vatalanib.
  • Exemplary MetAP2 inhibitors include fumagillol analogs, meaning any compound that includes the fumagillin core structure, including fumagiilamine, that inhibits the ability of MetAP-2 to remove NtU-tcrminal methionines from proteins as described in Rodeschini et al., J. Org.
  • ceil cycle progression inhibitors include, but are not limited to, CDK inhibitors such as BMS-387032 and PD0332991; Rho-kinase inhibitors such as GSK429286; checkpoint kinase inhibitors such as AZD7762; aurora kinase inhibitors such as AZDI 152, MLN8054 and MLN8237; PLK inhibitors such as BI 2536, BI6727 (Volasertib), GSK461364, ON-01910 (Estybon); and KSP inhibitors such as SB 743921, SB 715992 (ispinesib), MK- 0731, AZD8477, AZ3146 and ARRY-520.
  • CDK inhibitors such as BMS-387032 and PD0332991
  • Rho-kinase inhibitors such as GSK429286
  • checkpoint kinase inhibitors such as AZD7762
  • aurora kinase inhibitors such as AZ
  • Exemplary PBK/m-TOR/AKT signaling pathway inhibitors include, but are not limited to, phosphoinositide 3 -kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors and PDK-1 inhibitors.
  • PI3K phosphoinositide 3 -kinase
  • Non-limiting examples of exemplary PI3 kinase inhibitors are disclosed in U.S. Patent No. 6,608,053, and include BEZ235, BGT226, BKM120, CAL 101 , CAL263, demethoxyviridin, GDC-0941, GSK615, IC871 14, LY294002, Pafomid 529, perifosine, PI- 103, PF-04691502, PX-866, SAR245408, SAR245409, SF 1 126, Wortmannin, XL 147 and XL765.
  • Exemplary AKT inhibitors include, but are not limited to, AT7867.
  • Exemplary MAPK signaling pathway inhibitors include, but are not limited to, MEK, Ras, JNK, B-Raf and p38 MAPK inhibitors,
  • Exemplary B-raf inhibitors include, but are not limited to, CDC-0879, PLX-4032, and SB590885.
  • Exemplary p38 MAPK inhibitors include, but are not limited to, BIRB 796, LY2228820 and SB 202190.
  • RTK Receptor tyrosine kinases
  • Exemplary specific RTK targets include, but not limited to, ErbB2, FLT-3, c-Kit, and c-Met.
  • Exemplary inhibitors of ErbB2 receptor include, but are not limited to, AEE788 (NVP-AEE 788), BIBW2992, (Afatinib), Lapatinib, Erlotinib (Tarceva), and Gefitinib (Iressa).
  • Exemplary RTK inhibitors targeting more than one signaling pathway include, but are not limited to, AP24534 (Ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR and Bcr-Abl receptors; ABT-869 (Linifanib) that targets FLT-3 and VEGFR- PDGFR receptors: AZD2171 that targets VEGFR-PDGFR, Fit- 1 and VEGF receptors; CHR-258 (Dovitinib) that targets VEGFR-PDGFR, FGFR, Flt-3, and c- Kit receptors; Sunitinib (Sutent) that targets VEGFR, PDGFR, KIT, FLT-3 and CSF-IR; Sorafenib (Nexavar) and Vatalanib that target VEGFR, PDGFR as well as intracellular serine/threonine kinases in the Rat/Mck/Erk pathway.
  • AP24534 Panatinib
  • ABT-869
  • HSP90 inhibitors include, but are not limited to, 17AAG derivatives, BIIB021, BIIB028, S X-5422, NVP-AUY-922 and KW-2478.
  • Exemplary WD AC inhibitors include, but are not limited to, Belinostat (PXD101), CUDC-101, Droxinostat, ITF2357 (Givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP- LAQ824, Dacinostat), LBH-589 (Panobinostat), MC I 568, MGCD0103 (Mocetinostat), M S -275 (Entinostat), PCI-24781, Pyroxamide (NSC 696085), SB939, Trichostatin A and Vorinostat (SAHA).
  • Exemplary PARP inhibitors include, but are not limited to, iniparib (BSI 201), olaparib (AZD-2281), ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281 ), LT-673, 3- aminobenzamide, A-966492, and AZD2461.
  • Exemplary Wnt/Hedgehog signaling pathway inhibitors include, but are not limited to, vismodegib (RG3616/GDC-0449), cyclopamine (11-deoxojervine) (Hedgehog pathway inhibitors) and XAV-939 (Wnt pathway inhibitor).
  • Exemplary RNA polymerase inhibitors include, but are not limited to, amatoxins.
  • Exemplary amatoxins include a-amanitins, P-amanitins, y-amanitins, e-amanitins, amanuilin, amanullic acid, amaninamide, amanin, and proamanullin.
  • Exemplary protein synthesis inhibitors include, but are not limited to, trichothecene compounds.
  • the drug is a derivative of Sn-38, camptothecin, topotecan, exatecan, calicheamicin, nemorubicin, PNU-159682, anthracycline, maytansinoid, taxane, tnchothecene, CC1065, elinafide, vindesine, vinblastine, PI-103, AZD 8330, dolastatin, auristatin E, auristatin F, a duocarmycin compound, ispinesib, pyrrolobenzodiazepine, ARRY- 520 and stereoisomers, isosteres and analogs thereof.
  • a drug moiety may be linked, either directly or indirectly, to an antibody or antibody-binding fragment to provide a targeted conjugate.
  • an antibody drug conjugate (ADC) of the disclosure e.g. an ADC of formula (I)
  • a compound of the disclosure e.g. formula (III) or salts, solvates, tautomers, isomers or mixtures thereof
  • the linker is a single bond.
  • the linker when the linker is a single bond, the drug moiety is directly attached to an antibody or antibody-binding fragment.
  • a variety of target conjugates are known in the art and can be used with a compound of formula (III) and salts or solvates thereof.
  • the target conjugate is an antibody-drug conjugate, wherein one or more compounds of formula (III) are linked to the antibody.
  • the antibody drug conjugates of the present disclosure contain one or multiple compounds of formula (III) or salts, solvates, tautomers, isomers or mixtures thereof.
  • the linker has a number of repeating ethylene glycol units ranging from about 1 to about 25, or any number therebetween. In some embodiments, the linker includes about 3 to about 20, about 3 to about 5, about 4 to about 15, about 4 to about 8, about 4 to about 6, about 5 to about 12, about 6 to about 10, or about 7 to about 9 ethylene glycol units. In some embodiments, the linker includes about 8 ethylene glycol units.
  • the linker includes one or more amino acid moieties.
  • one or more amino acid moieties provides enhanced solubility for the drug moiety and/or provides amino acid sequences to enhance target binding, enhance compatibility with an antibody or binding fragment thereof, and/or enhance target binding recognition.
  • the linker includes one or more amino acid moieties that provide a suitable substrate motif for a protease.
  • the drug moiety may be released from a target bound conjugate to provide localized cytotoxic effects.
  • the linker includes an alkylene chain.
  • the alkylene chain is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11 or 12 carbons in length; and suitably the alkylene chain comprises -CH 2 - groups.
  • these substrate motifs are known in the art and are incorporated into the linker as desired to provide selective release from the target bound conjugate. In a non-limiting example, this selectivity is based on known presence of a desired protease within the localized delivery region of the conjugate drug.
  • other polymeric types of moieties may be incorporated in the linker, including but not limited to polyacids, polysaccharides, or polyamines.
  • other moieties such as substituted aromatic or heteroaromatic moieties are used to enhance rigidity or provide synthetically accessible sites on substituents therein for linking to reactive moieties or to the drug moiety.
  • the linker includes ethylene glycol repeating units, and/or an amino acid sequence.
  • the linker comprises or consists of the formula: -[CH 2 CH 2 O]P-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
  • the linker comprises or consists of the formula: -[CH 2 CH 2 O] P -X A A- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50.
  • p is an integer from 1 to 40.
  • p is an integer from 1 to 30.
  • p is an integer from 6 to 40.
  • p is an integer from 8 to 30.
  • p is an integer from 6 to 20.
  • p is an integer from 6 to 20.
  • p is an integer from 8 to 20.
  • p is an integer from 10 to 30.
  • p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
  • the linker (e.g. LA) comprises or consists of the formula: -[CH 2 CH 2 O] P -(CH 2 )I.5-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50, wherein XAA is not Val-Cit or Phe-Lys.
  • p is an integer from 1 to 40.
  • p is an integer from 1 to 30.
  • p is an integer from 6 to 40.
  • p is an integer from 8 to 30.
  • p is an integer from 6 to 20.
  • p is an integer from 6 to 20.
  • p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8. In some embodiments, -(CH 2 )I-S- is -(CH 2 )I-3-.
  • the linker (e.g. LA) comprises or consists of the formula: -[CH 2 CH 2 O] P -(CH 2 )I. 3 -C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50.
  • p is an integer from 1 to 40.
  • p is an integer from 1 to 30.
  • p is an integer from 6 to 40.
  • p is an integer from 8 to 30.
  • p is an integer from 6 to 20.
  • p is an integer from 6 to 20.
  • p is an integer from 8 to 20.
  • p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
  • the linker (e.g. LA) comprises or consists of the formula: -[CH 2 CH 2 O]P-(CH2)I-3-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50, wherein XAA is not Val-Cit or Phe-Lys.
  • p is an integer from 1 to 40.
  • p is an integer from 1 to 30.
  • p is an integer from 6 to 40.
  • p is an integer from 8 to 30.
  • p is an integer from 6 to 20.
  • p is an integer from 6 to 20.
  • p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
  • the linker (e.g. LA) comprises or consists of the formula: -[CH 2 CH 2 O] P -(CH 2 ) 2 -C(O)-X A A- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50.
  • p is an integer from 1 to 40.
  • p is an integer from 1 to 30.
  • p is an integer from 6 to 40.
  • p is an integer from 8 to 30.
  • p is an integer from 6 to 20.
  • p is an integer from 6 to 20.
  • p is an integer from 8 to 20.
  • PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence.
  • PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units.
  • PEG has 8 ethylene glycol units.
  • PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys.
  • PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
  • PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence.
  • PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units.
  • PEG has 8 ethylene glycol units.
  • p is 8.
  • the linker comprises the formula: -HN-PEG-(CH 2 )I- 5 -C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys.
  • PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
  • XAA is an amino acid sequence
  • the linker include 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-CH2- units, with the proviso that XAA is not Val-Cit or Phe-Lys.
  • the linker comprises the formula:
  • the linker comprises the formula:
  • the HN group is directly linked to an antibody or antibody-binding fragment.
  • the linker is or comprises:
  • the linker further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 19, 20, 23, 24, 35, 36, 37, 48, 49 or 50 ethylene glycol units. In some embodiments, the linker comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 -CH2- units. In some embodiments, the HN group is directly linked to an antibody or antibody-binding fragment.
  • XAA is valinealanine. In some embodiments, XAA is alanine-alanine-alanine. In some embodiments, XAA is glycine-glycine-phenylalanine-glycine.
  • amino acid sequence XAA is:
  • amino acid sequence XAA is:
  • R* is or comprises maleimide:
  • R* is or comprises a cyclooctyne.
  • the cyclooctyne is a dibenzocyclooctyne (DBCO) and derivatives thereof.
  • the cyclooctene is fused to one or more additional rings, including but not limited to cycloalkyl rings and/or heterocycloalkyl rings.
  • the cyclooctyne undergoes a cycloaddition reaction (e.g. click chemistry) with another group to form a heterocycle.
  • the cyclooctyne undergoes a cycloaddition reaction with a nitrone to form a triazole. In some embodiments, the cyclooctyne undergoes a cycloaddition reaction with an azide to form an isoxazolidine.
  • y g g also U.S. 2015/0320882, U.S. 2023/0102685, U.S. 2016/0107999, U.S. 2017/0008858, U.S.
  • n is an integer from 1 to 10. In some embodiments, n is an integer from
  • R* is an antibody or an antibody fragment.
  • the antibody or fragment thereof binds to a tumor-associated antigen, a cancer- stem-cell associated antigen or a viral antigen.
  • n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 5, or 3 to 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 4. See, for example, U.S. 20230295320, U.S. 11773150, U.S. 20160052966, all of which are incorporated by reference herein in their entireties.
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula: [00466] In some embodiments, the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the disclosure provides compounds comprising one or more linkers and one or more drug moieties.
  • the antibody-drug conjugates of the disclosure e.g. formula (I)
  • the antibody-drug conjugates of the disclosure comprise a compound of formula (III).
  • L is a linker
  • D comprises a drug moiety
  • the exatecan comprises or has the formula:
  • the PDD comprises or has the formula:
  • the compound comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula: [00491] In some embodiments, the linker comprises or consists of the formula:
  • the linker comprises or consists of the formula:
  • L-D has the formula:
  • L-D has the formula:
  • L is a linker of the formula R*-LI-LA-;
  • R* is maleimide
  • the compound is of formula (III-A), or salts, solvates, tautomers, isomers or mixtures thereof: formula (III-A) wherein in formula (III-A):
  • Li is -[CH 2 ]I- 3 -C(O)NH-; p is an integer from 6 to 20;
  • XAA 1 and XAA 2 are independently selected amino acid moieties
  • D is a topoisomerase inhibitor
  • formula (III-A) is has the formula -[CH2CH2O] P -(CH2)I-3. - C(O)-XAA-. In some embodiments, formula (III-A) is has the formula -[CH2CH2O] P -(CH2)2- C(O)-XAA-.
  • XAA 1 is selected from Vai, Tyr, Phe, Leu, Met, Thr, Ala, D- Val, and D-Ala. In some embodiments, XAA 1 is Vai.
  • -XAA’ -XAA 2 - is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai -Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.
  • -XAA 1 -XAA 2 - is Vai-Ala.
  • the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
  • L is a linker
  • D comprises a drug moiety
  • the linker has the following formula: R*-LI-L A - wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
  • the linker LA has the formula:
  • Aik designates C2-C4-alkylene
  • XAA is a dipeptide
  • p is an integer from 0 to 50.
  • R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
  • the drug moiety is selected from exatecan having the formula:
  • the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
  • L is a linker
  • Aik designates C2-C4-alkylene
  • R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
  • the drug moiety is selected from exatecan having the formula:
  • Alk designates C2-C4-alkylene
  • XAA is a dipeptide
  • p is an integer from 0 to 50.
  • Li is -[CH 2 ]o-i2-C(0)NH-.
  • the drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
  • the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
  • the linker has the following formula: R*-LI-L A - wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
  • the linker LA has the formula:
  • R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
  • Li is -[CH 2 ]o-i2-C(0)NH-.
  • the drug moiety is selected from:
  • XAA is a dipeptide
  • p is an integer from 0 to 50.

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Abstract

The present disclosure provides antibody-drug conjugates (ADCs) that specifically bind a tumor associated TAA and compounds thereof useful for treating a disease or disorder such as cancer.

Description

ANTIBODY DRUG CONJUGATES AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Nos. 63/620,515, filed January 12, 2024, 63/620,510, filed January 12, 2024, and 63/620,517, filed January 12, 2024, all of which are incorporated by reference herein in their entireties.
FIELD
[0002] The disclosure generally relates to antibody-drug conjugates that bind tumor- associated antigens (TAA) and methods of use thereof.
SEQUENCE LISTING
[0003] The instant application contains a Sequence Listing that has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The Sequence Listing for this application is labeled “133186-5020-WO Sequence Listing.xml”, which was created on January 12, 2025, and is 979,000 bytes in size.
BACKGROUND
[0004] While numerous chemotherapeutic agents have been developed, many often demonstrate unacceptable toxicity and or lack of specificity for cancer cells over non-cancerous tissues. To avoid the non-specific cytotoxic effects of chemotherapeutic agents, targeted antibody therapy has revolutionized cancer treatment with several monoclonal antibodies demonstrating clinical potential. Because antibodies against tumor-associated antigens (TAA) often lack therapeutic activities, they have been conjugated to cytotoxic agents in order to combine the effectiveness of chemotherapy with the targeting of antibodies. In principle, selective delivery of cytotoxic agents to specific tumor tissues by antibody binding should reduce the systemic toxicity of traditional small-molecule chemotherapeutics.
[0005] Despite a deepening understanding of disease-specific proteins, the need for specific TAA-targeted ADCs that can be used for therapeutic purposes in the treatment of cancer and other disorders remains unmet. SUMMARY
[0006] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab comprises an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) a tumor-associated antigen (TAA) as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B;
L is a linker of the formula -R*-LI-LA-;
R* is a reactive moiety;
Li is -[CH2]i-3-C(O)NH-;
LA is -[CH2CH2O]P-(CH2)I-5-C(O)-XAA-, wherein p is an integer from 5 to 10, and XAA is an amino acid sequence having 2 to 5 amino acid moieties; n is an integer from 1 to 20; and
| — [CH2]2-C(O)NH- — I
In some embodiments, Li is . In some embodiments, p is 7 or 8. In some embodiments, p is 8. In some embodiments, R* is selected from a succinimide, an oxime, a heterocycle (e.g. triazolyl or isoxazolidinyl), an amide, and a thioether, an alkenyl phosphorous group, and an alkyl phosphorous group, optionally R* is a succinimide. In some embodiments, XAA is an amino acid sequence having 2 amino acid moieties. In some embodiments, XAA is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met,
Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai -Met, Leu-Met, Ala- Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met. In some embodiments, XAA is valine-alanine.
In some embodiments, XAA is an amino acid sequence having 3 amino acid moieties. In some embodiments, XAA is selected from alanine-alanine-alanine, glutamic acid-valine-citrulline, and valine-lysine-glycine. In some embodiments, XAA is an amino acid sequence having 4 amino acid moieties. In some embodiments, XAA is selected from glycine-glycine- phenylalanine-glycine, glutamic acid-aspartic acid-phenylalanine-tryptophan, glycine- phenylalanine-leucine-glycine, and alanine-leucine-alanine-leucine.
In some embodiments, LA is -[CH2CH2O]P-(CH2)2-C(O)-XAA-. In some embodiments, L has the formula:
[0010] In some embodiments, n is an integer from 4 to 8. In some embodiments, n is 4. In some embodiments, n is 8.
[0011] In some embodiments, the antibody or binding fragment thereof is selected from a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, nanobody, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody.
[0012] In some embodiments, the antibody or antigen binding fragment thereof comprises: (i) a heavy chain variable region (VH) that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Tables 2A-C (any one of SEQ ID NOs: 1-393 or 1002-1050), and (ii) a VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Tables 2A-C (any one of SEQ ID NOs: 394-786 or 1051-1085).
[0013] In some embodiments, the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
[0014] In some embodiments, the antibody or antigen binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and
(ii) a VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1051-1085).
[0015] In some embodiments, the antibody or antigen binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 229-236); and
(ii) a VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 622-629).
[0016] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in Table 2 (any one of SEQ ID NOs: 1-393 or 1002-1050); and and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in Table 2 (any one of SEQ ID NOs: 394-786 or 1051-1085).
[0017] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085).
[0018] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 229-236);
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 622-629).
[0019] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789, and (ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
[0020] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 as set forth in SEQ ID NO: 787, a HCDR2 as set forth in SEQ ID NO: 788, and a HCDR3 as set forth in SEQ ID NO: 789, and (ii) a light chain variable region (VL) comprising: a LCDR1 as set forth in SEQ ID NO: 790, a LCDR2 as set forth in SEQ ID NO: 791, and a LCDR3 as set forth in SEQ ID NO: 792.
[0021] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 229); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 622).
[0022] In some embodiments, the antibody or binding fragment thereof comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3 (any one of SEQ ID NOs: 793-811 or 1086-1107).
[0023] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (SEQ ID NOs: 793-811 or 1086-1107).
[0024] In some embodiments, the antibody or binding fragment thereof comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
[0025] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Table 3B (SEQ ID NOs: 1086-1107).
[0026] In some embodiments, the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4 (any one of SEQ ID NOs: 812-841 or 1108-1111).
[0027] In some embodiments, the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4 (any one of SEQ ID NOs: 1108-1111).
[0028] In some embodiments, the antibody or binding fragment thereof comprises a nanobody is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824. [0029] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108- 1111).
[0030] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
[0031] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 824.
[0032] In some embodiments, the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
[0033] In aspects, the disclosure provides a pharmaceutical composition comprising an antibody drug conjugate of formula (I); and a pharmaceutically acceptable carrier.
[0034] In aspects, the disclosure provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of an antibody drug conjugate of formula (I), or a pharmaceutical composition of the disclosure.
[0035] In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi’s sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin’s disease, non-Hodgkin’s lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma, and the like. In other embodiments, the cancer is acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, triple-negative breast cancer (TNBC), bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing’s tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm’s tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin’s disease, multiple myeloma, non-Hodgkin’s lymphoma, polycythemia vera, or Waldenstrom’s macroglobulinemia. In some embodiments, the cancer in triple-negative breast cancer (TNBC).
[0036] In some aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab comprises an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B;
D comprises a drug moiety; n is an integer from 1 to 20; and
L has the formula:
[0037] In some embodiments, the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
[0038] In some embodiments, the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
[0039] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 2A-2C (any one of SEQ ID NOs: 1-393 or 1002-1050), and (ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 2A-2C (any one of SEQ ID NOs: 394- 786 or 1051-1085).
[0040] In some embodiments, the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
[0041] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 2C (any one of SEQ ID NOs: 1051-1085). [0042] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236); and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629).
[0043] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH comprising three HCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a VL comprising three LCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0044] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH comprising three HCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a VL comprising three LCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0045] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229); and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622).
[0046] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in Tables 2A-2C (any one of SEQ ID NOs: 1-393 or 1002-1050), and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in Tables 2A-2C (any one of SEQ ID NOs: 394-786 or 1051-1085).
[0047] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1051-1085).
[0048] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629).
[0049] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH comprising and/ or consisting of three HCDR as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a VL comprising or consisting of three LCDR as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0050] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 229); and
(ii) a lighy chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 622).
[0051] In some embodiments, the antibody or binding fragment thereof comprises a scFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
[0052] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
[0053] In some embodiments, the antibody or binding fragment thereof comprises a scFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107). [0054] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
[0055] In some embodiments, the antibody or binding fragment thereof comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108-1111).
[0056] In some embodiments, the antibody or binding fragment thereof comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
[0057] In some embodiments, the antibody or binding fragment thereof comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
[0058] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108- 1111).
[0059] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
[0060] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 824.
[0061] In some embodiments, the drug moiety is selected from
[0062] In some embodiments, the drug moiety is selected from
[0063] In some embodiments, the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
[0064] In aspects, the disclosure provides an antibody-drug conjugate having formula (I): Ab-[L-D]n formula (I) wherein in formula (I):
Ab comprises an antibody or antigen binding fragment thereof that binds a TAA as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; n is an integer from 1 to 20; and
L-D has the formula:
[0065] In some embodiments, the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
[0066] In some embodiments, the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
[0067] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Tables 2A-C (any one of SEQ ID NOs: 1-393 or 1002-1050); and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Tables 2A-C (any one of SEQ ID NOs: 394-786 or 1051-1085).
[0068] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and (ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in Table 2C (any one of SEQ ID NOs: 1051-1085).
[0069] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 229-236; and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 622-629.
[0070] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH comprising three HCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in SEQ ID NO: 787 (HCDR1), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a VL comprising three LCDR that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0071] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH comprising three HCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth SEQ ID NO: 787 (HCDR3), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a VL comprising three LCDR that comprise 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to an amino acid sequence as set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0072] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in SEQ ID NO: 229; and
(ii) a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence set forth in SEQ ID NO: 622.
[0073] In some embodiments, the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in Tables 2A-C (any one of SEQ ID NOs: 1-393 or 1002-1050); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in Tables 2A-C (any one of SEQ ID NOs: 394-786 or 1038-1061).
[0074] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in Table 2C (any one of SEQ ID NOs: 1002-1050); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in Table 2C (any one of SEQ ID NOs: 1038-1061).
[0075] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in Table 2 (any one of SEQ ID NOs: 229-236); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in Table 2 (any one of SEQ ID NOs: 622-629).
[0076] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of three HCDR of amino acid sequence as set forth in SEQ ID NO: 787 (HCDR1),, SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and
(ii) a light chain variable region (VL) comprising or consisting of three LCDR of amino acid sequence set forth in SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
[0077] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 229); and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 622).
[0078] In some embodiments, the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107).
[0079] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Tables 3A-B (any one of SEQ ID NOs: 793-811 or 1086-1107). [0080] In some embodiments, the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
[0081] In some embodiments, the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in Table 3B (any one of SEQ ID NOs: 1086-1107).
[0082] In some embodiments, the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Tables 4A-B (any one of SEQ ID NOs: 812-841 or 1108-1111).
[0083] In some embodiments, the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in Table 4B (any one of SEQ ID NOs: 1108-1111).
[0084] In some embodiments, the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
[0085] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in Table 4 (any one of SEQ ID NOs: 812-841).
[0086] In some embodiments, the binding fragment is a nanobody comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 824.
[0087] In some embodiments, the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
[0088] In some embodiments, n is an integer from 1 to 10, 2 to 8, or 4 to 8, optionally n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, optionally n is 4 or 8, optionally n is 4, optionally n is 8.
[0089] In aspects, the disclosure provides an antibody-drug conjugate having any one of formula 1030-1064 or 1101-1118, wherein Ab is an antibody that binds (e.g., specifically binds) to a TAA as disclosed in Table 1, or binding fragment thereof. [0090] In some embodiments, the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
[0091] In aspects, the disclosure provides an antibody-drug conjugate of any one of embodiments (I)-(XVII).
[0092] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B; n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050; and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 793-811 or 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 812-841 or 1108-1111. [0093] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A or 4B; n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1108-1111.
[0094] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-236; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629;
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
[0095] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 1, 2, or 3 amino acid substitutions relative to SEQ ID
NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 792.
[0096] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
[0097] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1; L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO:229; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
[0098] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B ; n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 793-811 or 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
[0099] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds to a TAA as disclosed in Table 1A, IB, 1C, 2A, 2B, 3A, 3B, 4A, or 4B ; n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1108-1111.
[00100] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-236; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629;
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
[00101] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula:
wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 SEQ ID NO: 792.
[00102] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
[00103] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4; L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO:229; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
[00104] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1; n is 8;
L-D has the formula:
wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 793-811 or 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
[00105] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antigen binding fragment thereof that binds (e.g., specifically binds) to a TAA as disclosed in Table 1; n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085;
(B) a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1086-1107; or
(C) a nanobody comprising or consisting of an amino acid sequence set forth in any one of SEQ ID NOs: 1108-1111.
[00106] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-236; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629;
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
[00107] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula:
wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
[00108] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
[00109] In aspects, the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8; L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO:229; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
[00110] In aspects, the disclosure provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of the antibodydrug conjugate of formula (I).
BRIEF DESCRIPTION OF THE DRAWINGS
[00111] The foregoing summary, as well as the following detailed description of embodiments of the disclosure, will be better understood when read in conjunction with the appended drawings and figures.
[00112] FIGS. 1A, IB, and 1C illustrate experimental data demonstrating that in in vitro studies, trastuzumab-Compound 30 was found to be less potent in HER2+++ line than T-Dxd ADC (FIGS. 1A and 1C) despite free payloads being approximately equivalent in potency (FIG. IB). FIG. 1A is a table showing EC50 values for compounds in a HER2+++ line. FIG. IB illustrates the percent viable cells based on concentration of Dxd, Exatecan, or TOPO1 inhibitor control. FIG. 1 C illustrates the percent viable cells based on concentration of ADC (trastuzumab-Compound 30, isotype-Compound 30, or trastuzumab-Dxd). [00113] FIG. 2 illustrates experimental data demonstrating that in vivo efficacy shows more prolonged/ sustained regressions with trastuzumab-Compound 30 compared to Enhertu®. JIMT-1 CDX in vivo efficacy (HER2+).
[00114] FIG. 3 is a graph of experimental data showing the in vivo efficacy of a PTK7- based ADC in the MDA-MB-468 breast cancer model.
DETAILED DESCRIPTION
[00115] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties.
Definitions
[00116] As used herein, the terms “administer,” “administration” or “administering” refer to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and/or (2) putting into, taking or consuming by the mammal, according to the disclosure.
[00117] The terms “co-administration,” “co-administering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.
[00118] The terms “active pharmaceutical ingredient” and “drug” antibodies, conjugates, and compounds described herein. The terms “active pharmaceutical ingredient” and “drug” may also include those compounds described herein that bind proteins, including but not limited to TAAs, and thereby modulate protein activity.
[00119] The term “isostere” refers to a group or molecule whose chemical and/or physical properties are similar to those of another group or molecule. A “bioisostere” is a type of isostere and refers to a group or molecule whose biological properties are similar to those of another group or molecule. For example, a carboxylic acid may be replaced by one of the following bioisosteres for carboxylic acids, including, without limitation, alkyl esters (COOR), acylsulfonamides (CONR-SO2R), hydroxamic acids (CONR-OH), hydroxamates (CONR- OR), tetrazoles, hydroxyisoxazoles, isoxazol-3-ones, and sulfonamides (SO2NR), where each R may independently represent hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00120] The term “in vivo” refers to an event that takes place in a subject’s body.
[00121] The term “in vitro” refers to an event that takes places outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
[00122] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc., which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g. , the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
[00123] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[00124] As used herein, the terms “treat,” “treatment,” and/or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and/or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g. , placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and/or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition. [00125] As used herein, the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g. , a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g. , increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule.
[00126] The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or once daily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day, or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die, three times a day, or three times daily. The terms “QID,” “qid,” or “q.i.d.” mean quater in die, four times a day, or four times daily.
[00127] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
[00128] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.
[00129] A “prodrug” refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g. , two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4- hydroxyproline, hydroxy lysine, desmosine, isodesmosine, 3- methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters). Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the disclosure with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like. As further examples, free hydroxyl groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups. Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Moreover, any compound that can be converted in vivo to provide the bioactive agent is a prodrug within the scope of the disclosure. Various forms of prodrugs are well known in the art. A comprehensive description of pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood Academic Publishers, 1991). In general, prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. , organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g., dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the disclosure.
[00130] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13C- or 14C-enriched carbons, are within the scope of this disclosure.
[00131] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1-10)alkyl or C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range, e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, //-butyl, isobutyl, secbutyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), //-propyl (Pr), 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1 , 1 -dimethylethyl (/-butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or P0(0Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00132] “Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
[00133] “Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
[00134] “Alkylheterocycloalkyl” refers to an -(alkyl) heterocyclic radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
[00135] An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
[00136] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (/'.<?. , (C2-io)alkenyl or C2-10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl and penta- 1 ,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00137] “Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
[00138] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (/'.<?. , (C2-io)alkynyl or C2-10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g. , “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00139] “Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
[00140] “Acylsulfonamide” refers to the group -C(=O)NRa-S(=O)2Ra, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[00141] “Carboxaldehyde” refers to a -(C=O)H radical.
[00142] “Carbonyl” refers to the group -C(=O)-. Carbonyl groups may be substituted with the following exemplary substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -NRa-ORa-, -C(O)ORa, - OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00143] “Carboxyl” refers to a -(C=O)OH radical.
[00144] “Cyano” refers to a -CN radical.
[00145] “Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (z.e. , (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range - e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbomyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -S(O)tRa- (where t is 1 or 2), -OC(O)- Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00146] “Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
[00147] “Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively. [00148] “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
[00149] The term “alkoxy” refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
[00150] The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (z.e., -©-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, acylsulfonamido, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00151] The term “alkoxy carbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (Ci-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
[00152] The term “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-O- C(O)- wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -
N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00153] “Acyl” refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00154] “Acyloxy” refers to a R(C=O)O- radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. [00155] ‘ ‘Amino” or “amine” refers to a -N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(Ra)2 group has two Ra substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -N(Ra)2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00156] The term “substituted amino” also refers to N-oxides of the groups -NHRd, and NRdRd each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
[00157] ‘ ‘Amide” or “amido” refers to a chemical moiety with formula -C(O)NRaRb or -NRaC(O)Rb, where Ra and Rb are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The Ra and Rb of - C(O)N RaRb amide may optionally be taken together with the nitrogen to which they are attached to form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, amino, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. [00158] ‘ ‘Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms
(e.g. , Ce-Cio aromatic or Ce-Cio aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g. , a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -
N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00159] “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
[00160] “Ester” refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00161] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
[00162] “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
[00163] “Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, acylsulfonamido, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, - S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00164] “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively. [00165] “Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.
[00166] “Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.
[00167] “Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.
[00168] “Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical (e.g, C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range - e.g. , “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [c/]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[6][l,4]oxazinyl, 1,4- benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3 ,2-flQpyrimidiny 1 , benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[t/]pyrimidinyl, 6,7-dihydro-5//-cyclopcnta[4,5]thicno[2,3-t/]pyrimidinyl, 5,6- dihydrobenzo[/z]quinazolinyl, 5,6-dihydrobenzo[/z]cinnolinyl, 6,7-dihydro-5/7- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[tZ]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[t/]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[tZ]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, isoxazol-3-one, 5,8-methano-5,6,7,8- tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[/z]quinazolinyl, 1 -phenyl- IZT-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-tZ]pyrimidinyl, pyrido[3,4- flQpyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5, 6,7,8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tctrahydro-5/7- cyclohepta[4,5]thieno[2,3-<7]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-tZ]pyrimidinyl, thieno[3,2-t/]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SIU, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), - S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00169] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.
[00170] “Heteroarylalkyl” refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
[00171] “Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range - e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[ 1 ,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1 , 1 -dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SIU, -S(O)tRa- (where t is 1 or 2), -OC(O)-Ra,
N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO(ORa)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00172] “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
[00173] “Hydroxamate” refers to the -C(O)NRaORa moiety, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00174] “Nitro” refers to the -NO2 radical. [00175] ‘ ‘Oxa” refers to the -O- radical.
[00176] “Oxo” refers to the =0 radical.
[00177] ‘ ‘Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (5). Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (5). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (5)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[00178] ‘ ‘Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (/?)- or an (5)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (/?)- or (5)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (5)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (5)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.
[00179] In some embodiments, an enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw- Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).
[00180] The terms “enantiomerically enriched” and “non-racemic,” as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (k)-cnant iomcr, means a preparation of the compound having greater than 50% by weight of the (k)-cnantiomcr relative to the (/?)-cnantiomcr, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
[00181] “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[00182] “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lZ/)-one tautomers.
[00183] A “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
[00184] “Protecting group” is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).
[00185] ‘ ‘Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
[00186] “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.
[00187] “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).
[00188] “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl). [00189] “Sulfonyl” refers to groups that include -S(C>2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -8(6)2)- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).
[00190] “Sulfonamidyl” or “sulfonamide” refers to a -S(=O)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamide group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
[00191] “Sulfoxyl” refers to a -S(=O)2OH radical.
[00192] “Sulfonate” refers to a -S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
[00193] Compounds of the disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
[00194] The term “antigen” herein refers to the molecular structure or to any molecule or linear molecular fragment derived from the processing of the native antigen being recognized by an antibody or by T cell receptors. Broadly speaking, an antigen can be a virus or virus- derived molecule, a bacteria or bacteria-derived molecule, a protein or protein fragment, a molecule such as a toxin, a chemical, a drug, or any other structure recognized by the immune system as being foreign and eliciting an immune response.
[00195] The term “tumor-associated antigen (TAA)” herein describes a large family of antigens that includes antigens derived from genes overexpressed in tumors, differentiation antigens, and cancer germline/cancer testis antigens. Antigens derived from genes overexpressed in tumors comprise a class of normal self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a results of their malignant profile.
[00196] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen-binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
[00197] An exemplary antibody such as an IgG comprises two heavy chains and two light chains. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
[00198] The hypervariable region generally encompasses amino acid residues from about amino acid residues 24-34 (LCDR1; “L” denotes light chain), 50-56 (LCDR2) and 89-97 (LCDR3) in the light chain variable region and around about 31-35 (HCDR1; “H” denotes heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region; Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and/or those residues forming a hypervariable loop (e.g. residues 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3) in the light chain variable region and 26-32 (HCDR1), 53-55 (HCDR2) and 96-101 (HCDR3) in the heavy chain variable region; Chothia and Lesk (1987) J. Mol. Biol. 196:901- 917.
[00199] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
[00200] The terms “nanobody,” “single-domain antibody (sdAb)”, “variable domain of a heavy chain-only antibody (VHH),” or “single domain-based VHH,” as used herein are used interchangeably and refer to single-domain heavy chain-only antibody derived from the Camelidae family. In some embodiments, a nanobody is an antibody fragment derived from the Camelidae heavy-chain only IgG antibody.
[00201] The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a variable heavy domain (VH) connected to a variable light domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
[00202] The term “chimeric” antibody refers to a recombinant antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
[00203] A “human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies known to one of skill in the art. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including methods described in Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al, J. Immunol, 147(I):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol, 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized HuMab mice (see, e.g., Nils Lonberg et al., 1994, Nature 368:856-859, WO 98/24884, WO 94/25585, WO 93/1227, WO 92/22645, WO 92/03918 and WO 01/09187 regarding HuMab mice), xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology) or Trianni mice (see, e.g., WO 2013/063391, WO 2017/035252 and WO 2017/136734).
[00204] The term “humanized antibody” refers to an antibody that has been engineered to comprise one or more human framework regions in the variable region together with non- human (e.g., mouse, rat, or hamster) complementarity-determining regions (CDRs) of the heavy and/or light chain. In certain embodiments, a humanized antibody comprises sequences that are entirely human except for the CDR regions. Humanized antibodies are typically less immunogenic to humans, relative to non-humanized antibodies, and thus offer therapeutic benefits in certain situations. Those skilled in the art will be aware of humanized antibodies and will also be aware of suitable techniques for their generation. See for example, Hwang, W. Y. K., et al., Methods 36:35, 2005; Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989; Jones et al., Nature, 321:522-25, 1986; Riechmann et al., Nature, 332:323-27, 1988; Verhoeyen et al., Science, 239:1534-36, 1988; Orlandi et al., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989; U.S. Pat. Nos. 5,225,539; 5,530,101; 5,585,089; 5,693,761; 5,693,762; 6,180,370; and Selick et al., WO 90/07861, each of which is incorporated herein by reference in its entirety.
[00205] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 8, E, y, and p, respectively. The immunoglobulin disclosed herein can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule. The immunoglobulins can be derived from any species. In one aspect, however, the immunoglobulin is of human, murine, or rabbit origin.
[00206] A “binding fragment thereof” refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Such fragment is sometimes referred to as “antigen-binding domain” of an antibody (or simply “binding domain” ). Examples of an binding fragment thereof includes (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., 1989 Nature 341 :544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR), disulfide-linked Fvs (dsFv), diabodies; linear antibodies; single-chain antibody molecules (e.g., ScFv); nanobodies; anti-idiotypic (anti-Id) antibodies and intrabodies. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they may be joined, using recombinant methods (e.g., by a synthetic linker) thus enabling them to be produced as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (ScFv)); see e.g., Bird et al., Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121-1123).
[00207] An antibody “variable domain” refers to the variable region of the antibody light chain (VL) or the variable region of the antibody heavy chain (VH), either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs), and contribute to the formation of the antigen-binding site of antibodies.
[00208] “Complementarity determining region” or “CDR” as the terms are used herein refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. There are three CDRs (termed CDR1, CDR2, and CDR3) within each VL and each VH. [00209] As will be appreciated by those in the art, the exact numbering and placement of the CDRs can be different among different numbering systems. However, it should be understood that the disclosure of a variable heavy and/or variable light sequence includes the disclosure of the associated CDRs. Accordingly, the disclosure of each variable heavy region is a disclosure of the vhCDRs (e.g., vhCDRl, vhCDR2 and vhCDR3) and the disclosure of each variable light region is a disclosure of the vlCDRs (e.g., vlCDRl, vlCDR2 and vlCDR3). [00210] In certain embodiments, the CDRs of an antibody can be determined according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132- 136 and Lefranc M-P et al, (1999) Nucleic Acids Res 27: 209-212. Unless stated otherwise herein, references to residue numbers in the variable domain of antibodies means residue numbering by the IMGT numbering system.
[00211] In other embodiments, the CDRs of an antibody can be determined according to MacCallum RM et al, (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Diibel, eds., Chapter 31 , pp. 422-439, Springer- Verlag, Berlin (2001). In other embodiments, the CDRs of an antibody can be determined according to the AbM numbering scheme, which refers to AbM hypervariable regions, which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.). Residues in a variable domain are numbered according Kabat, which is a numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies. See, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 ofH2 and inserted residues (e.g., residues 82a, 82b, and 82c, according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. Various algorithms for assigning Kabat numbering are available. The algorithm implemented in the version 2.3.3 release of Abysis (www.abysis.org) is used herein to assign Kabat numbering to variable regions LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3. [00212] “Framework” or “framework region” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4.
[00213] A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), Vols. 1-3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup Ill as in Kabat et al., supra.
[00214] The “hinge region” is generally defined as stretching from 216-238 (EU numbering) or 226-251 (Kabat numbering) of human IgGl. The hinge can be further divided into three distinct regions, the upper, middle (e.g., core), and lower hinge.
[00215] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991).
[00216] A “blocking” antibody or an “antagonist” antibody is one which inhibits or reduces biological activity of the antigen it binds. Certain blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.
[00217] An “epitope” is a term of art that indicates the site or sites of interaction between an antibody and its antigen(s). As described by (Janeway, C, Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3- 8. New York, Garland Publishing, Inc.): “An antibody generally recognizes only a small region on the surface of a large molecule such as a protein... Certain epitopes are likely to be composed of amino acids from different parts of the antigen polypeptide chain that have been brought together by protein folding. Antigenic determinants of this kind are known as conformational or discontinuous epitopes because the structure recognized is composed of segments of the protein that are discontinuous in the amino acid sequence of the antigen but are brought together in the three-dimensional structure. In contrast, an epitope composed of a single segment of polypeptide chain is termed a continuous or linear epitope” (Janeway, C. Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3-8. New York, Garland Publishing, Inc.).
[00218] The epitope/paratope residue can be defined by a specific criterion, e.g., distance between atoms in the Ab and the Ag (e.g., a distance of equal to or less than about 4 A from a heavy atom of the cognate antibody and a heavy atom of the antigen). In another aspect, an epitope/paratope residue can be characterized as participating in a hydrogen bond interaction with the cognate antibody/antigen, or with a water molecule that is also hydrogen bonded to the cognate antibody/antigen (water-mediated hydrogen bonding). In another aspect, an epitope/paratope residue can be characterized as forming a salt bridge with a residue of the cognate antibody/antigen. In yet another aspect, an epitope/paratope residue can be characterized as a residue having a non-zero change in buried surface area (BSA) due to interaction with the cognate antibody/antigen. At a less detailed level, epitope/paratope can be characterized through function, e.g., by competition binding with other Abs. The epitope/paratope can also be defined more generically as comprising amino acid residues for which substitution by another amino acid will alter the characteristics of the interaction between the Ab and Ag (e.g., alanine scanning).
[00219] An “antibody that binds to the same epitope” as a reference antibody refers to an antibody that contacts an overlapping set of amino acid residues of the antigen as compared to the reference antibody or blocks binding of the reference antibody to its antigen in a competition assay by 50% or more. The amino acid residues of an antibody that contact an antigen can be determined, for example, by determining the crystal structure of the antibody in complex with the antigen or by performing hydrogen/deuterium exchange. In some embodiments, residues of an antibody that are within 5 A the antigen are considered to contact the antigen. In some embodiments, an antibody that binds to the same epitope as a reference antibody blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
[00220] “Fv” consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. [00221] “Single-chain Fv” also abbreviated as “sFv” or “ScFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pliickthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994).
[00222] The term an “isolated antibody” when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non- proteinaceous solutes. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) approaches. For a review of methods for assessment of antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). In an embodiment, the antibody will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
[00223] An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. In a non-limiting example, an antibody that specifically or preferentially binds to a TAA epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other TAA epitopes or non-TAA epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety, or epitope) which specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.
[00224] “Specific binding” or “preferential binding” includes a compound, e.g., a protein, a nucleic acid, an antibody, and the like, which recognizes and binds to a specific molecule, but does not substantially recognize or bind other molecules in a sample. For instance, an antibody which recognizes and binds to its cognate antigen in a sample, but does not substantially recognize or bind other molecules in the sample, specifically binds to that cognate antigen. Thus, under designated assay conditions, the specified binding moiety (e.g., an antibody or an antigen-binding portion thereof) binds preferentially to a particular target molecule and does not bind in a significant amount to other components present in a test sample.
[00225] The term “specific binding” or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of 10 4 M or lower, alternatively 10 s M or lower, alternatively 10 6 M or lower, alternatively 10 7 M or lower, alternatively 10 s M or lower, alternatively 10 9 M or lower, alternatively 10’10 M or lower, alternatively 10 1 1 M or lower, alternatively 10 12 M or lower or a Kd in the range of 10 4 M to 10 6 M or 10 6 M to 10 10 M or 10 7 M to 10 9 M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In one embodiment, the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. As used herein the terms “specific binding,” “specifically binds,” and “selectively binds,” refer to antibody binding to an epitope of a TAA. [00226] A variety of assays may be used to select an antibody or peptide that specifically binds a molecule of interest. For example, solid-phase ELISA immunoassay, immunoprecipitation, BIAcore™ (GE Healthcare, Piscataway, NJ), fluorescence-activated cell sorting (FACS), Octet™ (ForteBio, Inc., Menlo Park, CA) and Western blot analysis are among many assays that may be used to identify an antibody that specifically reacts with an antigen or a receptor, or ligand binding portion thereof, that specifically binds with a cognate ligand or binding partner. Typically, a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background, even more specifically, an antibody is said to “specifically bind” an antigen when the equilibrium dissociation constant (KD) value is less or equal to 1 pM, such as less or equal to 100 nM, less or equal to 10 nM, less or equal to 100 pM, less or equal to 10 pM, or less or equal to 1 pM. [00227] The term “affinity,” as used herein, means the strength of the binding of an antibody to an epitope. The affinity of an antibody is given by the dissociation constant Kd, defined as [Ab]x[Ag]/[Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined by 1/Kd. Methods for determining the affinity of mAbs can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which references are entirely incorporated herein by reference. One standard method well known in the art for determining the affinity of mAbs is the use of surface plasmon resonance (SPR) screening (such as by analysis with a BIAcore™ SPR analytical device).
[00228] The term “compete”, as used herein with regard to an antibody, means that binding of a first antibody, or an antigen-binding portion thereof, to an antigen reduces the subsequent binding of the same antigen by a second antibody or an antigen-binding portion thereof. In general, the binding a first antibody creates steric hindrance, conformational change, or binding to a common epitope (or portion thereof), such that the binding of the second antibody to the same antigen is reduced. Standard competition assays may be used to determine whether two antibodies compete with each other. One suitable assay for antibody competition involves the use of the Biacore technology, which can measure the extent of interactions using surface plasmon resonance (SPR) technology, typically using a biosensor system (such as a BIACORE® system). For example, SPR can be used in an in vitro competitive binding inhibition assay to determine the ability of one antibody to inhibit the binding of a second antibody. Another assay for measuring antibody competition uses an ELISA-based approach.
[00229] The term “KD”, as used herein, is intended to refer to the dissociation constant of a particular antibody-antigen interaction. It is calculated by the formula: Koff/Kon=KD.
[00230] The term “IC50”, as used herein, is intended to refer to the effective concentration of antibody of the present invention needed to neutralize 50% of the bioactivity of IL-23 on human lymphoma DB cells in the bioassay described in Example 5: Inhibition of STAT3 activation in human DB cell Assay.
[00231] “EC50” with respect to an agent and a particular activity (e.g., binding to a cell, inhibition of enzymatic activity, activation or inhibition of an immune cell), refers to the efficient concentration of the agent which produces 50% of its maximum response or effect with respect to such activity. “EC 100” with respect to an agent and a particular activity refers to the efficient concentration of the agent which produces its substantially maximum response with respect to such activity.
Antibodies
[00232] In one aspect, the disclosure provides antibodies and antigen binding fragment thereof useful within the antibody-drug conjugates (ADCs) and other compounds and/or conjugates described herein. In some embodiments, the antibody and/or binding fragment thereof binds to an antigen (e.g., specifically binds to an antigen), as listed in Tables 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B below.
[00233] Tumor-associated antigens Tumor-associated antigens (TAAs) are a large family of antigens that includes antigens derived from genes overexpressed in tumors, differentiation antigens, and cancer germline/cancer testis antigens. Antigens derived from genes overexpressed in tumors comprise a class of normal self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a result of their malignant profile. The proteins which are usually overexpressed (e.g., EGFR, hTERT, p53, carbonic anhydrase IX) are mainly involved in the survival of the cancer cells and therefore are not susceptible to downregulation mechanisms, making them an attractive target for cancer therapeutic approaches. See Feola S, Chiaro J, Martins B, Cerullo V. Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process. Cancers (Basel). 2020 Jun 23; 12(6): 1660.
[00234] TAA are major targets for cancer therapies. Antibody- based agents targeting cancer biomarkers include monoclonal antibodies (MoAbs), radiolabeled MoAbs, bispecific T cell engagers (BiTEs), and antibody-drug conjugates (ADCs). Antibodies targeting CD 19, CD20, CD22, CD30, CD33, CD38, CD79B, SLAMF7, and HER2 (Trastuzumab) are in clinical applications for hematological malignancies. CD 123, CLL-1, B cell maturation antigen, and CD 138 are targets for cancer immunotherapeutic agents. Immune checkpoint inhibitors (ICIs) against PD- 1 , PD-L 1 , and CTLA-4 have led to the revolution of cancer immunotherapy. More ICIs targeting IDO, LAG3, TIM-3, TIGIT, SIGLECs, VISTA and CD47 are being explored. Small molecule inhibitors (SMIs) against tyrosine kinase oncoproteins such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, EGFR, ALK, HER2, PTK7, VEGFR, FGFR, MEK, and MET have fundamentally changed the landscape of cancer therapy. SMIs against BCL-2, IDHs, BRAF, PI3 kinase, mTOR, PARP, and CDKs have become the mainstay in the treatment of a variety of cancer types. In some embodiments, the tumor-associated antigen is protein tyrosine kinase 7 (PTK7). In some embodiments, the tumor-associated antigen is HER2. Protein tyrosine kinase 7 (PTK7)
[00235] The PTK7 gene (also referred to as colon carcinoma kinase 4, CCK4; HGNC: 9618; NCBI Entrez Gene: 5754; Ensembl: ENSG00000112655; RefSeq: NM_002821; UniProtKB/Swiss-Prot: QI 3308) encodes a member of the receptor protein tyrosine kinase family of proteins that transduce extracellular signals across the cell membrane. The encoded protein lacks detectable catalytic tyrosine kinase activity, is involved in the Wnt signaling pathway and plays a role in multiple cellular processes including polarity and adhesion. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.
[00236] PTK7 is highly expressed in colon, lung, liver, pancreas, kidney, placenta and melanocytes and is weakly expressed in thyroid gland, ovary, brain, heart and skeletal muscle. In particular, PTK7 gene is thought to be expressed in colon carcinomas but not in normal colon, and can be used as a marker for tumor progression.
[00237] The PTK7 gene has been previously disclosed as a therapeutic target in at least U.S. Patent Nos. 8,222,375B2, 9,777,070B2, 9,914,784B2, U.S. Patent Application publication Nos. US2020/0140815A1, US2023/0140802A1, US2023/0181750A1, PCT Application publication Nos. W02023/020551A1, and WO2023/084399A1, each of which is incorporated herein in its entirety.
Epidermal growth factor receptor 2
[00238] HER2 is a transmembrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. HER2, also known as epidermal growth factor receptor 2, belongs to a family of epidermal growth factor receptors (EGFRs) including HER1 (ErbB 1), HER3 (ErbB3), and HER4 (ErbB4) (Hudis, 2007, N Engl J Med 357(l):39-51). The ErbB receptors typically dimerize on ligand binding. Although HER2 has no known ligand, it is the preferential dimerization partner of other members of the ErbB family. (Hudis, 2007, N Engl J Med 357(l):39-51). Overexpression of HER2 results in the induction of angiogenesis, a component of cancer growth, and the evocation of an antitumor T-cell response (Menard et ah, 2003, Oncogene 22:6570-6578). HER2 is overexpressed in about one-quarter of breast cancer patients (Bange et al, 2001, Nature Medicine 7:548- 552).
[00239] Due to the overexpression or amplification of human epidermal growth factor receptor 2 (HER2) with poor prognosis in a myriad of human tumors, recent studies have focused on HER2-targeted therapies. Deregulation in HER2 signaling pathways is accompanied by sustained tumor cells growth concomitant with their migration and also tumor angiogenesis and metastasis by stimulation of proliferation of a network of blood vessels. A large number of studies have provided clear evidence that the emerging HER2-directed treatments could be the outcome of patients suffering from HER2 positive breast and also gastric/gastroesophageal cancers.
[00240] HER2 has been previously disclosed as a therapeutic target in at least U.S. Patent Nos. 11091561 B2, PCT Application publication Nos. WO 2011/084496 Al, and WO 2023/154780 Al, each of which is incorporated herein in its entirety.
[00241] In some embodiments, the antibody and/or binding fragment thereof binds to HER2. In some embodiments, the antibody and/or binding fragment thereof is selected from Trastuzumab, Pertuzumab, or Margetuximab. In some embodiments, the antibody and/or binding fragment thereof is Trastuzumab. Trastuzumab comprises a heavy chain (VH) having a sequence as set forth in SEQ ID NO: 229 and a light chain (VL) having a sequence as set forth in SEQ ID NO: 622, and has three heavy chain CDRs, referred to herein (in amino- to carboxy-terminal order) as HCDR1 (GFNIKDTYIH; SEQ ID NO: 787), HCDR2 (RIYPTNGYTRYADSVKG; SEQ ID NO: 788) and HCDR3 (WGGDGFYAMDY; SEQ ID NO: 789), and three light chain CDRs referred to herein (in amino- to carboxy-terminal order) as LCDR1 (RASQDVNTAVA; SEQ ID NO: 790), LCDR2 (SASFLYS; SEQ ID NO: 791) and LCDR3 (QQHYTTPPT; SEQ ID NO: 792). In some embodiments, one or more of the CDRs comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NOs:787- 792.
[00242] Deimmunized variants of trastuzumab have one or more substitutions in the framework and/or CDR regions. Exemplary positions where one or more substitutions can be made that result in a variant of trastuzumab with reduced immunogenicity relative to trastuzumab include the heavy chain positions R83 and W95 and the light chain positions Q27, D28 and A34. Exemplary substitutions that can be made at the foregoing positions that result in deimmunized variants of trastuzumab include one or more of the following heavy chain substitutions: R83K or W95F. Exemplary substitutions in the light chain that result in deimmunized variants of trastuzumab include one or more of the following substitutions: Q27S, Q27L, Q27F, D28L, D28N, A34D, and A34V. Combinations of one or more deimmunizing VL chain substitutions and one or more deimmunizing VH chain substitutions can also be made, including, for example, the following VL combinations: D28N + A34D, Q27S + A34D, Q27L + A34V, D28L + A34D or Q27F + A34D. In one aspect, the anti-HER2 antibody or anti-HER2 binding fragment of an antibody of the disclosure comprises CDRs having overall at least 80% sequence identity to CDRs having amino acid sequences SEQ ID NO: 787 (HCDR1), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3); and/or SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3), wherein the anti-HER2 antibody or anti-HER2 binding fragment has reduced immunogenicity as compared to an antibody having a VH of SEQ ID NO: 229 and a VL of SEQ ID NO: 622.
[00243] A list of exemplary heavy chain (CH), variable heavy chain (VH), light chain (CL), and variable light chain (VL) sequences is disclosed in Tables 2A-2C; a list of exemplary single-chain variable fragment (scFv) sequences is disclosed in Tables 3A-3B; a list of exemplary nanobody (VHH) sequences is disclosed in Tables 4A-4B.
[00244] Non-limiting examples of TAAs that can be targeted using the antibody-drug conjugation are described herein. Many other TAAs of interest are listed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; this list is exemplary and in no way limiting to the present disclosure.
Non-cancer related targets
[00245] In embodiments, the target is an antigen unrelated to cancer. In embodiments, the target is associated with and/or presents constitutively or elicited in immunological contexts other than cancer, such as acute inflammatory states, infections, auto-immune diseases or allergies. In a non-limiting example, targets of interest undergo transient changes in expression and post-translational modifications similar to what is observed on malignant cells where they are considered to be tumor-associated antigens (TAA). In some embodiments, the target is related to autoimmune diseases. In some embodiments, the target is related to bacterial pathogens. In some exemplary embodiments, the bacterial pathogen-related target is selected from Anthrax Toxin (Cya), Clumping Factor A (ClfA), Botulinum neurotoxin (NT), or Pseudomonas aeruginosa. In some embodiments, the target is related to viral pathogens. In some exemplary embodiments, the viral pathogen-related target is selected from CMV glycoprotein B, EBVA, HIV/HIV-l, Rabies virus glycoprotein, alpha-hemolysin, Influenza H1N5, or Sars-CoV-2. In some embodiments, the target is a molecule that is not a protein. In some exemplary embodiments, the non-protein targets are selected from gangliosides, dabigatran, or cotinine.
[00246] In embodiments, TAAs and other antigens, viral peptides for example, share structural similarities, as well as comparable patterns of contact with antibodies or T cell receptors. In embodiments, bacterial antigens also share structural similarity with TAAs, and thus antibodies specific to one may cross react with the other. Non-limiting examples of TAAs useful in this disclosure include those listed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B.
Table 1A: Exemplary TAAs and other targets
Table IB: Exemplary TAA sequences
[00247] In some aspects, the TAA is a human protein. In some aspects, the TAA is a cynomologus monkey (cyno) protein. In some aspects, the TAA is a mouse protein. In some aspects, TAA is a primate protein. Exemplary TAAs are provided in Tables 1A-1B.
Antibodies
[00248] In some embodiments, an antibody or binding fragment thereof that binds a TAA comprises one or more of sequences as listed in Table 2, Table 3, and/or 4.
[00249] In some embodiments, the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
[00250] In some embodiments, the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
[00251] In some embodiments, the antibody or binding fragment thereof may comprise one or more conservative amino acid substitutions. A person of skill in the art will recognize that a conservative amino acid substitution is a substitution of one amino acid with another amino acid that has similar structural or chemical properties, such as, for example, a similar side chain. Exemplary conservative substitutions are described in the art, for example, in Watson et al., Molecular Biology of the Gene, The Benjamin/Cummings Publication Company, 4th Ed. (1987).
[00252] In some embodiments, antibody or binding fragment thereof comprises a heavy chain variable region with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050. In still further embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region sequence set forth in any one of SEQ ID NOs: 1-393 or 1002- 1050 and has one or more conservative amino acid substitutions, e.g., 1, 2, 3, 4, 5, 1-2, 1-3, 1- 4 or 1-5 conservative amino acid substitutions in the heavy chain variable region sequence. In yet further embodiments, the one or more conservative amino acid substitutions fall within one or more framework regions in any one of SEQ ID NOs: 1-393 or 1002-1050 (based on the numbering system of Kabat).
[00253] In particular embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to a heavy chain variable region sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an antibody that comprises a heavy chain variable region as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain variable region as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
[00254] In some embodiments, the antibody or binding fragment thereof comprises a light chain variable region sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051 - 1085. In other embodiments, the antibody or binding fragment thereof retains the binding and/or functional activity of an antibody or binding fragment thereof that comprises a light chain variable region sequence set forth in any one of SEQ ID NOs: 394-786 or 1051- 1085.
[00255] In still further embodiments, the antibody or binding fragment thereof comprises a light chain variable region sequence set forth in any one of SEQ ID NOs: 394-786 or 1051- 1085 and has one or more conservative amino acid substitutions, e.g., 1, 2, 3, 4, 5, 1-2, 1-3, 1- 4 or 1-5 conservative amino acid substitutions in the light chain variable region sequence.
[00256] In yet further embodiments, the one or more conservative amino acid substitutions fall within one or more framework regions of the light chain variable region sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085 (based on the numbering system of Kabat).
[00257] In particular embodiments, the antibody or binding fragment thereof comprises a light chain variable region sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to a light chain variable region sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an antibody that comprises a heavy chain variable region sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain variable region sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085. [00258] Sequences of exemplary antibodies that bind a TAA are shown U.S. Patent Nos. U.S. 5674994 A, U.S. 5985278 A, U.S. 6037454 A, U.S. 6210671 Bl, U.S. 6790938 Bl, U.S. 6824780 Bl, U.S. 6972125 B2, U.S. 6972323 Bl, U.S. 6972324 B2, U.S. 6989145 B2, U.S.
7033589 Bl, U.S. 7223393 B2, U.S. 7323170 B2, U.S. 7354584 B2, U.S. 7378504 B2, U.S.
7501121 B2, U.S. 7501498 B2, U.S. 7582445 B2, U.S. 7655230 B2, U.S. 7662381 B2, U.S.
7718174 B2, U.S. 7723485 B2, U.S. 7767205 B2, U.S. 7803377 B2, U.S. 7834155 B2, U.S.
7851181 B2, U.S. 7868140 B2, U.S. 7868141 B2, U.S. 7910703 B2, U.S. 7919594 B2, U.S. 7923011 B2, U.S. 7982011 B2, U.S. 8029783 B2, U.S. 8039597 B2, U.S. 8080247 B2, U.S. 8128929 B2, U.S. 8221749 B2, U.S. 8318161 B2, U.S. 8323647 B2, U.S. 8349330 B2, U.S. 8404239 B2, U.S. 8410250 B2, U.S. 8415459 B2, U.S. 8420084 B2, U.S. 8486398 B2, U.S. 8507657 B2, U.S. 8617552 B2, U.S. 8709414 B2, U.S. 8828390 B2, U.S. 8877913 B2, U.S. 8986952 B2, U.S. 8993261 B2, U.S. 8993261 B2, U.S. 9005617 B2, U.S. 9023996 B2, U.S. 9056910 B2, U.S. 9073992 B2, U.S. 9085615 B2, U.S. 9314538 B2, U.S. 9328169 B2, U.S.
9433687 B2, U.S. 9458240 B2, U.S. 9463251 B2, U.S. 9487584 B2, U.S. 9487586 B2, U.S. 9522954 B2, U.S. 9545451 B2, U.S. 9587026 B2, U.S. 9695237 B2, U.S. 9701756 B2, U.S. 9725519 B2, U.S. 9783615 B2, U.S. 9809653 B2, U.S. 9828423 B2, U.S. 9855291 B2, U.S. 9982058 B2, U.S. 9988455 B2, U.S. 10005836 B2, U.S. 10011652 B2, U.S. 10023630 B2, U.S. 10040858 B2, U.S. 10047155 B2, U.S. 10160809 B2, U.S. 10189910 B2, U.S. 10195209 B2, U.S. 10227402 B2, U.S. 10358500 B2, U.S. 10428156 B2, U.S. 10465011 B2, U.S. 10576148 B2, U.S. 10590202 B2, U.S. 10611838 B2, U.S. 10662247 B2, U.S.
10688178 B2, U.S. 10711068 B2, U.S. 10745489 B2, U.S. 10793636 B2, U.S. 10913800 B2 , U.S. 10934359 B2, U.S. 10975166 B2, U.S. 11002738 B2, U.S. 11008395 B2, U.S. 11008400 B2, U.S. 11021531 Bl, U.S. 11028176 B2, U.S. 11028181 B2, U.S. 11041019 B2, U.S. 11045522 B2, U.S. 11078273 B2, U.S. 11091561 B2, U.S. 11098130 Bl, U.S.
11117963 B2, U.S. 11136381 B2, U.S. 11155606 B2, U.S. 11208494 B2, U.S. 11242399 B2, U.S. 11242402 B2, U.S. 11253590 B2, U.S. 11267896 B2, U.S. 11279764 B2, U.S. 11306141 B2, U.S. 11325967 B2, U.S. 11332534 B2, U.S. 11390688 B2, U.S. 11427649 B2, U.S. 11434269 B2, U.S. 11434301 B2, U.S. 11440959 B2, U.S. 11447566 B2, U.S. 11492409 B2, U.S. 11525001 B2, U.S. 11525005 B2, U.S. 11566075 B2, U.S. 11572411 B2, U.S. 11578139 Bl, U.S. 11584790 B2, U.S. 11608375 B2, U.S. 11613568 B2, U.S.
11628224 B2, U.S. 11643467 B2, U.S. 11655307 B2, U.S. 11661451 B2, U.S. 11661462 B2, U.S. 11667700 B2, U.S. 11719699 B2, and U.S. 11739142 B2; U.S. Patent Applications Nos. U.S. 2006/0275211 Al, U.S. 2006/0280679 Al , U.S. 2007/0237761 Al, U.S. 2007/0269442 Al, U.S. 2008/0085241 Al, U.S. 2008/0118978 Al, U.S. 2008/0146784 Al , U.S. 2008/0187547 Al, U.S. 2008/0219974 Al, U.S. 2008/0253962 Al, U.S. 2008/0292632 Al , U.S. 2008/0311115 Al, U.S. 2008/0279847 Al, U.S. 2009/0028851 Al, U.S. 2009/0041659 Al, U.S. 2009/0047735 Al, U.S. 2009/0053224 Al, U.S. 2009/0110681 Al, U.S. 2009/0162382 Al, U.S. 2009/0175881 Al, U.S. 2009/0221003 Al, U.S. 2009/0232823 Al, U.S. 2009/0299039 Al, U.S. 2009/0311779 Al , U.S. 2010/0008906 Al, U.S. 2010/0015135 Al, U.S. 2010/0111852 Al, U.S. 2010/0189722 Al , U.S. 2010/0196398 Al, U.S. 2010/0221822 Al, U.S. 2010/0278832 Al, U.S. 2010/0292095 Al , U.S. 2011/0117104 Al, U.S. 2011/0206686 Al , U.S. 2011/0239316 Al, U.S. 2011/0250203 Al, U.S. 2011/0280866 Al, U.S. 2011/0280881 Al, U.S. 2012/0014960 Al, U.S. 2012/0023600 Al, U.S. 2012/0034215 Al, U.S. 2012/0064081 Al, U.S. 2012/0076790 Al, U.S. 2012/0114672 Al, U.S. 2012/0266264 Al , U.S. 2013/0005033 Al, U.S. 2013/0129735 Al, U.S. 2013/0266594 Al, U.S. 2013/0267688 Al, U.S. 2013/0280253 Al, U.S. 2013/0295113 Al, U.S. 2014/0161803 Al, U.S. 2014/0220040 Al, U.S. 2014/0294809 Al, U.S. 2014/0356359 Al, U.S. 2015/0023978 Al, U.S. 2015/0110792 Al, U.S. 2015/0125454 Al, U.S. 2015/0218267 Al, U.S. 2015/0231240 Al, U.S. 2015/0232546 Al, U.S. 2015/0307599 Al, U.S. 2015/0307625 Al, U.S. 2015/0337037 Al, U.S. 2015/0337048 Al, U.S. 2016/0096891 Al, U.S. 2016/0200823 Al, U.S. 2016/0206764 Al, U.S. 2016/0251447 Al, U.S. 2016/0257741 Al, U.S. 2016/0319003 Al, U.S. 2016/0319035 Al, U.S. 2016/0326249 Al, U.S. 2016/0347858 Al, U.S. 2016/0355587 Al, U.S. 2017/0051058 Al, U.S. 2017/0072066 Al , U.S. 2017/0107294 Al, U.S. 2017/0145106 Al, U.S. 2017/0173151 Al, U.S. 2017/0218061 Al, U.S. 2017/0247440 Al, U.S. 2017/0320956 Al, U.S. 2017/0349665 Al, U.S. 2017/0362336 Al, U.S. 2018/0186873 Al, U.S. 2018/0186885 Al, U.S. 2018/0236071 Al, U.S. 2018/0237529 Al, U.S. 2018/0244785 Al , U.S. 2018/0355041 Al, U.S. 2019/0022242 Al, U.S. 2019/0031767 Al, U.S. 2019/0048073 Al, U.S. 2019/0119398 Al, U.S. 2019/0119400 Al, U.S. 2019/0127470 Al, U.S. 2019/0144565 Al, U.S. 2019/0225685 Al, U.S. 2019/0225698 Al, U.S. 2019/0263931 Al, U.S. 2019/0269791 Al , U.S. 2019/0270821 Al, U.S. 2019/0276559 Al, U.S. 2019/0284262 Al , U.S. 2019/0328897 Al, U.S. 2019/0330318 Al, U.S. 2019/0330318 Al, U.S. 2019/0345261 Al, U.S. 2019/0359698 Al, U.S. 2019/0365916 Al, U.S. 2019/0365916 Al, U.S. 2019/0367619 Al , U.S. 2019/0375841 Al, U.S. 2019/0382481 Al, U.S. 2020/0017568 Al, U.S. 2020/0048365 Al, U.S. 2020/0062844 Al, U.S. 2020/0109198 Al, U.S. 2020/0140549 Al, U.S. 2020/0165351 Al, U.S. 2020/0199240 Al, U.S. 2020/0277386 Al, U.S. 2020/0325247 Al, U.S. 2020/0362032 Al, U.S. 2020/0390902 Al, U.S. 2020/0392241 Al, U.S. 2020/0407454 Al, U.S. 2021/0000875 Al, U.S. 2021/0002373 Al, U.S. 2021/0015940 Al, U.S. 2021/0030885 Al, U.S. 2021/0032346 Al, U.S. 2021/0040184 Al, U.S. 2021/0070868 Al, U.S. 2021/0079109 Al, U.S. 2021/0087280 Al, U.S. 2021/0087283 Al, U.S. 2021/0095039 Al, U.S.
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2022/0098323 Al, U.S. 2022/0105196 Al, U.S. 2022/0112283 Al, U.S. 2022/0112284 Al, U.S. 2022/0112303 Al, U.S. 2022/0112308 Al, U.S. 2022/0119507 Al, U.S. 2022/0125845 Al, U.S. 2022/0144927 Al, U.S. 2022/0144966 Al, U.S. 2022/0144968 Al , U.S.
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2023/0227566 Al, U.S. 2023/0235055 Al, U.S. 2023/0235073 Al, U.S. 2023/0235076 Al, U.S. 2023/0242645 Al , U.S. 2023/0257472 Al, U.S. 2023/0265174 Al, U.S. 2023/0279110 Al, U.S. 2023/0295293 Al, U.S. 2023/0295313 Al, U.S. 2023/0295330 Al, and U.S. 2023/0322916 Al; International Application Publications Nos. WO 2011/084496 Al, WO 2017/066714 Al, WO 2017/112829 Al, WO 2022/147298 Al, WO 2022/200498 Al, WO 2022/204095 Al, WO 2023/154780 Al, and WO 2023/164513 A2; as well as foreign Patent Application Publication Nos. CN 108424455 A, EP 2264063 Al, and EP 3753579 Al, each of which is incorporated by reference herein in its entirety.
[00259] Sequences of exemplary scFvs that bind a TAA are shown U.S. Patent Nos. U.S.
9416188 B2, U.S. 10005831 B2, and U.S. 11117963 B2, as well as U.S. Patent Applications Nos. U.S. 2005/0129693 Al, U.S. 2010/0285030 Al, U.S. 2012/0114704 Al, U.S. 2012/0213699 Al, U.S. 2012/0282257 Al, U.S. 2018/0256744 Al, U.S. 2019/0144532 Al, U.S. 2021/0038648 Al, U.S. 2021/0047435 Al, U.S. 2021/0070878 Al, U.S. 2021/0070878 Al, U.S. 2022/0220212 Al , U.S. 2023/0018888 Al, U.S. 2023/0242677 Al, U.S.
2023/0279121 Al, and U.S. 2023/0279121 Al , each of which is incorporated by reference herein in its entirety.
[00260] Sequences of exemplary nanobodies that bind a TAA are shown U.S. Patent Nos. U.S. 9028816 B2, U.S. 9771423 B2, U.S. 9803018 B2, U.S. 11248039 B2, U.S. 11384151 B2, U.S. 11517632 B2, U.S. 11597769 B2, and U.S. 11597769 B2, as well as U.S. Patent Applications Nos. U.S. 2013/0280259 Al, U.S. 2015/0210762 Al, U.S. 2015/0246967 Al, U.S. 2017/0226204 Al, U.S. 2018/0002439 Al, U.S. 2019/0045758 Al , U.S. 2019/0322747 Al, U.S. 2019/0367635 Al, U.S. 2020/0239534 Al, U.S. 2020/0369774 Al , U.S.
2021/0147541 Al, U.S. 2022/0251217 Al, ,U.S. 2022/0259296 Al, U.S. 2022/0348670 Al, U.S. 2023/0002503 Al , U.S. 2023/0076670 Al, U.S. 2023/0124851 Al , U.S. 2023/0136252 Al, U.S. 2023/0203167 Al, and U.S. 2023/0203185 Al, each of which is incorporated by reference herein in its entirety.
[00261] In some embodiments, the ADC is used to treat cancer.
[00262] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 comprising a VH complementarity determining regions one, two and three (HCDR1, HCDR2, and HCDR3) and/or a light chain variable region having the amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085 comprising a VL complementarity determining regions one, two and three (LCDR1, LCDR2, and LCDR3).
Table 2A: Exemplary antibody heavy chain regions (or heavy chain variable regions; VH) and antibody light chain regions (or light chain variable regions; VL) sequences. Constant heavy (CH) and light (CL) chains are bolded and underscored.
Table 2B: Trastuzumab Complementarity Determining Regions (CDRs)
Table 2C: Anti-PTK7 antibody heavy chain regions (or heavy chain variable regions) and anti-
PTK7 antibody light chain regions (or light chain variable regions)
[00263] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region (VH) that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 orl002-1050.
[00264] In some embodiments, the antibody or binding fragment thereof comprises a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
[00265] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region (VH) that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050.
[00266] In some embodiments, the antibody or binding fragment thereof comprises a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085.
[00267] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region (VH) that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 229-236.
[00268] In some embodiments, the antibody or binding fragment thereof comprises a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 622-629.
[00269] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain variable region (VH) that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 229.
[00270] In some embodiments, the antibody or binding fragment thereof comprises a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 622.
[00271] In some embodiments, the antibody or binding fragment thereof comprises a VH that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
[00272] In some embodiments, the antibody or binding fragment thereof comprises a VH that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1002-1050, and a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 1051-1085.
[00273] In some embodiments, the antibody or binding fragment thereof comprises a VH that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 229-236, and a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 622-629.
[00274] In some embodiments, the antibody or binding fragment thereof comprises a VH that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 229, and a VL that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence set forth in SEQ ID NO: 622.
[00275] In some embodiments, the antibody or binding fragment thereof comprises a VH that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1-393 or 1002- 1050.
[00276] In some embodiments, the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051- 1085.
[00277] In some embodiments, the antibody or binding fragment thereof comprises a VH that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1002-1050.
[00278] In some embodiments, the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1051-1085.
[00279] In some embodiments, the antibody or binding fragment thereof comprises a VH that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 229-236.
[00280] In some embodiments, the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 622-629.
[00281] In some embodiments, the antibody or binding fragment thereof comprises a VH that is 100% identical to an amino acid sequence of SEQ ID NO: 229.
[00282] In some embodiments, the antibody or binding fragment thereof comprises a VL that is 100% identical to an amino acid sequence of SEQ ID NO: 622.
[00283] Any combination of a VH sequence and a VL sequence shown in Tables 2A-C is also encompassed by the present disclosure.
[00284] In some embodiments, the antibody or binding fragment that binds a TAA is a single-chain variable fragment (scFv) comprising an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107 as listed in Tables 3A-B below. Table 3 A: Exemplary single-chain variable fragments (scFv) sequences. Heavy chain regions (or heavy chain variable regions) are italicized) and antibody light chain regions (or light chain variable regions) are underscored. Linkers are bolded. Constant regions are underscored and bolded.
Table 3B: Anti-PTK7 single-chain variable fragment (scFv). Heavy chain variable regions are italicized and antibody light chain variable regions are underscored. Linkers are bolded.
[00285] In some embodiments, the binding fragment thereof is a single-chain variable fragment (scFv) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
[00286] In some embodiments, the binding fragment thereof is a single-chain variable fragments (scFv) comprising an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
[00287] In some embodiments, the binding fragment thereof is a single-chain variable fragment (scFv) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1086-1107.
[00288] In some embodiments, the binding fragment thereof is a single-chain variable fragments (scFv) comprising an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1086-1107.
[00289] In some embodiments, the binding fragment thereof is a nanobody comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111 as listed in Tables 4A-B below.
Table 4A: Exemplary nanobody sequences.
Table 4B: Anti-PTK7 nanobodies sequences.
[00290] In some embodiments, the binding fragment thereof is a nanobody that comprises an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 812-841 or 1108-1111.
[00291] In some embodiments, the binding fragment thereof is a nanobody that comprises an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1108-1111.
[00292] In some embodiments, the binding fragment thereof is a nanobody that comprises an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 824. [00293] In some embodiments, the antibody or binding fragment thereof is a nanobody that comprises or consists of an amino acid sequence that is 100% identical to an amino acid sequence of any one of SEQ ID NOs: 812-841.
[00294] In some embodiments, the antibody or binding fragment thereof is a nanobody that comprises or consists of an amino acid sequence that is 100% identical to an amino acid sequence of SEQ ID NO: 824.
[00295] Several human, humanized, and chimeric antibodies are disclosed in the patent literature (see, e.g., Table 2 above depicting the heavy chain, heavy chain variable region, light chain, and/or light chain variable regions of such antibodies). Such sequences can be found, for example, in U.S. Patent documents as disclosed in Table 2A or 2B.
[00296] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1-393 or 1002-1050.
[00297] In some embodiments, the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085.
[00298] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and (c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085.
[00299] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 394-786 or 1051-1085.
[00300] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1002-1050.
[00301] In some embodiments, the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1051-1085. [00302] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1051-1085.
[00303] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1002- 1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and (c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1051- 1085.
[00304] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 229-236.
[00305] In some embodiments, the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 622-629.
[00306] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 622-629.
[00307]
[00308] In some embodiments, the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 622-629.
[00309] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 229.
[00310] In some embodiments, the antibody or binding fragment thereof comprises a light chain that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 622.
[00311] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789, wherein the VH comprises or consists of an amino acid sequence of SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence of SEQ ID NO: 622. In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence of SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
[00312] (c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence of SEQ ID NO: 622. In some embodiments, the antibody or binding fragment thereof is a scFv that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
[00313] In some embodiments, the antibody or binding fragment thereof is a single chain variable fragment (ScFv) comprising:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3); and wherein the scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
[00314] In some embodiments, the antibody or binding fragment thereof is a single chain variable fragment (ScFv) comprising:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions; and wherein the scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 793-811 or 1086-1107.
[00315] In some embodiments, the antibody or binding fragment thereof is a scFv that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1086- 1107.
[00316] In some embodiments, the antibody or binding fragment thereof is a single chain variable fragment (ScFv) comprising: (i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions; and wherein the scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1086-1107.
[00317]
[00318] In some embodiments, the antibody or binding fragment thereof is a single chain variable fragment (ScFv) comprising:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3); and wherein the scFv comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 1086-1107. [00319] In some embodiments, the antibody or binding fragment thereof is a nanobody that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 812-841 or 1108-1111.
[00320] In some embodiments, the antibody or binding fragment thereof is a nanobody that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of any one of SEQ ID NOs: 1108-1111.
[00321] In some embodiments, the antibody or binding fragment thereof is a nanobody that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of SEQ ID NOs: 824.
[00322] In some embodiments, the antibody or binding fragment thereof is a nanobody comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 812-841.
[00323] In some embodiments, the antibody or binding fragment thereof is a nanobody comprising or consisting of an amino acid sequence of SEQ ID NOs: 824.
[00324] In certain embodiments, the antibody or binding fragment thereof comprises an Fc domain. The Fc domain can be derived from IgA (e.g., IgAi or IgA2), IgG, IgE, or IgG (e.g., IgGi, IgG2, IgG3, or IgG4). In some embodiments, the Fc domain comprises wild type sequence of an Fc domain. In some embodiments, the Fc domain comprises one or more mutations resulting in altered biological activity. For example, mutations may be introduced into the Fc domain to increase the homogeneity during the production of the recombinant protein. In some embodiments, the Fc domain is the Fc domain of human IgG. In some embodiments, the lysine located in the C-terminal position of the Fc domain is deleted to increase the homogeneity during the production of the recombinant protein. In some embodiments, the lysine located in the C-terminal position of the Fc domain is present.
[00325] In certain embodiments, the antibody or binding fragment thereof is encoded by a DNA polynucleotide sequence. As is well-understood in the art, introduction of the DNA into a competent mammalian cell will result in the production of the polypeptide comprising the antibody or binding fragment thereof. Exemplary methods of antibody production by these means are disclosed in U.S. Patent Nos. 8,008,449, 10,934,571 and 11,339,215. [00326] Also provided by the present disclosure is an antibody, or binding fragment thereof that binds to the same epitope as any of the antibodies or antigen binding fragment thereof described herein. For example, antibody competition assay (and overlapping epitope analysis) can be assessed by surface plasmon resonance (SPR) or bio-layer interferometry (BLI).
[00327] In some embodiments, the antibody or antibody fragment thereof comprises one or more conservative amino acid substitutions. A person of skill in the art will recognize that a conservative amino acid substitution is a substitution of one amino acid with another amino acid that has similar structural or chemical properties, such as, for example, a similar side chain. Exemplary conservative substitutions are described in the art, for example, in Watson et al., Molecular Biology of the Gene, The Benjamin/Cummings Publication Company, 4th Ed. (1987).
[00328] “Conservative modifications” refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequences. Conservative modifications include amino acid substitutions, additions and deletions. Conservative substitutions are those in which the amino acid is replaced with an amino acid residue having a similar side chain. The families of amino acid residues having similar side chains are well defined and include amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine), amide (e.g., asparagine, glutamine), beta- branched side chains (e.g., threonine, valine, isoleucine) and sulfur-containing side chains (cysteine, methionine). Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis (MacLennan et al. (1998) Acta Physiol Scand Suppl 643: 55-67; Sasaki et al. (1998) Adv Biophys 35: 1-24). Amino acid substitutions to the antibodies of the invention may be made by known methods for example by PCR mutagenesis (U.S. Patent No. 4,683,195).
[00329] The binding affinity of an antibody can be expressed as an equilibrium dissociation constant (KD) value, which refers to the dissociation rate of a particular antigen-antibody interaction. KD is the ratio of the rate of dissociation, also called the “off-rate (koff)”, to the association rate, or “on-rate (kon)”. Thus, KD equals koff/kon (dissociation/association) and is expressed as a molar concentration (M), and the smaller the KD, the stronger the affinity of binding. KD values for antibodies can be determined using methods well established in the art. Unless otherwise specified, “binding affinity” refers to monovalent interactions (intrinsic activity; e.g., binding of an antibody to an TAA through a monovalent interaction).
[00330] In certain embodiments, the antibody, or binding fragment thereof, of the invention has an affinity (KD) value of or less than about 350 nM, about 325 nM, about 323.10 nM, about 300 nM, about 286.44 nM, about 275 nM, about 250 nM, about 232.13 nM, about 225 nM, about 219.13 nM, about 200 nM, about 195.54 nM, about 175 nM, about 158 nM, about 150 nM, about 125 nM, or about 100 nM.
[00331] In some embodiments, the antibody, or binding fragment thereof, binds an epitope (e.g. TAA) with a KD value of or less than about 95 nM, about 90 nM, about 80 nM, about 79.89 nM, about 75 nM, about 70 nM, about 69.50 nM, about 65 nM, about 63.44 nM, about 60 nM, about 55 nM, about 52.88 nM, about 50 nM, about 45 nM, about 44.50 nM, about 41.99 nM, about 40 nM, about 35 nM, about 30 nM, about 25 nM, about 20 nM, about 10 nM, about 5 nM, or about 1 nM.
[00332] In some embodiments, the antibody, or binding fragment thereof, binds an epitope (e.g. TAA) with a KD value of or less than about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3.12 nM, about 3 nM, about 2.90 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, about 900pM, about 800pM, about 700pM, about 600pM, about 500pM, about 400pM, about 300pM, about 250pM, about 200pM, about 150pM, about lOOpM, about 50pM, about 40pM, about 30pM, about 25pM, about 20pM, about 15pM, about lOpM, about 5pM, or about IpM.
[00333] The value of KD can be determined directly by well-known methods, and can be computed even for complex mixtures by methods such as those, for example, set forth in Caceci et al., (1984, Byte 9: 340-362). For example, the KD may be established using a double-filter nitrocellulose filter binding assay such as that disclosed by Wong & Lohman (1993, Proc. Natl. Acad. Sci. USA 90: 5428-5432). Other standard assays to evaluate the binding ability of ligands such as antibodies towards target antigens are known in the art, including for example, ELIS As, Western blots, RIAs, and flow cytometry analysis, and other assays exemplified elsewhere herein.
[00334] One exemplary method for measuring binding affinity (KD) value is surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE® system. SPR refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE® system. BIAcore kinetic analysis comprises analyzing the binding and dissociation of an TAA from a chip with an immobilized molecule (e.g., a molecule comprising an antigen-binding domain), on their surface; or the dissociation of an antibody, or binding fragment thereof, from a chip with an immobilized TAA.
[00335] In certain embodiments, the SPR measurement is conducted using a BIACORE® T100 or T200 instrument. For example, a standard assay condition for surface plasmon resonance can be based on antibody immobilization of approximately 100-500 Response Units (RU) of IgG on the SPR chip. Purified target proteins are diluted in buffer to a range of final concentrations and injected at a requisite flow rate (e.g., 10-100 pl/min)to allow the calculation of Ka. Dissociation is allowed to proceed to establish off-rate, followed by 3 M MgCh (or 20 mM NaOH) for regeneration of the chip surface. Sensorgrams are then analyzed using a kinetics evaluation software package.
[00336] In certain embodiments, the binding affinity (KD) value is measured using solutionbased kinetic exclusion assay (KinExA™). In a particular embodiment, the KinExA measurement is conducted using a KinExA™ 3200 instrument (Sapidyne). The Kinetic Exclusion Assay (KinExA™) is a general purpose immunoassay platform (basically a flow spectrofluorimeter) that is capable of measuring equilibrium dissociation constants, and association and dissociation rate constants for TAA/antibody interactions. Since KinExA™ is performed after equilibrium has been obtained it is an advantageous technique to use for measuring the KD of high affinity interactions where the off-rate of the interaction may be very slow. The KinExA™ methodology can be conducted generally as described in Drake et al., (2004) Analytical Biochem. 328, 35-43.
[00337] Another method for determining the KD of an antibody is by using Bio-Layer Interferometry (BLI), typically using OCTET® technology (e.g., Octet QKe system) from ForteBio. In certain embodiments, the BLI measurement is conducted according to the following: sensor tips coated with a proprietary anti-human antibody (ForteBio) undergo BLI signal stabilization by dipping in running buffer (such as lOmM Hepes Buffered Saline (HBS) containing 0.05% tween-20) for 120 seconds. The antibody is then captured by dipping the sensors into a running buffer solution (buffer may contain l-10ug/mL of the antibody) for 300s. The signal is then stabilized by dipping the sensor tips back into running buffer for 120s. The tips are then transferred into solution containing the cognate TAA. The binding of antibody- TAA is measured over 180s prior to the sensor tips being transferred to running buffer in order to monitor receptor dissociation over 180s.
[00338] In some embodiments, the TAA is a human antigen, cyno antigen, or mouse antigen. In general, an antibody should bind to the tartet with high affinity. It is desirable that the antibody have binding affinities (KD) to the human antigen in low nanomolar range, such as about 40 nM or lower. In some embodiments, the target is a human TAA and the KD value is about 40 nM, about 45 nM or about 50 nM. In some embodiments, the antigen is a cyno TAA and the KD value is about 62 nM, about 64 nM, about 66 nm, about 68 nM, or about 70 nM.
Drug Moieties
[00339] Any antibody, antibody-drug conjugate, antibody fragment, and/or linker disclosed herein can be conjugated to a drug moiety.
[00340] In some embodiments, the drug moiety is a cytotoxic agent, an immunomodulating agent, an imaging agent, a chemotherapeutic agent, or a therapeutic protein.
[00341] In some embodiments, the drug moiety is a small molecule having a molecular weight preferably less than about 5 kDa, more preferably less than about 4 kDa, more preferably less than about 3 kDa, most preferably less than about 1.5 kDa or less than about 1 kDa.
[00342] In some embodiments, the drug moiety has an ICso of about less than about 1 nM.
[00343] In some embodiments, the drug moiety has an ICso of about greater than 1 nM, for example, the therapeutic agent has an ICso of about 1 to about 50 nM.
[00344] Some drug moieties having an ICso of greater than about 1 nM (e.g., “less potent drugs”) are unsuitable for conjugation with an antibody using art-recognized conjugation techniques. Without wishing to be bound by theory, such drug moieties have a potency that is insufficient for use in targeted antibody-drug conjugates using conventional techniques as sufficient copies of the drug (i.e., more than 8) cannot be conjugated using art-recognized techniques without resulting in diminished pharmacokinetic and physiochemical properties of the conjugate. However sufficiently high loadings of these less potent drugs can be achieved using the conjugation strategies described herein thereby resulting in high loadings of the therapeutic agent while maintaining the desirable pharmacokinetic and physiochemical properties. Thus, in some embodiments, the disclosure also relates to an antibody-drug conjugate which includes an antibody, a linker, and at least eight drug moieties moieties, wherein the therapeutic agent has an ICso of greater than about 1 nM.
[00345] In some embodiments, the small molecule therapeutic agents used in this disclosure (e.g., antiproliferative (cytotoxic and cytostatic) agents capable of being linked to a targeting moiety via the linker(s) of the disclosure) include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, ceil cycle progression inhibitors, PI3K/m-TOR/AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperones inhibitors, HDAC inhibitors, PARP inhibitors, nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, Wnt Hedgehog signaling pathway inhibitors and RNA polymerase inhibitors.
[00346] Broad spectrum cytotoxins include, but are not limited to, DNA-binding, intercalating or alkylating drugs, microtubule stabilizing and destabilizing agents, platinum compounds, topoisomerase inhibitors (including topoisomerase I and topoisomerase II inhibitors) and protein synthesis inhibitors.
[00347] In some embodiments, the drug moiety comprises one or more cGAS/stimulator of interferon genes (STING) pathway agonists. Non-limiting examples of STING agonists include DMXAA, ADUS100/MIW815, MK-1454, MK-2118, SB11285, GSK3745417, BMS- 986301, BI-STING (BI 1387446), E7766, TAK-676, SNX281, SYNB1891. Additional nonlimiting examples of STING agonists and combinations with other cytotoxic agents and/or ENPP1 inhibitors can be found in Amouzegar et al., Cancers 13: 2695 (2021), which is incorporated herein by reference in its entirety.
[00348] Exemplary DNA-binding, intercalation or alkylating drugs include, but are not limited to, CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin, nemorubicin and its derivatives, PNU- 159682), bisnapththalimide compounds such as elinafide (LU79553).and its analogs, alkylating agents, such as calicheamicins, dactinomycins, mitomycins, pyrrolobenzodiazepines, indolinobenzodiazepines and the like. Exemplary CC-1065 analogs include, but are not limited to, duocarmycin SA, duocarmycin A, duocarmycin CI , duocarmycin C2, duocarmycin B 1, duocarmycin B2, duocarmvcin D, DU- 86, KW-2189. adozeiesin, bizelesin, carzeiesin. seco-adozelesin, and related analogs and prodrug forms, examples of which are described in U.S. Patent Nos. 5,475,092; 5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316. Doxorubicin and its analogs include those described in U.S. Patent No. 6,630,579. Calicheamicins include, e.g., enediynes, e.g., esperamicin, and those described in U.S. Patent Nos. 5,714,586 and 5,739, 116. Duocarmycins include those described in U.S. Patent Nos. 5,070,092; 5, 101,038; 5, 187, 186; 6,548,530; 6,660,742; and 7,553,816 B2; and Li et al., Tel Letts., 50:2932 - 2935 (2009).
[00349] Exemplary topoisomerase inhibitors (e.g. topoisomerase I and/or topoisomerase II) include, but are not limited to, camptothecin, camptothecin derivatives, camptothecin analogs and non-natural camptothecins, such as, for example, exatecan, Dxd, Sn-38 (7-ethyl-10- hydroxy-camptothecin), CPT-1 1 (irinotecan), GI-147211C, topotecan, 9-aminocamptothecin, 7-hydroxymethyl camptothecin, 7-aminomethyl camptothecin, 10-hydroxy camptothecin, (20S)-camptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, diflomotecan, belotecan, lurtotecan and S39625, and any analogues thereof. Non-limiting examples of other topoisomerase inhibitors (e.g. topoisomerase I and/or topoisomerase II) that can be used in the present disclosure include those described in WO 2020/00880 and WO 2021/148501. Nonlimiting examples of other camptothecin compounds that can be used in the present disclosure include those described in J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23 :554 (1980); J. Med. Chem,, 30: 1774 (1987). In some embodiments, the drug moiety is exatecan and/or an analogue thereof. In some embodiments, the drug moiety is Dxd and/or an analogue thereof.
[00350] Non-limiting examples of pyrrolobenzodiazepines (PBD) and analogs thereof include, but are not limited to, those described in Denny, Exp. Opin. Ther. Patents., 10(4):459- 474 (2000), Antonow and Thurston, Chem Rev., 2815-2864 (2010), Min et al., ACS Omega 5:25798-25809 (2020), and Hartley Exp. Opin. Biol. Therapy 7:931-943 (2020).
[00351] Exemplary microtubule stabilizing and destabilizing agents include, but are not limited to, taxane compounds, such as paclitaxel, docetaxel, tesetaxel and carbazitaxel; maytansinoids, auristatins and analogs thereof, vinca alkaloid derivatives, epothilones and cryptophycins.
[00352] Exemplary maytansinoids or maytansinoid analogs include, but are not limited to maytansinoi and maytansinol analogs, maytansine or DM-i and DM-4 are those described in U.S. Patent Nos. 5,208,020; 5,416,064; 6,333.410, 6,441, 163; 6,716,821; RE39, 151 and 7,276,497. In certain embodiments, the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. 52: 127-131), maytansinoids or maytansinoid analogs. Examples of suitable maytansinoids include, but are not limited to, maytansinol and maytansinol analogs. Non-limiting examples of suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866, 4,450,254; 4,322,348; 4,371 ,533, 6,333,410; 5,475,092; 5,585,499; and 5,846,545.
[00353] Exemplary auristatins include, but are not limited to, auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F, auristatin F phenylenediamine (AFP), auristatin F hydroxylpropylamide (AF FTP A), monomethyl auristatin F hydroxylpropylamide (MMAF HP A), and dolastatin. Non-limiting examples of suitable auristatins are also described in U.S. Publication Nos. 2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/ 117531 , WO 2005/08171 1 , WO 04/010957; WO 02/088172 and WO 01/24763, and U.S. Patent Nos. 7,498,298; 6,884,869; 6,323,315; 6,239,104; 6,124,431; 6,034,065; 5,780,588; 5,767,237, 5,665,860; 5,663,149; 5,635,483, 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, the disclosures of each of which are incorporated herein by reference in their entirety. In some embodiments, the drug moiety is monomethyl auristatin E (MMAE) and/or an analogue thereof.
[00354] Exemplary vinca alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, and navelbine (vinorelbine). Suitable Vinca alkaloids that can be used in the present disclosure are also disclosed in U.S. Publication Nos. 2002/0103136 and 2010/0305149, and in U.S. Patent No. 7,303,749, the disclosures of each of which are incorporated herein by reference in their entirety.
[00355] Exemplary epothilone compounds include, but are not limited to, epothilone A, B, C, D, E and F, and derivatives thereof. Suitable epothilone compounds and derivatives thereof are described, for example, in U.S. Patent Nos, 6,956,036; 6,989,450, 6,121,029; 6,117,659; 6,096,757, 6,043,372; 5,969,145; and 5,886,026; and WO 97/19086; WO 98/08849; WO 98/22461; WO 98/25929; WO 98/38192, WO 99/01124; WO 99/02514; WO 99/03848; WO 99/07692; WO 99/27890; and WO 99/28324; the disclosures of all of which are incorporated herein by reference in their entireties.
[00356] Non-limiting examples of cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021, the disclosures of each of which are incorporated herein by reference in their entireties.
[00357] Exemplary platinum compounds include, but are not limited to, cisplatin (PLATINOL®), carboplatin (PARAPLAT !N®), oxaliplatin (ELOXAT1NE®), iproplatin, ormaplatin, and tetraplatin,
[00358] Non-limiting examples of other classes of compounds or compounds with these or other cytotoxic modes of action may be selected, including, e.g., mitomycin C, mitomycin A, daunorubicin, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, aminopterin, bleomycin, l-(chloromethyl)-2, 3 -dihydro- lH-benzo[e]indol-5-ol, pyrridinobenzodiazepines (PDD), pyrrolobenzodiazepine (PBD) and polyamide and dimers thereof. Non-limiting examples of other suitable cytotoxic agents include puromycins, topotecan, rhizoxin, echinomycin, combretastatin, netropsin, estramustine, cryptophysins, cemadotin, discodermolide, eleutherobin, and mitoxantrone.
[00359] Angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors, VEGF inhibitors, PIGF inhibitors, VGFR inhibitors, PDGFR inhibitors, MetAP2 inhibitors. Exemplary VGFR and PDGFR inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent) and vatalanib. Exemplary MetAP2 inhibitors include fumagillol analogs, meaning any compound that includes the fumagillin core structure, including fumagiilamine, that inhibits the ability of MetAP-2 to remove NtU-tcrminal methionines from proteins as described in Rodeschini et al., J. Org. Chem., 69, 357-373, 2004 and Liu, et al., Science 282, 1324-1327, 1998, Non limiting examples of “fumagillol analogs” are disclosed in J Org. Chem. , 69, 357, 2004; J. Org. Chem., 70, 6870, 2005; European Patent Application 0 354 787; J. Med. Chem., 49, 5645, 2006; Bioorg. Med. Chem., 1 1, 5051, 2003; Bioorg. Med. Chem., 14, 91, 2004; Tel Lett 40, 4797, 1999; WO 99/61432; U.S. Patent Nos. 6,603,812; 5,789,405; 5,767,293; 6,566,541; and 6,207,704.
[00360] Exemplary ceil cycle progression inhibitors include, but are not limited to, CDK inhibitors such as BMS-387032 and PD0332991; Rho-kinase inhibitors such as GSK429286; checkpoint kinase inhibitors such as AZD7762; aurora kinase inhibitors such as AZDI 152, MLN8054 and MLN8237; PLK inhibitors such as BI 2536, BI6727 (Volasertib), GSK461364, ON-01910 (Estybon); and KSP inhibitors such as SB 743921, SB 715992 (ispinesib), MK- 0731, AZD8477, AZ3146 and ARRY-520.
[00361] Exemplary PBK/m-TOR/AKT signaling pathway inhibitors include, but are not limited to, phosphoinositide 3 -kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors and PDK-1 inhibitors.
[00362] Non-limiting examples of exemplary PI3 kinase inhibitors are disclosed in U.S. Patent No. 6,608,053, and include BEZ235, BGT226, BKM120, CAL 101 , CAL263, demethoxyviridin, GDC-0941, GSK615, IC871 14, LY294002, Pafomid 529, perifosine, PI- 103, PF-04691502, PX-866, SAR245408, SAR245409, SF 1 126, Wortmannin, XL 147 and XL765.
[00363] Exemplary AKT inhibitors include, but are not limited to, AT7867.
[00364] Exemplary MAPK signaling pathway inhibitors include, but are not limited to, MEK, Ras, JNK, B-Raf and p38 MAPK inhibitors,
[00365] Non-limiting exemplary MEK inhibitors are disclosed in U.S. Patent No. 7,517,994, and include GDC-0973, GSK1120212, MSC1936369B, AS703026, R05126766 and R04987655, PD0325901, AZD6244, AZD 8330 and GDC-0973.
[00366] Exemplary B-raf inhibitors include, but are not limited to, CDC-0879, PLX-4032, and SB590885.
[00367] Exemplary p38 MAPK inhibitors include, but are not limited to, BIRB 796, LY2228820 and SB 202190. [00368] Receptor tyrosine kinases (RTK) are cell surface receptors which are often associated with signaling pathways stimulating uncontrolled proliferation of cancer cells and neoangiogenesis. Many RTKs, which over express or have mutations leading to constitutive activation of the receptor, have been identified, including, but not limited to, VEGFR, EGFR, FGFR, PDGFR, EphR and RET receptor family receptors. Exemplary specific RTK targets include, but not limited to, ErbB2, FLT-3, c-Kit, and c-Met.
[00369] Exemplary inhibitors of ErbB2 receptor (EGFR family) include, but are not limited to, AEE788 (NVP-AEE 788), BIBW2992, (Afatinib), Lapatinib, Erlotinib (Tarceva), and Gefitinib (Iressa).
[00370] Exemplary RTK inhibitors targeting more than one signaling pathway (multitargeted kinase inhibitors) include, but are not limited to, AP24534 (Ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR and Bcr-Abl receptors; ABT-869 (Linifanib) that targets FLT-3 and VEGFR- PDGFR receptors: AZD2171 that targets VEGFR-PDGFR, Fit- 1 and VEGF receptors; CHR-258 (Dovitinib) that targets VEGFR-PDGFR, FGFR, Flt-3, and c- Kit receptors; Sunitinib (Sutent) that targets VEGFR, PDGFR, KIT, FLT-3 and CSF-IR; Sorafenib (Nexavar) and Vatalanib that target VEGFR, PDGFR as well as intracellular serine/threonine kinases in the Rat/Mck/Erk pathway.
[00371] Exemplary protein chaperon inhibitors include, but are not limited to, HSP90 inhibitors.
[00372] Exemplary HSP90 inhibitors include, but are not limited to, 17AAG derivatives, BIIB021, BIIB028, S X-5422, NVP-AUY-922 and KW-2478.
[00373] Exemplary WD AC inhibitors include, but are not limited to, Belinostat (PXD101), CUDC-101, Droxinostat, ITF2357 (Givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP- LAQ824, Dacinostat), LBH-589 (Panobinostat), MC I 568, MGCD0103 (Mocetinostat), M S -275 (Entinostat), PCI-24781, Pyroxamide (NSC 696085), SB939, Trichostatin A and Vorinostat (SAHA).
[00374] Exemplary PARP inhibitors include, but are not limited to, iniparib (BSI 201), olaparib (AZD-2281), ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281 ), LT-673, 3- aminobenzamide, A-966492, and AZD2461.
[00375] Exemplary NAMPT inhibitors include, but are not limited to, FK866 (AP0866) and
CHS828, GPP 78, GMX1778 (CHS828), STF-1 18804, STF-31, CB 300919, CB 30865, GNE- 617, IS001, TP201565, Nampt-IN-1, P7C3, MPC-9528, CB30865, MPI0479883 and (£)-N-(5- ((4-(((2-(l-H-Indol-3-yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3- yl)acrylamide. [00376] Exemplary Wnt/Hedgehog signaling pathway inhibitors include, but are not limited to, vismodegib (RG3616/GDC-0449), cyclopamine (11-deoxojervine) (Hedgehog pathway inhibitors) and XAV-939 (Wnt pathway inhibitor).
[00377] Exemplary RNA polymerase inhibitors include, but are not limited to, amatoxins. Exemplary amatoxins include a-amanitins, P-amanitins, y-amanitins, e-amanitins, amanuilin, amanullic acid, amaninamide, amanin, and proamanullin.
[00378] Exemplary protein synthesis inhibitors include, but are not limited to, trichothecene compounds.
[00379] In some embodiments, the drug moiety is a topoisomerase inhibitor (such as, for example, a non-natural camptothecin compound), vinca alkaloid, kinase inhibitor (e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)), MEK inhibitor, KSP inhibitor, RNA polymerase inhibitor, protein synthesis inhibitor, PARP inhibitor, NAMPT inhibitor, docetaxel, paclitaxel , doxorubicin, duocarmycin, auristatin, dolastatin, calicheamicins, topotecan, SN38, camptothecin, exatecan, nemorubicin and its derivatives, PNU- 1.59682, CC1065, elinafide, trichothecene, pyrrolobenzodiazepines, maytansinoids, DNA-binding drugs or a platinum compound, and analogs thereof. In some embodiments, the drug is a derivative of Sn-38, camptothecin, topotecan, exatecan, calicheamicin, nemorubicin, PNU-159682, anthracycline, maytansinoid, taxane, tnchothecene, CC1065, elinafide, vindesine, vinblastine, PI-103, AZD 8330, dolastatin, auristatin E, auristatin F, a duocarmycin compound, ispinesib, pyrrolobenzodiazepine, ARRY- 520 and stereoisomers, isosteres and analogs thereof.
[00380] In some embodiments, the drug moiety D is a topoisomerase inhibitor having a structure of the formula:
[00381] In some embodiments, the drug moiety used in the disclosure is a combination of two or more drugs, such as, for example, PI3 kinase inhibitors and MEK inhibitors, broad spectrum cytotoxic compounds and platinum compounds; PARI3 inhibitors, NAMPT inhibitors and platinum compounds, broad spectrum cytotoxic compounds and PARP inhibitors.
[00382] In some embodiments, the drug moiety used in the disclosure is auristatin F- hydroxypropylamide-L-alanine. Linker
[00383] In one aspect, a drug moiety, may be linked, either directly or indirectly, to an antibody or antibody-binding fragment to provide a targeted conjugate. In some embodiments, an antibody drug conjugate (ADC) of the disclosure (e.g. an ADC of formula (I)), contains a linker group, wherein the antibody or antibody -binding fragment is attached to the drug moiety through the linker group. In some embodiments, a compound of the disclosure (e.g. formula (III) or salts, solvates, tautomers, isomers or mixtures thereof), contains a linker group, wherein the antibody or antibody-binding fragment is attached to the drug moiety through the linker group. In some embodiments, the linker is a single bond. In a non-limiting example, when the linker is a single bond, the drug moiety is directly attached to an antibody or antibody-binding fragment. In some embodiments, a variety of target conjugates are known in the art and can be used with a compound of formula (III) and salts or solvates thereof. In a non-limiting example the target conjugate is an antibody-drug conjugate, wherein one or more compounds of formula (III) are linked to the antibody. In embodiments, the antibody drug conjugates of the present disclosure contain one or multiple compounds of formula (III) or salts, solvates, tautomers, isomers or mixtures thereof.
[00384] Any linker suitable for attaching a drug moiety to an antibody or antibody-binding fragment is contemplated by the present disclosure, as would be understood by one of ordinary skill in the art.
[00385] In some embodiments, the linker is a bond or is a moiety having 1 -200 nonhydrogen atoms selected from C, N, O, S, or halogen, and optionally incorporates alkyl, ether, oxo, carboxyl, carboxamide, carboxamidyl, ester, urethanyl, branched, cyclic, unsaturated, amino acid, heterocyclyl, aryl or heteroaryl moieties. In embodiments, the linker is unbranched or branched, flexible or rigid, short or long and optionally incorporates any combination of moieties as deemed useful. In some embodiments, at least a portion of the linker has a polyalkylene oxide polymeric region. In a non-limiting example, polyalkylene oxide polymeric region are capable of enhancing solubility of the drug moiety. In some embodiments, the linker has a repeating unit of ethylene glycol.
[00386] In some embodiments, the linker has a number of repeating ethylene glycol units ranging from about 1 to about 25, or any number therebetween. In some embodiments, the linker includes about 3 to about 20, about 3 to about 5, about 4 to about 15, about 4 to about 8, about 4 to about 6, about 5 to about 12, about 6 to about 10, or about 7 to about 9 ethylene glycol units. In some embodiments, the linker includes about 8 ethylene glycol units.
[00387] In some embodiments, at least a portion of the linker includes one or more amino acid moieties. In a non-limiting example, one or more amino acid moieties provides enhanced solubility for the drug moiety and/or provides amino acid sequences to enhance target binding, enhance compatibility with an antibody or binding fragment thereof, and/or enhance target binding recognition. In some embodiments, the linker includes one or more amino acid moieties that provide a suitable substrate motif for a protease. In a non-limiting example, when a set of amino acid moieties are incorporated into the linker that provide a substrate motif specific for a selected protease, the drug moiety may be released from a target bound conjugate to provide localized cytotoxic effects.
[00388] In some embodiments, the linker includes an alkylene chain. In some embodiments, the alkylene chain is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11 or 12 carbons in length; and suitably the alkylene chain comprises -CH2- groups. In some embodiments, these substrate motifs are known in the art and are incorporated into the linker as desired to provide selective release from the target bound conjugate. In a non-limiting example, this selectivity is based on known presence of a desired protease within the localized delivery region of the conjugate drug. In some embodiments, other polymeric types of moieties may be incorporated in the linker, including but not limited to polyacids, polysaccharides, or polyamines. In some embodiments, other moieties such as substituted aromatic or heteroaromatic moieties are used to enhance rigidity or provide synthetically accessible sites on substituents therein for linking to reactive moieties or to the drug moiety.
[00389] In a non-limiting example, the linker includes ethylene glycol repeating units, and/or an amino acid sequence.
[00390] In some embodiments, the linker comprises or consists of the formula: -[CH2CH2O]P-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00391] In some embodiments, the linker comprises or consists of the formula: -[CH2CH2O]P-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00392] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)I-5-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00393] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)I.5-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50, wherein XAA is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8. In some embodiments, -(CH2)I-S- is -(CH2)I-3-.
[00394] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)I.3-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00395] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)I-3-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50, wherein XAA is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00396] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)2-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00397] In some embodiments, the linker (e.g. LA) comprises or consists of the formula: -[CH2CH2O]P-(CH2)2-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50, wherein XAA is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.
[00398] In some embodiments, a suitable number of ethylene glycol units can be used in the linker. In some embodiments, the linker includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 19, 20, 23, 24, 35, 36, 37, 48, 49, or more ethylene glycol units. In some embodiments, the linker includes 1 to 10, 4 to 10, 6 to 10, or 7 to 9 ethylene glycol units. In some embodiments, the linker includes 8 ethylene glycol units. Non-limiting examples of commercially available ethylene glycol groups (polyethylene glycol, PEG) suitable in the linker include EEN-PEGs- C(O)OH, having a discrete (“d”) polyethylene glycol having 8 ethylene glycol repeating units. Non-limiting examples of other discrete PEG units are commercially available and known to one of skill in the art, such as by Advanced ChemTech. In some embodiments, the linker comprises the formula:
-HN-PEG-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00399] In some embodiments, the linker comprises the formula:
-HN-PEG-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00400] In some embodiments, the linker comprises the formula:
-HN-PEG-(CH2)I-5-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units. In some embodiments, p is 8.
[00401] In some embodiments, the linker comprises the formula: -HN-PEG-(CH2)I-5-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00402] In some embodiments, the linker comprises the formula: -HN-PEG-(CH2)I-3-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units. In some embodiments, p is 8.
[00403] In some embodiments, the linker comprises the formula: -HN-PEG-(CH2)I-3-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00404] In some embodiments, the linker comprises the formula: -HN-PEG-(CH2)2-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00405] In some embodiments, the linker comprises the formula:
-HN-PEG-(CH2)2-C(O)-XAA- wherein PEG has 1-50 ethylene glycol units, and XAA is an amino acid sequence, with the proviso that XAA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1-10 ethylene glycol units, about 4-10 ethylene glycol units, or about 7-9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.
[00406] In another non-limiting example, the linker includes an alkylene chain, and/or an amino acid sequence. In some embodiments, the linker comprises the formula:
-[CH2]O-I2-XAA- wherein XAA is an amino acid sequence; and the linker include 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-CH2- units.
[00407] In another non-limiting example, the linker includes an alkylene chain, and/or an amino acid sequence. In some embodiments, the linker comprises the formula:
-[CH2]O-I2-XAA- wherein XAA is an amino acid sequence; and the linker include 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-CH2- units, with the proviso that XAA is not Val-Cit or Phe-Lys.
[00408] In some embodiments, the linker comprises the formula:
-[CH2]O-12-XAA- wherein XAA is an amino acid sequence; and the linker include 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-CH2- units, with the proviso that XAA is not Val-Cit or Phe-Lys.
[00409] In some embodiments, the linker comprises the formula:
-HN-PEG8-C(O)-Val-Ala- wherein PEGs has 8 ethylene glycol units.
[00410] In some embodiments, the linker comprises the formula:
-HN-PEG8-(CH2)i-5-C(O)-Val-Ala- wherein PEGs has 8 ethylene glycol units.
[00411] In some embodiments, the linker comprises the formula:
-HN-PEG8-(CH2)i-3-C(O)-Val-Ala- wherein PEGs has 8 ethylene glycol units.
[00412] In some embodiments, the linker comprises the formula:
-HN-PEG8-(CH2)2-C(O)-Val-Ala- wherein PEGs has 8 ethylene glycol units.
[00413] In some embodiments, the linker also includes a variety of other connecting groups that connect the ethylene glycol portion to the amino acid sequence, or connect the ethylene glycol or amino acid sequence to an antibody or antibody-binding fragment, or the drug moiety. For example, the amino acid sequence can be connected to the drug moiety via a 4- amino benzyl carboxylate group. In some embodiments, the ethylene glycol portion ca be directly linked to an antibody or antibody-binding fragment. In some embodiments, the linker comprises or consists of the formula:
In some embodiments, the HN group is directly linked to an antibody or antibody-binding fragment.
[00414] In embodiments, the linker is or comprises:
wherein XAA is an amino acid sequence; and K2 is -[CfbChhOJo-so- or -[CH2]o-i2-. In some embodiments, the linker is attached to an antibody or antibody -binding fragment and the drug moiety in either direction. In some embodiments, the linker is (i), (ii), (iii), (iv), (vi), (viii) or (ix).
[00415] In embodiments, the linker is or comprises: wherein XAA is an amino acid sequence; and K2 is -[CH2CH20]o-so-[CH2]o-i2-C(0)-. In some embodiments, the linker is attached to an antibody or antibody -binding fragment and the drug moiety in either direction. In some embodiments, the linker is (i), (ii), (iii), (iv), (vi), (viii) or (ix).
[00416] In some embodiments, the linker is or comprises:
In some embodiments, the linker further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 19, 20, 23, 24, 35, 36, 37, 48, 49 or 50 ethylene glycol units. In some embodiments, the linker comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 -CH2- units. In some embodiments, the HN group is directly linked to an antibody or antibody-binding fragment.
[00417] In some embodiments, the linker comprises an amino acid portion which includes any suitable number of amino acid moieties, as described above. In a non-limiting example, the amino acid sequence XAA includes from 1 to 100 amino acid moieties, or from 1 to 10 amino acid moieties, or from 1 to 5 amino acid moieties, or from 2 to 5 amino acid moieties, or from 2 to 4 amino acid moieties.. In some embodiments, the linker includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid moieties. In some embodiments, the linker includes 2 amino acid moieties. In some embodiments, the linker includes 3 amino acid moieties. In some embodiments, the linker includes 4 amino acid moieties. In some embodiments, XAA is valinealanine. In some embodiments, XAA is alanine-alanine-alanine. In some embodiments, XAA is glycine-glycine-phenylalanine-glycine.
[00418] In some embodiments, XAA is an amino acid sequence having 2 amino acid moieties. In some embodiments, XAA is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met. Amino acid moieties disclosed herein are L-amino acids unless otherwise designated as a D-amino acid (e.g. D-Ala is D- alanine).
[00419] In some embodiments, XAA is an amino acid sequence having 3 amino acid moieties. In some embodiments, XAA is selected from alanine-alanine-alanine, glutamic acid- valine-citrulline, and valine-lysine-glycine.
[00420] In some embodiments, XAA is an amino acid sequence having 4 amino acid moieties. In some embodiments, XAA is selected from glycine-glycine-phenylalanine-glycine, glutamic acid-aspartic acid-phenylalanine-tryptophan, glycine-phenylalanine-leucine-glycine, and alanine-leucine-alanine-leucine.
[00421] In some embodiments, the amino acid sequence XAA is:
[00422] In some embodiments, the amino acid sequence XAA is:
[00423] In some embodiments, the linker comprises one or more groups selected from Ci- Ce alkyl, C=O, -NH-, ethylene glycol, optionally 2-10 ethylene glycol units, valine-citrulline (val-cit), 6-maleimidocaproyl (me), 6-succinimidylcaproyl, 6-(2,5-dioxo-3/?-pyrrolidin-l - yl)caproyl, methoxy-polyethylene glycol maleimide 6 (MalPeg6), p-aminobenzylcarbamate (PABC), dimethylaminoethanol (DMAE), 3-maleimidopropanoyl (MP), 3- succinimidylpropanoyl, 3-(2,5-dioxo-3/?-pyrrolidin-l -yl)propanoyl, hydrolyzed Peg- maleimides, hydrolyzed maleimide, hydrolyzed succinimide, valine-alanine (Vai-Ala), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2- pyridylthio) pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1 carboxylate (SMCC), N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SLAB), 6- maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-val-cit-PAB), and 6- maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate (mc-val-cit-PABC), an amino acid, optionally (D)-valine, (L)-valine, (D)-alanine, and/or (L)-alanine, and maleimide.
[00424] In some embodiments, the linker comprises one or more of Ci-Ce alkyl, C=O, -NH- , polyethylene glycol (PEG), optionally 2-10 PEG groups, an amino acid, optionally (D)-valine, (L)-valine, (D)-alanine, and/or (L)-alanine, and maleimide, succinimide, or 2,5-dioxo-3k3- pyrrolidin-l-yl. In some embodiments, the linker comprises or consists of valine-citrulline (val- cit). In some embodiments, the linker comprises or consists of valine-citrulline (val-cit)- p- aminobenzyloxycarbonyl (PAB).
[00425] In some embodiments, the linker comprises one or more reactive moieties capable of reacting with an antibody or an antibody fragment thereof. Non-limiting examples of reactive moieties include an azide, alkyne, bisulfone, carbohydrazide, hydrazine, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, pyrridopyridazine, semihydrazide, succinimidyl ester, sulfodichlorophenol ester, sulfonyl halide, sulfosuccinimidyl ester, 4-sulfotetrafluorophenyl ester, tetrafluorophenyl ester, thiazole, NHNH2, hydroxylamine (aminooxy), cyclooctyne (e.g. dibenzocyclooctyne (DBCO)), and alkynyl phosphorous group [00426] In some embodiments, the linker comprises R*, where R* is a reactive moiety capable of reacting with an antibody or fragment thereof. In some embodiments, the linker comprises or consists of the following formula:
R*-L wherein R* is a reactive moiety, a linking moiety, or an antibody or fragment thereof.
[00427] In some embodiments, R* is a reactive moiety, and capable of reacting with functional groups such as aldehydes, amines, disulfides, ketones, thiols in the antibody or fragment thereof, or in Staudinger reactions, Pictet-Spengler reactions and/or Click-type chemistry with the antibody or fragment thereof. For some reactive moieties suitable coupling reagents are used to react the reactive moiety with an antibody or fragment thereof, e.g. where R* is a carboxylic acid, carbodiimide coupling reagents maybe used. In some embodiments, R* is selected from an azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester, sulfonyl halide, hydroxylamine (aminooxy), cyclooctyne (e.g. dibenzocyclooctyne (DBCO)), an alkynyl phosphorous group, and an alkenyl phosphorous group
[00428] In some embodiments, R* is or comprises maleimide:
[00429] In some embodiments, R* is or comprises bisulfone. In some embodiments, the bisulfone is or comprises . In some embodiments, the bisulfone is or comprises
[00430] In some embodiments, R* is or comprises a cyclooctyne. In some embodiments, the cyclooctyne is a dibenzocyclooctyne (DBCO) and derivatives thereof. In some embodiments, the cyclooctene is fused to one or more additional rings, including but not limited to cycloalkyl rings and/or heterocycloalkyl rings. In a non-limiting example, the cyclooctyne undergoes a cycloaddition reaction (e.g. click chemistry) with another group to form a heterocycle. In some embodiments, the cyclooctyne undergoes a cycloaddition reaction with a nitrone to form a triazole. In some embodiments, the cyclooctyne undergoes a cycloaddition reaction with an azide to form an isoxazolidine. Non-limiting examples of , y g g . also U.S. 2015/0320882, U.S. 2023/0102685, U.S. 2016/0107999, U.S. 2017/0008858, U.S.
2017/0298145, and 2023/0099074 for additional examples of cyclooctynyl groups, all of which are incorporated by reference herein in their entireties.
[00431] In some embodiments, R* is or comprises hydroxylamine (aminooxy). In a nonlimiting example, the enhanced nucleophilicity of the hydroxylamine (aminooxy) group permits it to react efficiently and selectively with a variety of molecules that contain carbonyl- or dicarbonyl-groups, including but not limited to, ketones, aldehydes or other functional groups with similar chemical reactivity, including such groups that are present on an antibody or binding fragment thereof. In some embodiment, the oxime comprises or consists of the formula , wherein L is a linker, including but not limited to any linker L groups disclosed herein. In some embodiments, L comprises or consists of a substituted or unsubstituted alkyl group. In some embodiments, the formula has the structure
H2N^(CH2)n-4
° ’ , and n is an integer from 1 to 10. In some embodiments, n is an integer from
1 to 5, or 3 to 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments,
L comprises or consists of one or more polyethyleneglycol (PEG) groups. In some H2%Ay H2N x_x(CH2CH2O)n— | embodiments, the formula ' has the structure O • , and n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 5, or 3 to 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 4. See, for example, U.S. 2023/0295320, U.S. 11773150, and U.S. 2016/0052966, all ofwhich are incorporated by reference herein in their entireties.
[00432] In some embodiments, R* is or comprises an alkynyl phosphorous group. In some embodiments, the alkynyl phosphorous group has the formula , wherein R is an alkyl or aromatic group. In some embodiments, R is a PEG group comprising about 1 to about 10 PEG moieties. In some embodiments, R* is or comprises an alkenyl phosphorous group. In some embodiments, the alkynyl phosphorous group has the formula , wherein R is an alkyl or aromatic group. In some embodiments, R is a PEG group comprising about 1 to about 10 PEG moieties. See, for example U.S. 2023/0330258 and U.S. 2023/0158154, both ofwhich are incorporated by reference herein in their entireties.
[00433] In some embodiments, R* is or comprises an azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide.
[00434] Non-limiting examples of other chemistries are known for attachment of compounds to antibodies. U.S. 7,595,292 (Brocchini et al.) refers to linkers that form thioesters with the sulfurs in a disulfide bond of an antibody. U.S. 7,985,783 (Carico et al.) refers to the introduction of aldehyde residues into antibodies, which are used to couple compounds to the antibody.
[00435] In some embodiments, R* is an antibody or an antibody fragment. In some embodiments, the antibody or fragment thereof binds to a tumor-associated antigen, a cancer- stem-cell associated antigen or a viral antigen.
[00436] In various embodiments, the antibody or fragment thereof may bind to a target selected from an acute myeloid leukemia (AML M4) cell, an acute promyelocytic leukemia cell, an acute lymphoblastic leukemia cell, an acute lymphocytic leukemia cell, a chronic lymphocytic leukemia cell, a chronic myeloid leukemia cell, a chronic T-cell lymphocytic leukemia, a myelodysplasia syndromic cell, a multiple myeloma cell, a prostate carcinoma cell, a renal cell adenocarcinoma cell, a pancreatic adenocarcinoma cell, a lung carcinoma cell or a gastric adenocarcinoma cell, a gastric adenocarcinoma cell, a breast cancer cell, a colon cancer cell, a melanoma cell, a thyroid cancer cell, an ovarian cancer cell, a bladder cancer cell, a liver cancer cell, a head and neck cancer cell, an esophageal cancer cell, a Hodgkin lymphoma cell, a non-Hodgkin lymphoma cell, a mesothelioma cell, a neuroblastoma cell, a neuroendocrine tumor cell, a neurofibromatosis type 1 (NF1) cell, a neurofibromatosis type 2 (NF2) or an osteosarcoma cell.
[00437] In some embodiments, the reactive moiety and/or antibody or fragment thereof further comprises a linking moiety. In some embodiments, the linking moiety is attached to the reactive moiety and/or the antibody or fragment thereof and the linker to connect the reactive moiety and/or the antibody or fragment thereof to the linker. In some embodiments, the linking moiety comprises one or more groups selected from -[CH2]o-i2, -[CFbCFfcOJo-so- and -[CFbJo- 12-C(O)NH-.
[00438] In some embodiments, the linker comprises or consists of the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof. In some embodiments, the linker LA is conjugated to the drug moiety. [00439] In some embodiments, linker LA comprises or consists of the formula:
-[CH2CH2O]P-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, the linker LA further comprises
[00440] In some embodiments, linker LA comprises or consists of the formula:
-[CH2CH2O]P-(CH2)I-5-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, the linker LA further comprises
[00441] In some embodiments, linker LA comprises or consists of the formula:
-[CH2CH2O]P-(CH2)I-3-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, the linker LA further comprises
[00442] In some embodiments, linker LA comprises or consists of the formula:
-[CH2CH2O]P-(CH2)2-C(O)-XAA- wherein XAA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, the linker LA further comprises
[00443] In some embodiments, R* is a reactive moiety. In some embodiments, the reactive moiety is maleimide. In some embodiments, the reactive moiety is bisulfone.
[00444] In some embodiments, Li is comprises one or more groups selected from -[CH2]O- 12, -[CH2CH20]O-5O- and -[CH2]o i2-C(0)NH-. In some embodiments, Li is -[CH2]o-i2-C(0)NH- . In some embodiments, Li is -[CH2]2-C(O)NH-. In some embodiments, -[CH2]s-C(O)NH-.
[00445] In some embodiments, Li is -[CH2]I-3-C(O)NH-.
[00446] In some embodiments, Li further comprises a linking moiety, which is produced from the reaction of a reactive moiety and a functional group such as aldehydes, amines, disulfides, ketones thiols in the antibody or fragment thereof, or in Staudinger reactions, Pictet- Spengler reactions and/or Click-type chemistry of the antibody or fragment thereof. In some embodiments, Li further comprises a linking moiety selected from a triazole, an amide, a thioether, and a succinimide.
[00447] In some embodiments, Li further comprises succinimide (i.e., a succinimidyl moiety, “2,5-dioxo-3k3-pyrrolidin-l-yl”):
[00448] In some embodiments, Li is or comprises . In some embodiments, Li is or comprises In some embodiments, Li is or comprises some embodiments, Li is or comprises
[00449] In some embodiments, R* is a reactive moiety that has reacted with a functional group such as aldehydes, amines, disulfides, ketones thiols in an antibody or fragment thereof or in Staudinger reactions, Pictet-Spengler reactions and/or Click-type chemistry of an antibody or fragment thereof. In some embodiments, R* is selected from succinimide, a heterocycle (e.g. a triazole), an amide, a thioether, an oxime, an alkenyl phosphorous group, and an alkyl phosphorous group.
[00450] In some embodiments, L is a linker of the formula -R*-LI-LA. In a non-limiting example, R*is a reactive moiety that has reacted with a functional group of an antibody or fragment thereof. In some embodiments, R* is selected from succinimide, an oxime, a heterocycle, an amide, and a thioether, an alkenyl phosphorous group, and an alkyl phosphorous group. In some embodiments, the heterocycle is formed by a cycloaddition (e.g. click chemisty) between two or more unsaturated moieties. Non-limiting examples of heterocycles include a triazole (including but not limited to triazoles formed from cycloaddition (e.g. click chemistry) of an azide and an alkyne (such as a cyclooctenyl ring (e.g. dibenzocyclooctenyl (DBCO) ring)), and an isoxazolidine (including but not limited to isoxazolidine rings formed by a cycloaddition of a nitrone and an alkyne (such as a cyclooctenyl ring (e.g. dibenzocyclooctenyl (DBCO) ring)).
[00451] In some embodiments, R* is succinimide (z.e., a succinimidyl moiety, “2,5-dioxo- 3k3-pyrrolidin-l-yl”):
[00452] In some embodiments, R* is a heterocycle. In some embodiments, the heterocycle is formed by a cycloaddition (e.g. click chemisty) between two or more unsaturated moieties. In some embodiments, the heterocycle is fused to one or more additional rings, including but not limited to a cyclooctynyl ring. In some embodiments, R* is a triazole (triazolyl). In a nonlimiting example, the triazole (triazolyl) is formed by a cycloaddition reaction (e.g. click chemistry) between an azide and an alkyne. In some embodiments, R* is an isoxazolidine (isoxazolidinyl). In a non-limiting example the (isoxazolidine (isoxazolidinyl) is formed by a cycloaddition of a nitrone and an alkyne. In some embodiment, the alkyne is a cyclooctynyl group. Non-limiting examples of cyclooctynyl groups include dibenzocyclooctynye (DBCO) and derivatives thereof. In some embodiments, the cyclooctynyl ring is fused to one or more additional rings, including but not limited to cycloalkyl rings and/or heterocycloalkyl rings. , wherein R is hydrogen or a substituent and n is an integer from 0 to 8. See also U.S. 2015/0320882, U.S. 2023/0102685, U.S. 2016/0107999, U.S. 2017/0008858, U.S. 2017/0298145, and 2023/0099074 for additional examples of cyclooctynyl groups, all of which are incorporated by reference herein in their entireties.
[00453] In some embodiments, R* comprises an oxime group. In some embodiment, the oxime is or comprises the formula , wherein L is a linker, including but not limited to any linker L groups disclosed herein. In some embodiments, L comprises or consists of a substituted or unsubstituted alkyl group. In some embodiments, the formula V ' N\/L is yN z(CH2)n_| or comprises the formula ' , and n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 5, or 3 to 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, L comprises or consists of one or more polyethyleneglycol
(PEG) groups. In some embodiments, the formula is or comprises the formula , and n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 5, or 3 to 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 4. See, for example, U.S. 20230295320, U.S. 11773150, U.S. 20160052966, all of which are incorporated by reference herein in their entireties.
[00454] In some embodiments, R* is or comprises an alkenyl phosphorous group. In some embodiments, the alkenyl phosphorous group is or comprises the formula wherein R is an alkyl or aromatic group. In some embodiments, R is a PEG group comprising about 1 to about 10 PEG moieties. In some embodiments, R* is or comprises an alkyl phosphorous group. In some embodiments, the alkyl phosphorous group is or comprises the formula , wherein R is an alkyl or aromatic group. In some embodiments, R is a PEG group comprising about 1 to about 10 PEG moieties. See, for example U.S. 20230330258 and U.S. 20230158154, both of which are incorporated by reference herein in their entireties. [00455] In some embodiments, some embodiments,
[00456] In some embodiments, the linker comprises or consists of the formula:
[00457] In some embodiments, the linker comprises or consists of the formula:
[00458] In some embodiments, the linker comprises or consists of the formula:
[00459] In some embodiments, the linker comprises or consists of the formula:
[00460] In some embodiments, the linker comprises or consists of the formula:
[00461] In some embodiments, the linker comprises or consists of the formula:
[00462] In some embodiments, the linker comprises or consists of the formula:
[00463] In some embodiments, the linker comprises or consists of the formula:
[00464] In some embodiments, the linker comprises or consists of the formula:
[00465] In some embodiments, the linker comprises or consists of the formula: [00466] In some embodiments, the linker comprises or consists of the formula:
[00467] In some embodiments, the linker comprises or consists of the formula:
[00468] In some embodiments, the linker comprises or consists of the formula:
[00469] In some embodiments, the linker comprises or consists of the formula:
[00470] In some embodiments, the linker comprises or consists of the formula:
[00471] In some embodiments, the linker comprises or consists of the formula:
[00472] In some embodiments, the linker comprises or consists of the formula:
[00473] In some embodiments, the linker comprises or consists of the formula:
[00474] In some embodiments, the linker comprises or consists of the formula:
[00475] In some embodiments, R* is an antibody or antibody fragment.
Compounds
[00476] In one aspect, the disclosure provides compounds comprising one or more linkers and one or more drug moieties. In some embodiments, the antibody-drug conjugates of the disclosure (e.g. formula (I)) comprise a compound of formula (III).
[00477] In some embodiments, the compound is of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
[00478] In some embodiments, the linker L of formula (III) reacts with an antibody or antibody-binding fragment, including but not limited to Ab of formula (III) that has reacted with the antibody or fragment thereof to form a covalent bond with the antibody or fragment thereof. In a non-limiting example, the linker L of formula (III) comprises (a reactive group R* which reacts with the antibody or antibody fragment Ab to provide a conjugate of formula (I), wherein the linker L of formula (I) is the linker of formula (III) comprising the product of the reaction of R* with the targeting moiety (e.g. R* is a maleimide in formula (III), and is a succinimide in formula (I), and otherwise L is equivalent in each of formula (I) and formula (III)).
[00479] In some embodiments, the drug moiety D is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyrridinobenzodiazepines (PDDs).
[00480] In some embodiments, the exatecan comprises or has the formula:
[00481] In some embodiments, the PDD comprises or has the formula:
[00482] In some embodiments, the PDD comprises or has the formula:
[00483] In some embodiments, the PDD comprises or has the formula:
[00484] In some embodiments, the Sn-38 comprises or has the formula:
[00485] In some embodiments, the compound comprises or consists of the formula:
[00486] In some embodiments, the compound comprises or consists of the formula:
[00487] In some embodiments, the linker comprises or consists of the formula:
[00488] In some embodiments, the linker comprises or consists of the formula:
[00489] In some embodiments, the linker comprises or consists of the formula:
[00490] In some embodiments, the linker comprises or consists of the formula: [00491] In some embodiments, the linker comprises or consists of the formula:
[00492] In some embodiments, the linker comprises or consists of the formula:
[00493] In some embodiments, the linker comprises or consists of the formula:
[00494] In some embodiments, the linker comprises or consists of the formula:
[00495] In some embodiments, L-D has the formula:
[00496] In some embodiments, L-D has the formula:
[00497] In some embodiments, L-D has the formula:
[00498] In some embodiments, L-D has the formula:
[00499] In some embodiments, L-D has the formula:
[00501] In some embodiments, L-D has the formula: [00502] In some embodiments, L-D has the formula:
[00503] In some embodiments, L-D has the formula:
[00504] In some embodiments, L-D has the formula:
[00505] In some embodiments, the compound is of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker of the formula R*-LI-LA-;
R* is maleimide;
Li is -[CH2]I-3-C(O)NH-;
LA is -[CH2CH2O]P-(CH2)I-5-C(O)-XAA-, optionally -[CH2CH2O]P-(CH2)I.3-C(O)- XAA-, optionally -[CH2CH2O]P-(CH2)2-C(O)-XAA-, wherein p is an integer from 5 to 10, and XAA is an amino acid sequence having 2 amino acid moieties; and
[00506] In some embodiments, the compound is of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker of the formula R*-LI-LA-;
R* is maleimide;
Li is -[CH2]I-3-C(O)NH-;
LA is -[CH2CH2O]P-(CH2)I-5-C(O)-XAA-, optionally -[CH2CH2O]P-(CH2)I.3-C(O)- XAA-, optionally -[CH2CH2O]P-(CH2)2-C(O)-XAA-, wherein p is an integer from 5 to 10, and XAA is an amino acid sequence having 2 amino acid moieties; and
In some embodiments, XAA is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.
[00507] In some embodiments, XAA is Vai -Ala.
[00508] In some embodiments, the compound is of formula (III-A), or salts, solvates, tautomers, isomers or mixtures thereof: formula (III-A) wherein in formula (III-A):
Li is -[CH2]I-3-C(O)NH-; p is an integer from 6 to 20;
XAA1 and XAA2 are independently selected amino acid moieties; and
D is a topoisomerase inhibitor.
[00509] In some embodiments, formula (III-A) is has the formula -[CH2CH2O]P-(CH2)I-3. - C(O)-XAA-. In some embodiments, formula (III-A) is has the formula -[CH2CH2O]P-(CH2)2- C(O)-XAA-.
[00510] In some embodiments, XAA1 is selected from Vai, Tyr, Phe, Leu, Met, Thr, Ala, D- Val, and D-Ala. In some embodiments, XAA1 is Vai.
[00511] In some embodiments, XAA2 is selected from Ala, Arg, Gin, Cit, Met, Thr, Asn, D- Gln, and D-Ala. In some embodiments, XAA2 is Ala.
[00512] In some embodiments, -XAA’ -XAA2- is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai -Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.
[00513] In some embodiments, -XAA1 -XAA2- is Vai-Ala.
[00514] In some embodiments, the compound of formula (III) or the compound of formula (III-A) is selected from a compound of any one of formula 30 or 3031-3064, or salts, solvates, tautomers, isomers or mixtures thereof:
[00515] In some embodiments, the compound of formula (III) or the compound of formula (III- A) is selected from a compound of any one of formula 30 or 3101-3118, or salts, solvates, tautomers, isomers or mixtures thereof: formula (III)
formula (III-A)
[00516] In one embodiment (CI), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula: R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-5-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00517] In one embodiment (CI), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula: R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-3-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00518] In one embodiment (Clb), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula: R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Alk designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
[00519] In one embodiment (CII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula: R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-5-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00520] In one embodiment (Clla), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety. The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-3-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00521] In one embodiment (Cllb), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety. The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00522] In one embodiment (CIII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety. The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
[00523] In one embodiment (CIV), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula: R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is maleimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00524] In one embodiment (CV), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is maleimide
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00525] In one embodiment (CVI), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
[00526] In one embodiment (CVII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from azide, alkynes, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester and sulfonyl halide. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises °2
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
[00527] In one embodiment (CVIII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is maleimide.
Li is -[CH2]I-3-C(O)NH-. The drug moiety is selected from exatecan having the formula: , Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD).
[00528] In one embodiment (CIX), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety.
The linker has the following formula:
R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is maleimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula: Dxd, Sn-38, monomethyl auristatin E (MMAE), and a pyrridinobenzodiazepine (PDD). [00529] In one embodiment (CX), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any one of embodiments (CI) to (CX), wherein index p is 8.
[00530] In one embodiment (CXI), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any of embodiments (CI) to (CX), wherein Li is -[CH2]2-C(O)NH-.
[00531] In one embodiment (CXII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any one of embodiments (CI) to (CXI), wherein the drug moiety is selected from exatecan having the formula:
[00532] In one embodiment (XIII), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any one of embodiments (CI) to (CXII), wherein the drug moiety is selected from exatecan having the formula: [00533] In one embodiment (XIV), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any one of embodiments (CI) to (CXIII), wherein the drug moiety is exatecan having the formula:
[00534] In one embodiment (CXV), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) as defined in any one of embodiments (CI) to (CXIV), wherein XAA is not Val-Cit or Phe-Lys. [00535] In one embodiment (CXVI), the disclosure provides a compound of formula (III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein the moiety L-D has the following structure [00536] In one aspect, the disclosure provides a conjugate of formula (II):
Ab-L- formula (II) wherein Ab is an antibody or antibody fragment specifically binding any one of the targets disclosed in Tables 1, 2, 3, or 4, and L is a linker.
[00537] Any antibody, antibody fragment, and/or linker disclosed herein is contemplated within formula (II). In some embodiments, the linker comprises or consists of a partial structure, which is further conjugated to a drug moiety. In some embodiments, the linker comprises or consists of a complete structure, which can be further conjugated to a drug moiety. [00538] In some embodiments, the linker comprises or consists of the formula:
[00540] In some embodiments, the linker has the formula:
[00541] In some embodiments, the linker comprises or consists of the formula:
[00542] In some embodiments, the linker comprises or consists of the formula:
[00543] In some embodiments, the linker comprises or consists of the formula:
[00544] In some embodiments, the linker comprises or consists of the formula:
[00545] In some embodiments, the linker comprises or consists of the formula:
[00546] In some embodiments, the linker comprises or consists of the formula:
[00547] In some embodiments, the linker comprises or consists of the formula:
[00548] In some embodiments, the linker comprises or consists of the formula:
[00549] In some embodiments, the linker comprises or consists of the formula:
[00550] In some embodiments, the linker comprises or consists of the formula:
[00551] In some embodiments, the antibody or binding fragment thereof specifically binds one or more antigens disclosed in any one of Tables 1, 2, 3, or 4.
[00552] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, (b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, and
(c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions, wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of any one of amino acid sequence of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of any one of amino acid sequence of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789, wherein the VH comprises or consists of amino acid sequence of SEQ ID NO: 229 and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and (c) a VL complementarity determining region three (LCDR3) comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792, wherein the VL comprises or consists of amino acid sequence of SEQ ID NO: 622.
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein the VH comprises or consists of amino acid sequence of SEQ ID NO: 229 and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the VL comprises or consists of amino acid sequence of SEQ ID NO: 622.
[00553] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002- 1050 and/or comprises a VL that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 394-786 or 1051-1085.
[00554] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002-1050 and/or comprises a light chain that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 394-786 or 1051-1085.
[00555] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002- 1050 and/or comprises a VL that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1051-1085.
[00556] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises any one of amino acid sequence of SEQ ID NOs: 1-393 or 1002-1050 and/or comprises a light chain that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 1051-1085.
[00557] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 229-236 and/or comprises a VL that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 622-629.
[00558] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises any one of amino acid sequence of SEQ ID NOs: 229-236 and/or comprises a light chain that comprises or consists of any one of amino acid sequence of SEQ ID NOs: 622-629.
[00559] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of amino acid sequence of SEQ ID NO: 229 and/or comprises a VL that comprises or consists of amino acid sequence of SEQ ID NO: 622.
[00560] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises amino acid sequence of SEQ ID NO: 229 and/or comprises a light chain that comprises or consists of amino acid sequence of SEQ ID NOs: 622.
Antibody-drug conjugates
[00561] In one aspect, the disclosure provides an antibody-drug conjugate comprising one or more linkers and one or more drug moieties. In some embodiments, the antibody-drug conjugate comprises an antibody, antibody fragment, a linker and/or drug moiety described herein (e.g. formula (II) and/or formula (III)). In some embodiments, the antibody and/or antibody fragment is conjugated to a linker-drug moiety via a sulfur-containing moiety (e.g. thiol) on the antibody and/or antibody fragment. In some embodiments, the sulfur containing moiety comprises or consists of a sulfur moiety of one or more interchain disulfide bridges of the antibody and/or antibody fragment. In a non-limiting example, the interchain disulfide bridges holding the arms of the antibody (e.g. mAb) and/or antibody fragment together are broken using a reducing agent, and the linker and/or payload is conjugated to a sulfur moiety of the disulfide bridge. In a non-limiting example, all available thiols from interchain disulfides are occupied for a loading (DAR) of 8, due to the presence of 4 interchain disulfides in an antibody (e.g. mAb). In some embodiments, the antibody and/or antibody fragment is conjugated to a linker-drug moiety via one or more amino acid residues on the antibody and/or antibody fragment, including but not limited to amino acid residues comprising sulfur- containing side chains, (e.g. cysteine and/or methionine). In some embodiments, the antibody and/or antibody fragment is conjugated to a linker-drug moiety via one or more cysteine residues on the antibody and/or antibody fragment. In some embodiments, the antibody and/or antibody fragment is conjugated to a linker-drug moiety via one or more cysteine residues on the antibody. In some embodiments, the amino acid residue is non-engineered (e.g. a non- engineered cysteine and/or non-engineered methionine residue). In some embodiments, the amino acid residue is engineered (e.g. an engineered cysteine and/or engineered methionine residue). In some embodiments, the linker is selected from any of the linkers described herein. In some embodiments, the drug moiety is selected from any of the drug moieties described herein.
[00562] In one aspect, the disclosure provides an antibody-drug conjugate (ADC) having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab comprises an antibody or antibody-binding fragment;
L is a linker;
D comprises a drug moiety; and n is an integer from 1 to 20.
[00563] Any antibody, antibody fragment, linker, and/or drug moiety disclosed herein is contemplated within formula (III).
[00564] In some embodiments, the linker L of formula (I) is a linker of formula (III) that has reacted with antibody or antibody-binding fragment Ab (e.g. the linker comprises a reactive group R* which reacts with the antibody or antibody fragment Ab).
[00565] In some embodiments, the linker comprises or consists of the formula:
[00566] In some embodiments, the linker comprises or consists of the formula:
[00567] In some embodiments, the linker comprises or consists of the formula:
[00568] In some embodiments, the linker comprises or consists of the formula:
[00569] In some embodiments, the linker comprises or consists of the formula:
[00570] In some embodiments, the linker comprises or consists of the formula:
[00571] In some embodiments, the linker comprises or consists of the formula:
[00572] In some embodiments, the linker comprises or consists of the formula:
[00573] In some embodiments, the linker comprises or consists of the formula:
[00574] In some embodiments, the linker comprises or consists of the formula:
[00575] In some embodiments, the linker comprises or consists of the formula:
[00576] In some embodiments, the linker comprises or consists of valine-citrulline.
[00577] In some embodiments, the drug moiety D is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyrridinobenzodiazepines (PDDs).
[00578] In some embodiments, the exatecan comprises or has the formula:
[00579] In some embodiments, the PDD comprises or has the formula:
[00580] In some embodiments, the PDD comprises or has the formula:
[00581] In some embodiments, the PDD comprises or has the formula: [00582] In some embodiments, the Sn-38 comprises or has the formula:
[00584] In some embodiments, L-D has the formula:
[00585] In some embodiments, L-D has the formula:
[00586] In some embodiments, L-D has the formula:
[00587] In some embodiments, L-D has the formula:
[00588] In some embodiments, L-D has the formula:
[00589] In some embodiments, L-D has the formula:
[00590] In some embodiments, L-D has the formula:
[00591] In some embodiments, L-D has the formula:
[00592] In some embodiments, L-D has the formula:
[00593] In some embodiments, L-D has the formula:
[00594] In some embodiments, L-D has the formula: [00595] In some embodiments, the antibody-drug conjugate is of formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen, binds a tumor-associated antige n is an integer from 1 to 20; and
L-D has the formula:
In some embodiments, the tumor-associated antigen is PTK7. In some embodiments, the tumor-associated antigen is HER2.
[00596] In some embodiments, L-D has the formula -val-cit-MMAE.
[00597] In some embodiments, L-D has the formula -val-cit.PAB-MMAE.
[00598] In some embodiments, the antibody-drug conjugate is of formula (LA):
Ab-[Li-(CH2CH2O)p-XAA1-XAA2-D]I1 formula (I- A) wherein in formula (I- A):
Ab comprises an antibody or antibody-binding fragment; p is an integer from 6 to 20; XAA1 and XAA2 are independently selected amino acid moieties;
D is a topoisomerase inhibitor; and n is an integer from 1 to 20.
[00599] In some embodiments, the conjugate of formula (I) or the conjugate of formula (I- A) is selected from a conjugate of any one of formula 1030-1064:
[00600] In some embodiments, the conjugate of formula (I) or the conjugate of formula (I- A) is selected from a conjugate of any one of formula 1030 or 1101-1118:
formula (I- A)
[00601] In some embodiments, n is an integer from 1 to 25. In some embodiments, n is an integer from 1 to 10. In some embodiments, n is an integer from 4 to 8. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In some embodiments, n is 25 or greater. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.
[00602] In one embodiment (I), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a therapeutically relevant target, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-5-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00603] In one embodiment (la), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
[00604] In one embodiment (lb), the disclosure provides an antibody-drug conjugate having formula (I): Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof comprises wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-3-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00605] In one embodiment (lb), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4; L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00606] In one embodiment (II), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula: -[Alk-O]P-(CH2)i-5-C(O)-XAA- wherein
Alk designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether. Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00607] In one embodiment (Ila), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
Ab is an antibody or binding fragment thereof that specifically binds a tumor-associated antigen 0;
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)i-5-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Further, R* is or comprises optionally a bisulfone, optionally the bisulfone is or comprises
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from:
[00608] In one embodiment (III), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2A, 2B, 2C, 3A, 3B, 4A or 4B; L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions .
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from
[00609] In one embodiment (IV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein HCDR1- 3individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from
[00610] In one embodiment (V), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and/or a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or wherein the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and/or a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051- 1085; or wherein the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and/or a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs:622- 629; or wherein the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NOs: 229 and/or a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NOs: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from
[00611] In one embodiment (VI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4; L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00612] In one embodiment (VII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00613] In one embodiment (VIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions;
The linker has the following formula:
-R*-Li-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00614] In one embodiment (IX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises or consists of an amino acid sequence as set forth any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises or consists of an amino acid sequence as set forth any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises or consists of an amino acid sequence as set forth any one of SEQ ID NOs: 229-239, and
(ii) a light chain variable region (VL) that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is a reactive moiety selected from a succinimide, a triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00615] In one embodiment (X), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00616] In one embodiment (XI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622; L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00617] In one embodiment (XII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions;
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00618] In one embodiment (XIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is a dipeptide, p is an integer from 0 to 50.
R* is succinimide
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00619] In one embodiment (XIV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a therapeutically relevant target, wherein the therapeutically relevant target is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is succinimide
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00620] In one embodiment (XV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is succinimide
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula: [00621] In one embodiment (XVI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622; L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0 to 1 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0 to 1 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula: -[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is succinimide
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00622] In one embodiment (XVII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00623] In one embodiment (XVIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 20.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is a nonpolar dipeptide, p is an integer from 5 to 10, e.g. 5, 6, 7, 8, 9, or 10.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00624] In one embodiment (XIX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00625] In one embodiment (XX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy Tchain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00626] In one embodiment (XXI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises: (a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0 to 1 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0 to 1 substitutions.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8. R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00627] In one embodiment (XXII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy PTchain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
In one embodiment (XXIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy PTchain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and/or comprises a light chain that comprises an amino acid sequence as set forth in SEQ ID NOs: 394-786 or 1051-1085.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether. Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00628] In one embodiment (XXIV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00629] In one embodiment (XXV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622; or
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00630] In one embodiment (XXVI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises: (a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions;.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether. Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00631] In one embodiment (XXVII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622; L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00632] In one embodiment (XXVIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or (i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether.
Li is -[CH2]o-i2-C(0)NH-.
The drug moiety is selected from exatecan having the formula:
[00633] In one embodiment (XXIX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00634] In one embodiment (XXX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00635] In one embodiment (XXXI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The antibody or binding fragment thereof comprises
(i) a heavy chain variable region (VH) that comprises: (a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00636] In one embodiment (XXXII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in EQ ID NOs: 229, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622; or
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00637] In one embodiment (XXXIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[Alk-O]P-(CH2)2-C(O)-XAA- wherein
Aik designates C2-C4-alkylene,
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide. Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00638] In one embodiment (XXXIV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a TAA, wherein the TAA is selected from any one of Tables 1, 2, 3, or 4;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00639] In one embodiment (XXXV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or (i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00640] In one embodiment (XXXVI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622; or
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The antibody or binding fragment thereof comprises (i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00641] In one embodiment (XXXVII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises an amino acid sequence as set forth in SEQ ID NO: 622; or
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]p-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
In one embodiment (XXXVIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that consists of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) that consists of an amino acid sequence as set forth in SEQ ID NO: 622;
L is a linker;
D is a drug moiety; and n is an integer from 1 to 10, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The linker has the following formula:
-R*-LI-LA- wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof.
The linker LA has the formula:
-[CH2-CH2-O]P-(CH2)2-C(O)-XAA- wherein
XAA is Vai -Ala, p is 7 or 8.
R* is succinimide.
Li is -[CH2]I-3-C(O)NH-.
The drug moiety is selected from exatecan having the formula:
[00642] In one embodiment (XXXIX), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D] formula (I) as defined in any one of embodiments (I) to (XXXVIII), wherein index p is 8.
[00643] In one embodiment (XL), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) as defined in any of embodiments (I) to (XXXIX), wherein Li is -[CH2]2-C(O)NH-.
[00644] In one embodiment (XLI), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) as defined in any one of embodiments (I) to (XL), wherein the drug moiety is selected from exatecan having the formula:
[00645] In one embodiment (XLII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) as defined in any one of embodiments (I) to (XLI), wherein the drug moiety is exatecan having the formula:
[00646] In one embodiment (XLIII), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) as defined in any one of embodiments (I) to (XII), wherein XAA is not Val-Cit or Phe-Lys.
[00647] In one embodiment (XLIV), the disclosure provides an antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein the moiety -[L-D]n has the following structure wherein the moiety Ab- is as defined in any one of embodiments (I) to (XLIII), and wherein said moiety Ab- is reacted with the maleimide group.
[00648] In one embodiment (XLV), the disclosure provides a compound of formula
(III), or salts, solvates, tautomers, isomers or mixtures thereof:
L-D formula (III) wherein in formula (III):
L is a linker; and
D comprises a drug moiety, said formula (III) corresponding to formula (I) in any one of embodiments (I) to (XLIV), wherein Ab is absent and n is 1.
[00649] In embodiments, the disclosure provides an antibody-drug conjugate (ADC) having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or antibody-binding fragment that specifically binds a therapeutically relevant target as disclosed in any one of Tables 1, 2, 3, or 4;
L is a linker having formula -R*-LI-LA-, wherein LA is a linker, Li is a linking moiety, and R* is a reactive moiety or an antibody or fragment thereof;
D is a drug moiety; and n is an integer from 1 to 20. In embodiments, R* is a reactive moiety selected from a succinimide, triazole, an amide, and a thioether. In embodiments, R* is succinimide. In embodiments, Li is -[CH2]o-i2-C(0)NH-. In some embodiments, the linker LA has the formula -[Alk-O]p-(CH2)2-C(O)-XAA-. In some embodiments, the linker LA has the formula -[CH2CH2- O]P-(CH2)2-C(O)-XAA-, wherein p is an integer from 5 to 10. In embodiments, XAA is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Vai -Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D- Ala, and Phe-Met. In some embodiments, XAA is Vai-Ala. In some embodiments, Li is -[CH2] 1- 3-C(O)NH-. In some embodiments, Li is -[CH2]2-C(O)NH-. In some embodiments, p is 7 or 8. In some embodiments, p is 8.
[00650] In some embodiments, the antibody or binding fragment thereof specifically binds an TAA selected from any one of Tables 1, 2, 3, or 4.
[00651] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO: 787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO: 788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO: 789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO: 790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO: 791 , and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO: 792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622.
[00652] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and/or comprises a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085. In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and/or comprises a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085. In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and/or comprises a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622- 629. In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in SEQ ID NO: 229 and/or comprises a light chain that comprises an amino acid sequence as set forth in SEQ ID NO: 622.
[00653] In some embodiments, the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and the drug moiety D is or comprises exatecan.
[00654] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and the drug moiety D is or comprises exatecan.
[00655] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1), (b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and the drug moiety D is or comprises exatecan.
[00656] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and the drug moiety D is or comprises exatecan.
[00657] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises Dxd.
[00658] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises Dxd.
[00659] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and the drug moiety D is or comprises Dxd.
[00660] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and the drug moiety D is or comprises Dxd.
[00661] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00662] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00663] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00664] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00665] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00666] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00667] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00668] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and
(c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00669] In some embodiments, the PDD comprises or has the formula: [00670] In some embodiments, the PDD comprises or has the formula:
[00671] In some embodiments, the PDD comprises or has the formula:
[00672] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises Sn-38.
[00673] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) that comprises: (a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises Sn-38.
[00674] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein the VH comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the VL comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises Sn-38.
[00675] In some embodiments, the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1) of SEQ ID NO:787,
(b) a VH complementarity determining region two (HCDR2) of SEQ ID NO:788, and
(c) a VH complementarity determining region three (HCDR3) of SEQ ID NO:789, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1) of SEQ ID NO:790,
(b) a VL complementarity determining region two (LCDR2) of SEQ ID NO:791, and (c) a VL complementarity determining region three (LCDR3) of SEQ ID NO:792, wherein the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises Sn-38.
[00676] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises exatecan.
[00677] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises exatecan.
[00678] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises exatecan.
[00679] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises and/or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises exatecan.
[00680] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises Dxd.
[00681] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises Dxd. [00682] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises Dxd.
[00683] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises Dxd.
[00684] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00685] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00686] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB.
[00687] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises MMAE. In some embodiments, the linker is or comprises val-cit. In some embodiments, the linker comprises val-cit-PAB. [00688] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00689] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00690] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00691] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00692] In some embodiments, the PDD comprises or has the formula:
[00693] In some embodiments, the PDD comprises or has the formula:
[00694] In some embodiments, the PDD comprises or has the formula:
[00695] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises Sn-38.
[00696] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises Sn-38.
[00697] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises Sn-38.
[00698] In some embodiments, the antibody or binding fragment thereof comprises a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises Sn-38.
[00699] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises exatecan.
[00700] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002- 1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises exatecan.
[00701] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises exatecan.
[00702] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in SEQ ID NO: 229 and a light chain that comprises an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises exatecan. [00703] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises Dxd.
[00704] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002- 1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises Dxd.
[00705] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises Dxd.
[00706] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in SEQ ID NO: 229and a light chain that comprises an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises Dxd.
[00707] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises MMAE.
[00708] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002- 1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises MMAE.
[00709] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises MMAE. [00710] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in SEQ ID NO: 229 and a light chain that comprises an amino acid sequence as set forth in SEQ ID NOs: 622, and wherein the drug moiety D is or comprises MMAE.
[00711] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00712] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1002- 1050 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00713] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00714] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in SEQ ID NO: 229 and a light chain that comprises an amino acid sequence as set forth in SEQ ID NO: 622, and wherein the drug moiety D is or comprises a pyrridinobenzodiazepine (PDD).
[00715] In some embodiments, the PDD comprises or has the formula:
[00716] In some embodiments, the PDD comprises or has the formula:
[00717] In some embodiments, the PDD comprises or has the formula:
[00718] In some embodiments, the antibody or binding fragment thereof comprises a heavy chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 and a light chain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 385-768, and wherein the drug moiety D is or comprises Sn-38.
[00719] In some embodiments, the antibody is any antibody or binding fragment thereof disclosed herein. In some embodiments, the antibody or binding fragment thereof preferentially binds any portion of the polypeptide as set forth in Table 1. In some embodiments, the antibody or binding fragment thereof is an antibody that specifically binds a therapeutically relevant target as disclosed in any one of Tables 1, 2, 3, or 4.
[00720] In some embodiments, the antibody comprises HCDRs embedded within a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050 and comprises LCDRs embedded within a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
[00721] In some embodiments, the antibody comprises HCDRs embedded within a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002- 1050 and comprises LCDRs embedded within a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
[00722] In some embodiments, the antibody comprises HCDRs embedded within a VH that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229- 236 and comprises LCDRs embedded within a VL that comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
[00723] In some embodiments, the antibody comprises HCDRs embedded within a VH that comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 229 and comprises LCDRs embedded within a VL that comprises or consists of an amino acid sequence as set forth in SEQ ID NOs: 622.
[00724] In some embodiments, the antibody drug conjugate as described herein binds an TAA selected from any one of Tables 1, 2, 3, or 4 at pH 7.4 with a KD value of or less than about 1000 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 180 nM, about 160 nM, about 140 nM, about 120 nM, or about 100 nM.
[00725] In some embodiments, the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 25, or about 1 to about 10. In some embodiments, the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about
10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, or about 25 or greater, optionally DAR is about 4, optionally DAR is about 8.
[00726] In some embodiments, ADCs may be produced or generated having (a) an antibody, or binding fragment thereof (e.g. an antibody, or binding fragment thereof that binds to an TAA selected from any one of Tables 1, 2, 3, or 4); (b) a linker and (c) a drug moiety. The drug-to- antibody ratio (DAR) or drug loading indicates the number of drug (D) molecules and/or moieties that are conjugated per antibody. In some embodiments, the number of linker-drug moieties attached to an antibody can be any number suitable for development of an ADC. In some embodiments, the number of linker-drug moieties per antibody ranges from about 1 to about 25. In some embodiments, the number of linker-drug moieties per antibody is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about
12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, or about 25 or greater. In some embodiments, the number of linker-drug moieties per antibody ranges from about 1 to about 10. In some embodiments, the number of linker-drug moieties per antibody is about 10. In some embodiments, the number of linker-drug moieties per antibody is about 9. In some embodiments, the number of linker-drug moieties per antibody is about 8. In some embodiments, the number of linker-drug moieties per antibody is about 7. In some embodiments, the number of linker-drug moieties per antibody is about 6. In some embodiments, the number of linker-drug moieties per antibody is about 5. In some embodiments, the number of linker-drug moieties per antibody is about 4. In some embodiments, the number of linker-drug moieties per antibody is about 3. In some embodiments, the number of linker-drug moieties per antibody is about 2. In some embodiments, the number of linker-drug moieties per antibody is about 1. In some embodiments, the number of linker-drug moieties per antibody is greater than 4, such as 5, 6, 7, 8, 9, 10, 11, 12 or greater than 12 linker-drug moieties per antibody. Non-limiting examples for determining DAR include various conventional means such as UV spectroscopy, mass spectroscopy, ELISA assay, radiometric methods, hydrophobic interaction chromatography (HIC), electrophoresis and HPLC. In some embodiments, the DAR of an ADC of the disclosure is equivalent to the “n” referred to in formula (I). [00727] In some embodiments, the antibody drug conjugates (ADCs) of the disclosure (e.g., the ADCs of the disclosure comprising antibodies and/or antibody fragments, such as but not limited to antibodies and/or antibody fragments as disclosed in any one of Tables 1, 2, 3, or 4, conjugated to a drug moiety via a linker) are capable of being internalized. In another embodiment, the antibody drug conjugates (ADCs) of the disclosure are capable of inducing cell death of cells endogenously expressing said TAA selected from any one of Tables 1, 2, 3, or 4.
[00728] In some embodiments, L-D has the formula:
[00729] In some embodiments, L-D has the formula:
[00730] In some embodiments, L-D has the formula:
[00731] In some embodiments, L-D has the formula:
[00732] In some embodiments, L-D has the formula:
[00733] In some embodiments, L-D has the formula:
[00734] In some embodiments, L-D has the formula:
[00735] In some embodiments, L-D has the formula:
[00736] In some embodiments, L-D has the formula: -val-cit-MMAE.
[00737] In some embodiments, L-D has the formula:
-val-cit-PAB-MMAE.
Methods of Treatment
[00738] In one aspect, the conjugates (e.g. ADCs), compounds and compositions described herein (e.g. formula (I), formula (II), and/or formula (III)) can be used in methods for treating diseases. In some embodiments, the disease is cancer. In one embodiment, the disease is a hyperproliferative diseases. In some embodiments, the hyperproliferative disorder is cancer. In some embodiments, the cancer is pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi’s sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin’s disease, non-Hodgkin’s lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma, and the like. In other embodiments, the cancer is acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, triple-negative breast cancer (TNBC), bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing’s tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm’s tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin’s disease, multiple myeloma, non-Hodgkin’s lymphoma, polycythemia vera, or Waldenstrom’s macroglobulinemia. In some embodiments, the disease is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC)
[00739] In some embodiments, the antibody drug conjugate as described herein reduces mean tumor volume by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to mean tumor volume in untreated controls in a breast cancer MDA-MB-231 model. In some embodiments, the antibody drug conjugate reduces mean tumor volume by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to mean tumor volume in untreated controls in a breast cancer patient-derived xenograft model.
[00740] In some embodiments, the antibody drug conjugate as described herein reduces mean tumor volume by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to mean tumor volume in untreated controls in a breast cancer MDA-MB-468 model. In some embodiments, the antibody drug conjugate reduces mean tumor volume by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% as compared to mean tumor volume in untreated controls in a breast cancer patient-derived xenograft model.
[00741] In some embodiments, the method of treating a cancer comprises administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate described herein (e.g. formula (I)) or pharmaceutical composition thereof.
Combination Therapies/Conjugation Agents
[00742] As described herein, the present invention relates to, in various embodiments, antitumor agents that may be a part of a conjugate and/or compound of the invention or used in the context of various combination therapies encompassed by the present invention.
[00743] Combination therapy embraces the administration of an antibody-drug conjugate, and another therapeutic agent as part of a specific treatment regimen, optionally, including a maintenance phase, intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). Combination therapy generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
[00744] Combination therapy embraces administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent (e.g., a chemotherapeutic agent) can be administered orally, and a second agent (e.g., an ADC) can be administered intravenously. Further, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, both the therapeutic agents may be administered by intravenous or subcutaneous injection.
[00745] In the present disclosure the term sequential means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of an ADC and a chemotherapeutic agent, a sequential dosage regimen could include administration of the ADC before, simultaneously, substantially simultaneously, or after administration of the chemotherapeutic agent, but both agents will be administered in a regular sequence or order. The term separate means, unless otherwise specified, to keep apart one from the other. The term simultaneously means, unless otherwise specified, happening or done at the same time, i.e., the compounds of the invention are administered at the same time. The term substantially simultaneously means that the compounds are administered within minutes of each other (e.g., within 10 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two compounds separately). As used herein, concurrent administration and substantially simultaneous administration are used interchangeably. Sequential administration refers to temporally separated administration of the ADC and the chemotherapeutic agent.
[00746] In some embodiments, the chemotherapeutic agent is selected from alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel, ABRAXANE Cremophor-firee, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE, vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-a, Raf, H- Ras, EGFR (e.g, erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above.
[00747] In some embodiments, the anti-tumor agent is a cytotoxic agent. In some embodiments, the cytotoxic agent is selected from methotrexate, aminopterin, 6- mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1 -methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin, doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine, and mixtures thereof.
[00748] In some embodiments, the cytotoxic agent is selected from paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, and mixtures thereof.
[00749] In some embodiments, the present compositions and methods find use in combination with checkpoint inhibitors - e.g., in the treatment of various cancers. For instance, the present compositions and methods may supplement checkpoint inhibitor-based cancer therapies, e.g., by improving patient response to the same (e.g., by converting non-responders to responders, and/or increasing the magnitude of therapeutic response, and/or reducing the dose or regimen needed for therapeutic response, and/or reducing one or more side effects of the checkpoint inhibitor-based cancer therapies).
[00750] In some embodiments, the checkpoint inhibitor is an agent that targets one of TIM- 3, BTLA, PD-1, CTLA-4, B7-H4, GITR, galectin-9, HVEM, PD-L1, PD-L2, B7-H3, CD244, CD 160, TIGIT, SIRPa, ICOS, CD 172a, and TMIGD2. [00751] In some embodiments, the immune checkpoint immunotherapy agent modulates PD-1) In some embodiments, the agent that targets PD-1 is an antibody or antigen-binding portion thereof that is specific for PD-1, optionally selected from nivolumab, pembrolizumab, and pidilizumab. In some embodiments, an antibody or antigen-binding portion thereof specific for PD-1 is Nivolumab and can be administered at 240 mg every 2 weeks. In some embodiments, an antibody or antigen-binding portion thereof that is specific for PD-1 is Pembrolizumab and can be administered at 200 mg every 3 weeks. In some embodiments, an antibody or antigen-binding portion thereof that is specific for PD-1 is Pidilizumab and can be administered at 200 mg every 3 weeks.
[00752] In some embodiments, the immune checkpoint immunotherapy agent modulates PD-L1. In some embodiments, the agent that modulates PD-L1 is an antibody or antigenbinding portion thereof that is specific for PD-L1. In some embodiments, the antibody or antigen-binding portion thereof that is specific for PD-L1 is selected from Atezolizumab, Avelumab, Durvalumab, and BMS-936559. In some embodiments, the antibody or antigenbinding portion thereof that is specific for PD-L1 is BMS-936559 and can be administered at 0.1 mg/kg every 2 weeks. In some embodiments, the antibody or antigen-binding portion thereof that is specific for PD-L1 is Atezolizumab and can be administered at 1200 mg every 3 weeks. In some embodiments, the antibody or antigen-binding portion thereof that is specific for PD-L1 is Avelumab and can be administered at 10 mg/kg every 2 weeks. In some embodiments, the antibody or antigen-binding portion thereof that is specific for PD-L1 is Durvalumab and can be administered at 10 mg/kg every 2 weeks.
[00753] In some embodiments, the agent that targets CTLA-4 is an antibody or antigenbinding portion thereof that is specific for CTLA-4, optionally selected from ipilimumab and tremelimumab. In some embodiments, the antibody or antigen-binding portion thereof that is specific for CTLA-4 is tremelimumab and can administered at 3 mg/kg, 6 mg/kg or 10 mg/kg. In some embodiments, the antibody or antigen-binding portion thereof that is specific for CTLA-4 is Ipilimumab and can administered at 5 mg/mL 12 weeks.
[00754] In some embodiments, the hyperproliferative disorder (e.g., cancer) treated by the compounds and compositions described herein includes cells having p38a MAPK protein and/or p38a MAPK related protein expression. [00755] In one embodiment, the disclosure relates to a method of treating a disease alleviated by inhibiting the p38a MAPK protein in a patient in need thereof, including administering to the patient a therapeutically effective amount of a p38a MAPK inhibitor, wherein the p38a MAPK inhibitor is a compound capable of binding to a pocket near the ED substrate-docking site of p38a MAPK, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and one or more additional therapeutic agents, including chemotherapeutic and/or immunotherapeutic agents.
[00756] Efficacy of the compounds and combinations of compounds described herein in treating the indicated diseases or disorders can be tested using various models known in the art, and described herein, which provide guidance for treatment of human disease. Any and all of the described methods of treatment may include medical follow-up to determine the therapeutic or prophylactic effect brought about in the subject undergoing treatment with the compound(s) and/or composition(s) described herein.
Pharmaceutical Compositions
[00757] In an embodiment, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as any of the conjugates, drug moieties, linkers, compounds, and/or compositions of the disclosure, is provided as a pharmaceutically acceptable composition.
[00758] In one embodiment, the disclosure relates to a pharmaceutical composition including a therapeutically effective amount of one or more conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease is cancer. In one embodiment, the diseases is a cancer such as acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing’s tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, triplenegative breast cancer (TNBC), uterine cancer, Wilm’s tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin’s disease, multiple myeloma, non-Hodgkin’s lymphoma, polycythemia vera, or Waldenstrom’s macroglobulinemia. In some embodiments, the disease is triple-negative breast cancer (TNBC). In some embodiments, the disease is breast cancer. In some embodiments, the disease is colon cancer.
[00759] In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of the pharmaceutical composition. [00760] In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of the pharmaceutical composition.
[00761] In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v, or v/v of the pharmaceutical composition.
[00762] In some embodiments, the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v, or v/v of the pharmaceutical composition.
[00763] In some embodiments, the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the foregoing conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
[00764] In some embodiments, the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure, such as any of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
[00765] Each of the active pharmaceutical ingredients according to the disclosure is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. The clinically-established dosages of the conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I) formula (II), and/or formula (III)), of the disclosure may also be used if appropriate. [00766] In an embodiment, the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1:2.5, and more preferably about 1 : 1. In an embodiment, the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of20:l, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1,9:1,8:1,7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20. In an embodiment, the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of20:l, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1,9:1,8:1,7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
[00767] Described below are non-limiting pharmaceutical compositions and methods for preparing the same.
Dosages and Dosing Regimens [00768] The amounts of the pharmaceutical compositions administered using the methods herein, such as the dosages of conjugates, drug moieties, linkers, compounds, and /or compositions of the disclosure (e.g. formula (I), formula (II), and/or formula (III)), will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the active pharmaceutical ingredients and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day.
[00769] An effective amount of the combination of the active pharmaceutical ingredient may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
[00770] In some embodiments, the compositions described herein further include controlled-release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions. This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in the bloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and/or minimize side effects. Additionally, a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound. [00771] The following examples describe the disclosure in further detail. These examples are provided for illustrative purposes only, and should in no way be considered as limiting the disclosure.
EXAMPLES
Example 1 : Chemical Synthesis
General Remarks
[00772] All reagents and solvents were purchased from standard commercial suppliers and used as purchased. Anhydrous reactions were carried out under an inert atmosphere of argon using anhydrous solvents which were used as purchased, without further drying. Thin Layer Chromatography (TLC) was performed on silica gel aluminium plates (Merck 60, F254), and flash column chromatography was carried out using a Biotage Isolera One (automated flash chromatography system), whilst monitoring by UV (254 nm) and TLC.
[00773] All Nuclear Magnetic Resonance (NMR) spectra were obtained at room temperature using a Bruker 600 MHz Ultrashield with Cryoprobe (Bruker Avance NEO console with Cryoplatform) or a Varian Mercury Vx Agilent 400 MHz spectrometer, for which chemical shifts are expressed in ppm relative to the solvent and coupling constants are expressed in Hz. Microwave reactions were carried out on a Biotage Initiator+ microwave synthesizer. High Resolution Mass Spectrometry (HRMS) was performed on a Thermo Scientific-Exactive HCD Orbitrap Mass Spectrometer. Yields refer to isolated material (homogeneous by TLC and NMR) unless otherwise stated and names are assigned according to IUPAC nomenclature.
[00774] Liquid Chromatography Mass Spectrometry (LCMS) analysis Methods A-C were performed on a Waters Alliance 2695 with water (A) and acetonitrile (B) comprising the mobile phases. Formic acid (0.1 %) was added to both acetonitrile and water to ensure acidic conditions throughout the analysis. Function type: Diode array (535 scans). Column type: Monolithic C 18 50 X 4.60 mm. Mass spectrometry data were collected using a Waters Micromass ZQ instrument coupled to the HPLC with a Waters 2996 PDA. Waters Micromass ZQ parameters used were: Capillary (kV), 3.38; Cone (V), 35; Extractor (V), 3.0; Source temperature (°C), 100; De-solvation Temperature (°C), 200; Cone flow rate (L/h), 50; De-solvation flow rate (L/h), 250. Gradient conditions are described as follows.
[00775] Method A (10 min): from 95% A/5% B to 50% B over 3 min. Then from 50% B to 80% B over 2 min. Then from 80% B to 95% B over 1.5 min and held constant for 1.5 min. This was then reduced to 5% B over 0.2 min and maintained to 5% B for 1.8 min. The flow rate was 0.5 mL/min, 200 μL was split via a zero dead volume T piece which passed into the mass spectrometer. The wavelength range of the UV detector was 220-400 nm.
[00776] Method B (5 min): from 95% A/5% B to 90% B over 3 min. Then from 90% B to 95% B over 0.5 min and held constant for 1 min. This was then reduced to 5% B over 0.5 min. The flow rate was 1.0 mL/min, 100 μL was split via a zero dead volume T piece which passed into the mass spectrometer. The wavelength range of the UV detector was 220-500 nm.
[00777] Method C (5 min): from 95% A/5% B, which was increased to 90% B over 3 min and to 95% B over a further 0.5 min. The gradient was then held at 95% B for 1 min and then returned to 5% B over 0.5 min. The total duration of the run was 5 minutes and the solvent flow rate was 1 mL/min, 100 μL was split via a zero dead volume T piece which passed into the mass spectrometer. The wavelength range of the UV detector was 220-500 nm.
[00778] Liquid Chromatography Mass Spectrometry (LCMS) analysis Methods D-G were performed on a Shimadzu LC-20AD series, Binary Pump, Diode Array Detector. Column type: Agilent Poroshell 120 EC-C18, 2.7 pm, 4.6x50 mm. Mobile phase: A: 0.05% formic acid in water (v/v); B: 0.05% formic acid in acetonitrile (v/v). Flow Rate: 1 mL/min at 25 °C. Detector: 214 nm, 254 nm. Gradient stop time: 5 min. MS: 2020, Quadrupole LC/MS, Ion Source: API- ESI, TIC: 100-1300 m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min, Drying gas temperature: 250 °C, Vcap: 4500V. Sample preparation: samples were dissolved in methanol at 1-10 pg/mL, then filtered through a 0.22 pm filter membrane. Injection volume: 1- 10 μL. Gradient conditions are described as follows.
[00779] Method D (5 min): 20% A/80% B for 0.5 min, which was increased to 100% B over 3.5 min, then held at 100% B for 0.5 min. This was then returned to 20% A/80% B for 0.5 min.
[00780] Method E (5 min): 50% A/50% B for 0.5 min, which was increased to 100% B over 3.5 min, then held at 100% B for 0.5 min. This was then returned to 50% A/50% B for 0.5 min.
[00781] Method F (5 min): 85% A/15% B for 0.5 min, which was increased to 100% B over 3.5 min, then held at 100% B for 0.5 min. This was then returned to 85% A/15% B for 0.5 min.
[00782] Method G (5 min): 97% A/3% B for 0.5 min, which was increased to 30% A/70% B over 3.5 min, then to 100% B over 0.5 min. This was then returned to 97% A/3% B for 0.5 min.
[00783] Optical rotations were measured on an SGWzz-1 automatic Polarimeter (Shanghai Shen Guang Instrument Co., Ltd.) or Bellingham-Stanley ADP 440+ Polarimeter.
[00784] 4-(Benzyloxy)-3-methoxybenzaldehyde (2)
[00785]
[00786] A mixture of compound vanillin (1) (200 g, 1.31 mol), benzyl bromide (236 g, 1.38 mol) and potassium carbonate (545 g, 3.94 mol) in methanol (1.20 L) was refluxed for 5 h. The reaction mixture was filtered, and the filtrate evaporated under reduced pressure to afford the title compound (271 g, 85%) as a pale yellow solid.
[00787] 1 H NMR (400 MHz, CDCI3) δ 9.83 (s, 1H), 7.47-7.35 (m, 6H), 7.33 (d, .7=7.2 Hz,
1H), 6.98 (d, .7=8.2 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCI3) δ 191.0, 153.6, 150.1, 136.0, 130.3, 128.7, 128.2, 127.2, 126.6, 112.3, 109.3, 70.9, 56.1; MS (ES+): m/z = 243 (M+H)+; LCMS (Method A): tR = 7.53 min.
[00788] 4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (3)
[00789]
[00790] A solution of 4-(benzyloxy)-3-methoxybenzaldehyde (2) (130 g, 537 mmol) in trifluoroacetic acid (600 mL) was charged with a solution of potassium nitrate (65 g, 644 mmol), in trifluoroacetic acid (600 mL) dropwise at 0°C. The reaction mixture was stirred for 1 h and then diluted with water (2.40 L). The resulting precipitate was filtered and washed with cold water (500 mL x 2) to afford the title compound (125 g, 81%) as a yellow solid.
[00791] 1 H NMR (400 MHz, CDCI3) δ 10.43 (s, 1H), 7.67 (s, 1H), 7.46-7.30 (m, 6H), 5.27
(s, 2H), 4.02 (s, 3H); 13C NMR (100 MHz, CDCI3) δ 187.8, 153.7, 151.4, 134.85, 129.0, 128.9, 128.7, 127.6, 125.7, 110.0, 108.9, 71.6, 56.7; MS (ES-): m/z = 286 (M-H) ’; LCMS (Method
[00794] A solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (3) (100 g, 348 mmol) in glacial acetic acid (800 mL) was charged with an aqueous solution of hydrobromic acid (48% v/v, 88.0 mL, 522 mmol) and heated to 85 °C, with stirring for 1 h, after which the reaction was judged to be complete by TLC. After allowing the resulting mixture to cool to room temperature, it was then diluted in water (1.60 L), and the resulting precipitate filtered, and washed with cold water (100 mL x 3) to give the title compound (50.0 g, 73%) as a yellow solid, which was used immediately in the subsequent step without further purification.
[00795] 1 H NMR (400 MHz, DMSO-d6 δ 11.11 (br s, 1 H), 10.15 (br s, 1 H), 7.50 (s, 1 H), 7.35 (s, 1 H), 3.94 (s, 3 H); MS (ES-): m/z = 196 (M-H)’; LCMS (Method B): tR = 2.55 min.
[00796] 5-Methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzaldehyde (5)
[00798] A mixture of 4-hydroxy-5-methoxy-2-nitrobenzaldehyde (4) (50.0 g, 254 mmol), triisopropylsilyl chloride (59.7 mL, 279 mmol) and imidazole (51.8 g, 761 mmol) was heated and stirred at 100 °C for 30 min. The reaction mixture was poured onto ice-water and extracted with ethyl acetate (500 mL x 3). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (5%) to give the title compound (57.5 g, 64%) as a yellow solid.
[00799] 1 H NMR (400 MHz, CDCh) 8 10.42 (s, 1 H), 7.59 (s, 1 H), 7.40 (s, 1 H), 3.95 (s, 3
H), 1.33-1.24 (m, 3 H), 1.07 (s, 18 H).
[00800] 5-Methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzoic acid (6)
[00801]
[00802] A solution of sodium chlorite (80%, 46.0 g, 407 mmol) and sodium phosphate monobasic dihydrate (35.5 g, 228 mmol) in water (200 mL) was added to a solution of 5- methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzaldehyde (5) (57.5 g, 163 mmol) in tetrahydrofuran (800 mL) at room temperature. Hydrogen peroxide (30% w/w, 235 mL, 2.28 mol) was immediately added to the vigorously stirred biphasic mixture. The starting material dissolved, and the temperature of the reaction mixture rose to 45 °C. After 30 min, the reaction was judged to have completed by TLC. The mixture was subsequently acidified to pH = 3-4 with citric acid and extracted with ethyl acetate (500 mL x 3). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (10%) then methanol/di chloromethane (10%) to afford the title compound (38.0 g, 63%) as a yellow oil.
[00803] 1 H NMR (400 MHz, CDCI3) δ 9.81 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H),
1.26 (q, J=1A Hz, 3H), 1.09 (d, J=7.4 Hz, 18H); MS (ES-): m/z = 368 (M-H) ’; LCMS (Method roxymethyl)piperidin-l-yl)(5-methoxy-2-nitro-4 )phenyl)methanone (7) [ ]
[00806] A solution of 5-methoxy-2-nitro-4-((triisopropylsilyl)oxy)benzoic acid (6) (28.0 g, 75.8 mmol), HATU (31.7 g, 83.4 mmol) and dry triethylamine (44 mL) in dry dichloromethane (300 mL) was stirred at room temperature for 30 min. (5)-Piperidin-2-ylmethanol (11.4 g, 98.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane (500 mL x 2) and water (100 mL). The combined organic extracts were then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 50% to 75%), to give the title compound (20.0 g, 57%) as a yellow solid.
[00807] 1 H NMR (400 MHz, CDCb) mixture of rotamers, d 7.68-7.65 (m, 1H), 7.03-6.65 (m, 1H), 5.04-4.69 (m, 1H), 4.12-4.05 (m, 0.4H), 4.01-3.95 (m, 0.5H), 3.92-3.89 (m, 2.6H), 3.83-3.74 (m, 1.5H), 3.64-3.59 (m, 0.4H), 3.45-3.40 (m, 0.3H), 3.21-3.01 (m, 1.4H), 2.87-2.79 (m, 0.4H), 1.97-1.94 (m, 0.6H), 1.88-1.77 (m, 0.6H), 1.73-1.62 (m, 3H), 1.56-1.44 (m, 2H), 1.29-1.24 (m, 3H), 1.09 (d, .7=7.3 Hz, 18H); MS (ES+): m/z = 467 (M+H)+; LCMS (Method B): tR = 4.75 min.
[00808] (5)-(2-Amino-5-methoxy-4-((triisopropylsilyl)oxy)phenyl)(2- (hydroxymethyl)piperidin-l-yl)methanone (8)
[00809]
[00810] A solution of (5)-(2-(hydroxymethyl)piperidin-l-yl)(5-methoxy-2-nitro-4 ((triisopropylsilyl)oxy)phenyl)methanone (7) (1.00 g, 2.14 mmol) in tetrahydrofuran (5 mL) was charged with palladium on activated charcoal (10 wt. % basis, 100 mg), ammonium formate (1.10 g, 17.1 mmol) and water (1 mL), and stirred at room temperature, under argon, for 2 h. The resulting mixture was filtered through celite, the filter cake was washed with ethyl acetate (50 mL) and water (50 mL) and the filtrate separated. The organic phase was then extracted with brine (50 mL x 2), and dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 50% to 67%), gave the title compound (892 mg, 95%) as a yellow solid.
[00811] 1 H NMR (400 MHz, CDCI3) δ 6.67 (s, 1H), 6.30 (s, 1H), 4.00-3.81 (m, 4H), 3.72 (s, 3H), 3.57 (s, 1H), 3.08 (s, 1H), 1.68-1.64 (m, 4H), 1.57-1.43 (m, 2H), 1.28-1.17 (m, 3H), 1.08 (d, .7=7.4 Hz, 18H); 13C NMR (100 MHz, CDCI3) δ 171.8, 147.9, 143.7, 133.2, 112.5, 110.0, 109.5, 68.7, 61.0, 56.4, 30.9, 25.8, 19.9, 17.9, 12.9; MS (ES+): m/z = 437 (M+H)+; LCMS (Method C): tR = 4.07 min.
[00812] Allyl (A)-(2-(2-(hydroxymethyl)piperidine-l-carbonyl)-4-methoxy-5-
((triisopropylsilyl)oxy)phenyl)carbamate (9)
[00813]
[00814] A solution of (5)-(2-amino-5-methoxy-4-((triisopropylsilyl)oxy)phenyl)(2- (hydroxymethyl)piperidin-l-yl)methanone (8) (892 mg, 2.04 mmol) in dichloromethane (4 mL) was cooled to -10 °C and charged with pyridine (380 /zL) and allyl chloroformate (228 /zL, 2.14 mmol), dropwise under argon. After 35 min, the reaction mixture was diluted with dichloromethane (10 mL), then extracted with a saturated aqueous solution of copper sulfate (10 mL x 2) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 50% to 75%), gave the title compound (907 mg, 85%) as a pale yellow solid.
[00815] 1 H NMR (400 MHz, CDCI3) δ 8.08 (s, 1H), 7.62 (s, 1H), 6.75 (s, 1H), 5.92 (ddt,
.7=17.2, 10.7, 5.5 Hz, 1H), 5.32 (dt, J=17.3, 1.7 Hz, 1H), 5.20 (dt, J=10.6, 1.4 Hz, 1H), 4.61 (dt, J=5.5, 1.5 Hz, 2H), 3.88 (t, .7=10.7 Hz, 1H), 3.76 (s, 3H), 3.61-3.57 (m, 1H), 3.20-3.02 (m, 2H), 2.03 (s, 1H), 1.65-1.62 (m, 3H), 1.53-1.40 (m, 2H), 1.29-1.24 (m, 4H), 1.11-1.08 (m, 18H); MS (ES+): m/z = 522 (M+H)+; LCMS (Method A): fe = 9.62 min.
[00816] Allyl (6a.S')-6-hvdro\v-2-metho\v-12-o\o-3-((triisopropvlsilvl)o\v)-
6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12ZZ)-carboxylate (10)
[00817]
[00818] A solution of allyl (5)-(2-(2-(hydroxymethyl)piperidine-l-carbonyl)-4-methoxy-5- ((triisopropylsilyl)oxy)phenyl)carbamate (9) (17.0 g, 32.7 mmol) in dichloromethane (150 mL) was charged with (diacetoxyiodo)benzene (12.6 g, 39.2 mmol) and 2, 2,6,6- tetramethylpiperidine 1-oxyl (510 mg, 3.30 mmol), and stirred at room temperature for 16 h. The resulting mixture was then diluted with dichloromethane (350 mL), and sequentially washed with a saturated aqueous solution of sodium metabisulfite (100 mL) and a saturated aqueous solution of sodium hydrogen carbonate (100 mL). The organic extract was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was then purified by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 25% to 50%), to give the title compound (13.0 g, 77%) as a pale yellow solid.
[00819] 1 H NMR (400 MHz, CDCI3) δ 7.13 (s, 1H), 6.65 (s, 1H), 5.90 (d, .7=10.3 Hz, 1H), 5.76 (s, 1H), 5.14 (t, .7=12.1 Hz, 2H), 4.59 (dd, .7=13.1, 5.3 Hz, 1H), 4.44 (dd, .7=12.9, 5.1 Hz, 1H), 4.34 (dt, .7=13.5, 4.1 Hz, 1H), 3.83 (s, 3H), 3.77 (br, 1H), 3.45 (ddd, .7=10.1, 5.9, 4.0 Hz, 1H), 3.10-2.99 (m, 1H), 2.09-1.98 (m, 1H), 1.82-1.67 (m, 2H), 1.67-1.56 (m, 3H), 1.28-1.15 (m, 3H), 1.06 (dd, .7=7.4, 2.5 Hz, 18H); 13C NMR (100 MHz, CDCI3) δ 169.2, 156.2, 150.6, 147.6, 131.9, 127.0, 125.7, 121.2, 118.2, 110.9, 82.3, 66.9, 55.5, 55.3, 38.6, 23.2, 23.0, 18.2, 17.8, 12.8; MS (ES+): m/z = 519 (M+H)+; LCMS (Method A): fe = 8.67 min.
[00820] Allyl (6aA)-2-methoxy-12-oxo-6-((tetrahydro-2//-pyran-2-yl)oxy)-3-
((triisopropylsilyl)oxy)-6, 6a, 7,8,9, 10-hexahydrobenzo[e]pyrido[l,2-a][l, 4]diazepine-
5(12ZZ)-carboxylate (11)
[00822] A solution of allyl (6a5)-6-hydroxy-2-methoxy-12-oxo-3-((triisopropylsilyl)oxy)- 6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12Z7)-carboxylate (10) (14.0 g, 27.0 mmol) in tetrahydrofuran (130 mL) was charged with 3,4-dihydro-2//-pyran (24.6 g, 270 mmol) and p-toluenesulfonic acid monohydrate (140 mg, 0.76 mmol), and stirred for 18 h at room temperature. The resulting mixture was then diluted with ethyl acetate (360 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (200 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (17%), gave the title compound (12.5 g, 77%) as a yellow oil.
[00823] 1 H NMR (400 MHz, CDCI3) δ : 1 mixture of diastereomers, 3 7.13 (s, 0.4H), 7.10
(s, 0.5H), 6.90 (s, 0.5H), 6.52 (s, 0.4H), 6.15 (d, J=10.0 Hz, 0.4H), 5.98 (d, J=10.0 Hz, 0.5H), 5.80-5.68 (m, 1H), 5.17-4.94 (m, 3H), 4.64-4.21 (m, 3H), 3.91-3.85 (m, 1H), 3.83 (d, J=1.8 Hz, 3H), 3.66-3.39 (m, 2H), 3.14-3.00 (m, 1H), 2.08-1.87 (m, 1H), 1.83-1.33 (m, 12H), 1.26- 1.19 (m, 3H), 1.08-1.05 (m, 18H); MS (ES+): m/z = 603 (M+H)+; LCMS (Method A): tR = 9.95 min.
[00824] Allyl (6a5)-3-hydroxy-2-methoxy-12-oxo-6-((tetrahydro-2Zf-pyran-2-yl)oxy)- 6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12ZZ)-carboxylate (12)
[00826] A solution of allyl (6a5)-2-methoxy-12-oxo-6-((tetrahydro-2Zf-pyran-2-yl)oxy)-3- ((triisopropylsilyl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12Z7)- carboxylate (11) (10.5 g, 17.4 mmol) in tetrahydrofuran (33 mL) was charged with tetrabutylammonium fluoride (1 M in tetrahydrofuran, 26.1 mL, 26.1 mmol) at room temperature and stirred, to give an instantaneous orange colour. After 10 min, the reaction mixture was concentrated in vacuo, then immediately purified by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 0% to 100%), to give the title compound (7.13 g, 92%) as a white solid.
[00827] 1 H NMR (400 MHz, CDCI3), mixture of diastereomers, § 7.16 (s, 0.4H), 7.13 (s, 0.6H), 6.91 (br, 0.5H), 6.62 (br, 0.3H), 6.16 (d, J=10.1 Hz, 0.4H), 5.99 (d, J=10.1 Hz, 0.6H), 5.76 (ddd, .7=15.8, 10.3, 5.0 Hz, 0.8H), 5.14-5.03 (m, 2H), 4.98 (br, 0.5H), 4.61 (dd, J=13.7, 4.9 Hz, 0.8H), 4.55-4.48 (m, 0.3H), 4.48 (br, 0.3H), 4.40 (dd, J=13.9, 5.2 Hz, 0.5H), 4.32-4.20 (m, 1H), 3.90 (s, 3H), 3.88-3.81 (m, 1H), 3.63 (br, 0.4H), 3.59-3.52 (m, 0.6H), 3.49-3.43 (m, 1H), 3.11-2.98 (m, 1H), 1.97-1.89 (m, 1H), 1.80-1.47 (m, 12H); 13C NMR (100 MHz, CDCh), mixture of diastereomers, § 169.4, 169.2, 155.8, 147.9, 147.7, 146.6, 146.4, 132.2, 132.0, 128.4, 128.2, 125.9, 125.5, 117.0, 116.4, 115.8, 110.2, 109.8, 100.5, 95.3, 88.0, 84.1, 66.5, 66.3, 63.8, 63.2, 60.4, 56.2, 56.1, 55.4, 55.2, 38.8, 38.8, 31.0, 30.6, 25.2, 25.1, 23.22, 23.1, 23.0, 23.0, 20.1, 19.7, 18.4, 18.2; MS (ES+): m/z = 447 (M+H)+; LCMS (Method A): tR = 6.87 min.
[00828] Allyl (6aA)-2-methoxy-3-(4-methoxy-4-oxobutoxy)-12-oxo-6-((tetrahydro-2/7- pyran-2-yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12ZZ)- carboxylate (13)
[00829]
[00830] A solution of allyl (6a5)-3-hydroxy-2-methoxy-12-oxo-6-((tetrahydro-2Z/-pyran-2- yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12Z7)-carboxylate
(12) (1.0 g, 2.24 mmol) in A,A-dimethylformamide (5 mL) was charged with potassium carbonate (464 mg, 3.36 mmol) and methyl 4-bromobutanoate (296 /zL, 2.35 mmol) and the resulting mixture was stirred rapidly at room temperature for 16 h. After diluting into ethyl acetate (100 mL), the solution was washed with brine (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (silica), eluting with methanol/dichloromethane (from 0% to 2%) gave the title compound (1.02 g, 84%) as a cream solid (mixture of diastereomers).
[00831] 1 H NMR (400 MHz, CDCI3) δ 7.50 (s, 0.6H), 7.02 (s, 0.4H), 6.74 (s, 0.4H), 6.48 (s,
0.6H), 6.07 (d, .7=9.8 Hz, 0.6H), 5.9 (d, 7=10.2 Hz, 0.4H), 5.70-5.62 (m, 1H), 5.01-4.92 (m, 3H), 4.55-4.20 (m, 2H), 4.18-4.13 (m, 1H), 3.96-3.91 (m, 3H), 3.78 (s, 3H), 3.55 (s, 3H), 3.40- 3.34 (m, 2H), 3.00-2.91 (m, 1H), 2.24 (t, .7=7.0 Hz, 2H), 2.05-2.02 (m, 2H), 1.67-1.43 (m, 12H); 13C NMR (150 MHz, DMSO-^H 173.4, 168.5, 150.1, 149.2, 133.2, 127.6, 126.4, 116.9, 114.6, 110.8, 99.8, 94.7, 88.0, 83.9, 68.0, 66.0, 63.3, 62.5, 56.2, 55.4, 51.8, 38.6, 30.6, 30.2, 25.3, 24.3, 23.1, 19.7, 18.3; MS (ES+): m/z = 547 (M+H)+; LCMS (Method A): tR = 7.70 min. [00832] 4-(((6u.S')-5-((Allylo\y)earbonyl)-2-nietho\y-l 2-o\o-6-((tetrahydro-2//-pyran-
2-yl)oxy)-5,6,6a,7,8,9,10,12-octahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3- yl)oxy)butanoic acid (14)
[00833]
[00834] A solution of allyl (6a5)-2-methoxy-3-(4-methoxy-4-oxobutoxy)-12-oxo-6- ((tetrahydro-2Z7-pyran-2-yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2- a][l,4]diazepin-5(12Z7)-carboxylate (13) (770 mg, 1.40 mmol) in 1,4-dioxane (10 mL) was charged with an aqueous solution of sodium hydroxide (1 M, 10.0 mL, 10.00 mmol) and the resulting mixture was stirred at room temperature for 2 h, before concentrating in vacuo. Water (20 mL) was then added and neutralisation was brought about by cautious addition of an aqueous solution of acetic acid (5 M, 10 mL, 50 mmol). After extracting with ethyl acetate (2 x 50 mL), the combined organic extracts were then washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (700 mg, 93%) as a yellow oil (mixture of diastereomers). The product was employed in the subsequent step without any further purification.
[00835] 1 H NMR (400 MHz, DMSO-d6 )δ 12.15 (br. s„ 1H), 7.03 (s, 0.6H), 7.01 (s, 0.4H),
6.86 (s, 0.6H), 6.78 (s, 0.4H), 6.01 (d, J=\ 0.1 , 0.6 H), 5.92 (d, J=9.8, 0.4H), 5.83-5.69 (m, 1H), 5.11- 4.96 (m, 3H), 4.64- 4.36 (m, 2H), 4.16-4.02 (m, 1H), 400-3.92 (m, 2H), 3.80 (s, 3H), 3.79-3.70 (m, 2H), 3.54-3.46 (m, 1H), 2.89-2.83 (m, 1H), 2.36 (t, .7=7.2 Hz, 2H), 1.96-1.89 (m, 2H), 1.71-1.41 (m, 12H); 13C NMR (100 MHz, DMSO-d6) δ 174.5, 174.4, 168.5, 168.5, 150.1, 149.1, 133.1, 127.6, 126.3, 114.5, 110.7, 109.1, 99.7, 84.4, 68.0, 67.9, 56.2, 52.9, 38.5, 30.6, 30.3, 30.2, 25.4, 25.3, 23.1, 23.0, 18.3; MS (ES+/-): m/z = 533 (M+H)+, 531 (M-H)’; LCMS (Method A): ZR = 6.98 min.
[00836] tert-Butyl (l-methyl-5-((4-(2,2,2-trifluoroacetamido)phenyl)carbamoyl)-l//- pyrrol-3-yl
[00837] [00838] A solution of 4-((/e/7-butoxycarbonyl)amino)- 1 -methyl- 1 //-pyrrol -2-carboxy lie acid (647 mg, 2.69 mmol), 4-(dimethylamino)pyridine (898 mg, 7.35 mmol) and N-(3- dimcthylaminopropyl)-/V'-cthylcarbodiimidc hydrochloride (1.2 g, 6.25 mmol) in N,N- dimethylformamide (8 mL) was stirred for 30 min, after which M(4-aminophenyl)-2,2,2- trifluoroacetamide (500 mg, 2.45 mmol) was then added. The resulting solution was stirred at room temperature for 18 h and then quenched with a saturated aqueous solution of sodium hydrogen carbonate (15 mL). After extracting with ethyl acetate (2 x 50 mL), the combined organic extracts were dried over magnesium sulfate and then concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 0% to 100%), to give the title compound (839 mg, 80%) as a cream solid.
[00839] 1 H NMR (600 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.85 (s, 1H), 9.11 (s, 1H), 7.74 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 9.0 Hz, 2H), 6.94 (s, 1H), 3.81 (s, 3H), 1.46 (s, 9H); 13C NMR (150 MHz, DMSO-d6) δ 160.2, 153.3, 1375, 131.6, 123.1, 122.9, 121.8, 120.8, 118.4, 117.3, 115.4, 105.2, 78.8, 36.6, 28.7; MS (ES+): m/z = 427 (M+H)+; LCMS (Method B): fe = 3.83 min.
[00840] 4-Amino-l-methyl-A-(4-(2,2,2-trifluoroacetamido)phenyl)-lZf-pyrrole-2- carboxamide hydrochloride (16)
[00841] A solution of tert-butyl (l-methyl-5-((4-(2,2,2- trifluoroacetamido)phenyl)carbamoyl)-lZ/-pyrrol-3-yl)carbamate (15) (200 mg, 0.469 mmol) in dichloromethane/methanol (9:1, 1 mL) was charged with HC1 (4 M in 1,4-dioxane, 1 mL) and stirred at room temperature for 20 min, before concentrating in vacuo. Diethyl ether (10 mL) was then added to the residue, before concentrating again, and then applying strong vacuum for 1 h, to give the title compound (170 mg, crude) as a white solid, which was used immediately in the subsequent step without further purification.
[00842] MS (ES+): m/z = 327 (M+H)+; LCMS (Method A): tR = 4.80 min.
[00843] Allyl (6a5)-2-methoxy-3-(4-((l-methyl-5-((4-(2,2,2- trifluoroacetamido)phenyl)carbamoyl)-17/-pyrrol-3-yl)amino)-4-oxobutoxy)-12-oxo-6- ((t et rahvd ro-2//-pvra n-2-vl )oxy )-6,6a, 7.8,9, 10-hexahydrobenzo | c] pyrido [1,2- a] [l,4]diazepine-5(12ZZ)-carboxylate (17)
[00844] 4 -Amino-l-methyl-Af-(4-(2,2,2-trifluoroacetamido)phenyl)-177-pyrrole-2- carboxamide hydrochloride (16) (68 mg, 0.19 mmol) was added to a mixture of 4-(((6aS)-5- ((allyloxy)carbonyl)-2-mcthoxy-l2-oxo-6-((tctrahydro-2//-pyran-2-yl)oxy)-
5,6,6a,7,8,9,10,12-octahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3-yl)oxy)butanoic acid (14) (11.0 mg, 0.21 mmol), 4-(dimethylamino)pyridine (69 mg, 0.56 mmol) and N-(3- dimethylaminopropyl)-A7-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol) in N,N- dimethylformamide (4 mL), which was previously stirred for 30 min. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate (5 mL) and diluted with brine (50 mL). The aqueous phase was extracted with ethyl acetate (2 x 30 mL) and the combined organic extracts were then concentrated in vacuo. The resulting residue was purified by column chromatography (silica), eluting with methanol/dichloromethane (from 0% to 10%), to give the title compound (140 mg, 87%) as a viscous brown oil (mixture of diastereomers).
[00845] 1 H NMR (600 MHz, MeOD) 5 8.01 (s, 1H), 7.66 (d, J= 9.0 Hz, 2H), 7.63-7.60 (m,
2H), 7.16-7.14 (m, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 5.97 (d, J= 8.1 Hz, 1H), 5.80 (s, 1H), 5.09 (d, J= 11.3 Hz, 2H), 4.31-4.19 (m, 2H), 4.15-4.02 (m, 4H), 3.91-3.81 (m, 9H), 3.52 (dt, J = 10.2, 4.1 Hz, 1H), 2.56 (t, J= 12 Hz, 2H), 2.21-2.16 (m, 2H), 1.81-1.53 (m, 12H); 13C NMR (150 MHz, MeOD) 8 172.6, 171.5, 162.3, 157,0, 156.6, 152.0, 150.7, 137.9, 133.7, 133.5, 129.4, 126.7, 124.5, 123.2, 122.7, 122.4, 118.5, 118.0, 116.6, 115.8, 111.7, 106.8, 101.4, 83.6, 69.6, 67.6, 63.3, 58.0, 56.8, 54.9, 50.0, 40.1, 37.0, 31.7, 26.6, 24.1, 20.6, 19.3, 18.5; MS (ES+): m/z = 842 (M+H)+; LCMS (Method B): ZR = 4.00 min.
[00846] Allyl (6a5)-3-(4-((5-((4-aminophenyl)carbamoyl)-l-methyl-l/f-pyrrol-3- yl)amino)-4-oxobutoxy)-2-methoxy-12-oxo-6-((tetrahydro-2//-pyran-2-yl)oxy)- 6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12.H)-carboxylate (18)
[00847] A solution of allyl (6a5)-2-methoxy-3-(4-((l-methyl-5-((4-(2,2,2- trifluoroacetamido)phenyl)carbamoyl)-17f-pyrrol-3-yl)amino)-4-oxobutoxy)- 12-oxo-6-
((tetrahydro-2Z7-pyran-2-yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2- a][l,4]diazepine-5(12Z7)-carboxylate (17) (138 mg, 0.164 mmol) in 1,4-dioxane (5 mL) was charged with an aqueous solution of sodium hydroxide (1 M, 5.0 mL, 5.00 mmol). The reaction mixture was stirred at room temperature for 4 h and was then concentrated in vacuo, after which it was diluted into brine (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic extracts were then dried over sodium sulfate, filtered, and concentrated in vacuo, to give the title compound (120 mg, 98%) as a grey solid (mixture of diastereomers).
[00848] 1 H NMR (600 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.41 (s, 1H), 7.28 (d, J= 8.7 Hz, 2H), 7.17 (s, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 6.51 (d, J= 8.7 Hz, 2H), 5.98 (dd, J = 57.3, 9.9 Hz, 1H), 5.80-5.69 (m, 1H), 5.18-4.69 (m, 5H), 4.67-4.35 (m, 2H), 4.09-3.93 (m, 3H), 3.82 (s, 3H), 3.79 (d, J= 3.0 Hz, 3H), 3.79-3.72 (m, 2H), 3.56-3.45 (m, 1H), 2.90 (s, 1H), 2.42 (t, J= 7.1 Hz, 2H), 2.04-1.97 (m, 2H), 1.75-1.32 (m, 12H); 13C NMR (150 MHz, DMSO- d6) δ 169.3, 168.6, 162.8, 159.8, 150.3, 149.2, 145.2, 133.2, 128.7, 127.7, 126.3, 123.6, 122.6, 122.4, 118.5, 116.8, 114.5, 114.1, 110.9, 104.4, 94.7, 83.9, 68.5, 66.1, 56.2, 55.3, 38.7, 36.5, 36.2, 32.1, 31.2, 30.6, 25.4, 25.2, 24.9, 23.1, 23.0, 19.4, 18.3; MS (ES+): m/z = 745 (M+H)+; LCMS (Method A): tR = 5.88 min.
[00849] (.S')-V-(4-Aniinophenvl)-4-(4-((2-metho\v-12-o\o-6a,7.8,9,10,12- hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepm-3-yl)oxy)butanamido)-l-methyl-l//- pyrrol-2-carboxamide (19)
[00850] A solution of allyl (6a5)-3-(4-((5-((4-aminophenyl)carbamoyl)-l-methyl-lZf- pyrrol-3-yl)amino)-4-oxobutoxy)-2-methoxy-12-oxo-6-((tetrahydro-2Zf-pyran-2-yl)oxy)- 6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepine-5(12Z7)-carboxylate (18) (43 mg, 0.05 mmol) in dichloromethane (2 mL) was charged with tetrakis(triphenylphosphine)palladium(0) (3 mg, 5 mol%), and pyrrolidine (5 ,«L, 0.06 mmol). The resulting mixture was stirred at room temperature for 30 min and then concentrated in vacuo and subjected to strong vacuum for 40 min. Purification by flash column chromatography (silica) eluting with mcthanol/dichloromcthanc (from 0% to 10%) gave the title compound (21.8 mg, 78%) as cream solid.
[00851] [a]D 20 = 93.0° (c 1.36, DMSO); 1 H NMR (600 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.43
(s, 1H), 8.00 (d, J= 5.7 Hz, 1H), 7.31-7.26 (m, 3H), 7.17 (d, J= 1.8 Hz, 1H), 6.83 (d, J= 1.8 Hz, 1H), 6.80 (s, 1H), 6.51 (d, J= 8.8 Hz, 2H), 4.84 (s, 2H), 4.14-4.05 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.74-3.64 (m, 3H), 2.43 (t, J= 7 A Hz, 2H), 2.04 (dt, J= 13.9, 6.8 Hz, 2H), 1.90- 1.83 (m, 1H), 1.76-1.55 (m, 5H); 13C NMR (150 MHz, DMSO- d6) 66 168.8, 166.3, 164.7, 159.3, 150.2, 147.1, 144.7, 139.9, 128.2, 123.2, 122.1, 121.9, 120.7, 118.1, 113.7, 111.4, 109.5, 104.0, 67.8, 55.6, 54.9, 48.6, 39.5, 36.01, 31.9, 24.7, 23.7, 22.6, 17.7; MS (ES+): m/z = 559 (M+H)+; LCMS (Method B): = 2.53 min; HRMS (ESI, m/z): calc, for C30H35N6CV ([M]+H)+
559.2663 found 559.2651.
[00852] A-(4-((5)-2-((5)-2-(6-(2,5-Dioxo-2,5-dihydro-lZZ-pyrrol-l-yl)hexanamido)-3- methylbutanamido)propanamido)phenyl)-4-(4-(((5)-2-methoxy-12-oxo-6a,7,8,9,10,12- hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepm-3-yl)oxy)butanamido)-l-methyl-l/Z- pyrrole-2-carboxamide (20)
[00853] A solution of (5)-A-(4-aminophenyl)-4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12- hexahydrobenzo[e]pyrido[ 1 ,2-a] [ 1 ,4]diazepin-3-yl)oxy)butanamido)- 1 -methyl- 1 //-pyrrol-2- carboxamide (19) (350 mg, 0.63 mmol) and (6-(2,5-dioxo-2,5-dihydro-lZf-pyrrol-l- yl)hexanoyl)-Z-valyl-Z -alanine (252 mg, 0.95 mmol) in dichloromethane/methanol (19: 1, 20 mL) was cooled to 0 °C and charged with ethyl l,2-dihydro-2-ethoxy quinoline- 1 -carboxylate (234 mg, 0.95 mmol). The resulting mixture was stirred for 18 h at room temperature, whereupon it was diluted into petroleum spirit, 40-60 °C (300 mL) and filtered under reduced pressure. Preparative TLC (silica), eluting with methanol/ dichloromethane (5%) gave the title compound (158 mg, 27%) as a yellow solid.
[00854] 1 H NMR (400 MHz, DMSO-A) 8 9.91 (s, 1H), 9.84 (s, 1H), 9.76 (s, 1H), 8.13 (d, .7=6.8 Hz, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.82 (d, .7=8.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.57-7.46 (m, 2H), 7.27 (s, 1H), 7.21 (s, 1H), 6.99 (s, 2H), 6.97-6.91 (d, J=1.9 Hz, 1H), 6.80 (s, 1H), 4.37 (t, .7=7.2 Hz, 1H), 4.20-4.08 (m, 3H), 4.07-3.89 (m, 2H), 3.87-3.64 (m, 7H), 3.17 (d, J=52 Hz, 2H), 2.44 (t, J=1 A Hz, 2H), 2.24-2.10 (m, 2H), 2.05 (h, J=1.6, 7.2 Hz, 3H), 1.96 (q, .7=6.8 Hz, 1H), 1.89-E41 (m, 10H), 1.30 (d, .7=7.0 Hz, 3H), 1.23 (s, 1H), 0.84 (dd, J=16.0, 6.8 Hz, 6H); MS (ES+): m/z = 922 (M+H)+; LCMS (Method F): tR = 3.02 min.
[00855] Methyl 4-(4-((tert-butoxycarbonyl)ammo)phenyl)-l-methyl-l/Z-pyrrol-2- carboxylate (21) [00856] A solution of methyl 4-bromo-l -methyl- lZf-pyrrole-2-carboxylate (500 mg, 2.3 mmol), in acetonitrile (10 mL) and water (5 mL), was charged with tert-butyl (4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)carbamate (805 mg, 2.52 mmol), potassium carbonate (954 mg, 6.9 mmol), and tetrakis(triphenylphosphine)palladium (0) (140 mg, 5 mol%) and the resulting mixture was flushed with argon and then irradiated with microwaves at 100°C for 2 min. The mixture was then filtered through a pad of celite, which was washed with ethyl acetate and the resulting organic filtrate was concentrated in vacuo. Purification by flash column chromatography (silica), eluting with ethyl acetate/petroleum spirit, 40-60 °C (from 0% to 40%), gave the title compound (475 mg, 63%) as a white solid.
[00857] 1 H NMR (600 MHz, DMSO-A) J 9.29 (s, 1H), 7.50 (d, .7=2.0 Hz, 1H), 7.46-7.39
(m, 4H), 7.15 (d, 7=2.1 Hz, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 1.47 (s, 9H); 13C NMR (150 MHz, DMSO-A) <5 160.8, 152.7, 137.5, 128.0, 126.8, 124.8, 122.8, 122.2, 118.4, 113.7, 78.9, 50.9, 36.5, 28.1; MS (ES+): m/z = 331 (M+H)+; LCMS (Method B): = 4.22 min.
[00858] Methyl 4-(4-(4-((tert-butoxycarbonyl)ammo)-l-methyl-l/Z-pyrrol-2- carboxamido)phenyl)-l-methyl-l/Z-pyrrol-2-carboxylate (22)
[00859] A solution of methyl 4-(4-((tert-butoxycarbonyl)amino)phenyl)-l -methyl- \H- pyrrol-2-carboxylate (21) (950 mg, 2.88 mmol) in 1,4-dioxane (4 mL) and methanol (4 mL), was charged with hydrogen chloride (4 M in 1,4-dioxane, 8 mL), dropwise. The resulting mixture was stirred for 3 h and then concentrated in vacuo. The residue was then added to a mixture of 4-((terLbutoxycarbonyl)amino)-l-methyl-17f-pyrrol-2-carboxylic acid (830 mg, 3.45 mmol), 4-(dimethylamino)pyridine (1.05 g, 8.64 mmol) and A-(3-dimethylaminopropyl)- A'-ethylcarbodiimide hydrochloride (1.38 g, 7.20 mmol) in N, A-dimethylformamide (15 mL), which was previously stirred for 30 min. The resulting mixture was then stirred at room temperature for 18 h, before diluting into a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and brine (150 mL). This was then extracted with ethyl acetate (2 x 80 mL) and the combined organic extracts were then concentrated in vacuo. Purification by flash column chromatography (silica), eluting with acetone/petroleum spirit, 40-60 °C (from 0% to 40%), gave the title compound (860 mg, 66%) as a cream solid.
[00860] 1 H NMR (600 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.11 (s, 1H), 7.69 (d, .7=8.7 Hz, 2H),
7.55 (d, 7=2.0 Hz, 1H), 7.50 (d, 7=8.7 Hz, 2H), 7.19 (d, 7=2.1 Hz, 1H), 6.93 (d, J=6.2 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 1.46 (s, 9H); 13C NMR (150 MHz, DMSO-d6) δ 160.8, 159.6, 152.9, 137.4, 128.8, 127.0, 124.6, 122.8, 122.4, 122.2, 120.4, 117.7, 113.8., 104.6, 78.3, +
[00862] A solution of methyl 4-(4-(4-((/e/7-butoxycarbonyl)amino)-l -mcthyl-l //-pyrrol-2- carboxamido)phenyl)-l -methyl- lZf-pyrrol-2-carboxylate (22) (250 mg, 0.552 mmol) in 1,4- dioxane (1 mL) and methanol (1 mL), was charged with hydrogen chloride (4 M in 1 ,4-dioxane, 3 mL), dropwise. The resulting mixture was stirred for 4 h and then concentrated in vacuo. The residue was added to a mixture of 4-(((6aS)-5-((allyloxy)carbonyl)-2-methoxy-12-oxo-6- ((tetrahydro-27/-pyran-2-yl)oxy)-5,6,6a,7,8,9,10,12-octahydrobenzo[e]pyrido[l,2- a][l,4]diazepin-3-yl)oxy)butanoic acid (14) (272 mg, 0.511 mmol), 4-
(dimethylamino)pyridine (208 mg, 1.70 mmol) and A''-(3-dinicthylanrinopropyl)-/V'- ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol) in MAMimethylformamide (5 mL), which was previously stirred for 30 min. The resulting solution was stirred at room temperature for 18 h, before being diluted into ethyl acetate (60 mL), and washed with brine (50 mL). The organic phase was concentrated in vacuo. Purification by flash column chromatography (silica), eluting with acetone/ dichloromethane (from 0% to 30%), gave the title compound (242 mg, 51%) as a brown solid.
[00863] 1 H NMR (600 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.78 (s, 1H), 7.68 (d, ,7=8.8 Hz, 2H),
7.55 (d, ,7=1.9 Hz, 1H), 7.51 (d, ,7=8.7 Hz, 2H), 7.22 (d, .7=1.7 Hz, 1H), 7.20 (d, ,7=2.0 Hz, 1H), 7.06 (d, ,7=4.2 Hz, 1H), 6.94 (d, .7=1.8 Hz, 1H), 6.90 (s, 1H), 5.99-5.97 (m, 1H), 5.82-5.66 (m, 1H), 5.26-4.91 (m, 3H), 4.60-4.39 (m, 2H), 4.15-3.93 (m, 4H), 3.89 (s, 3H), 3.84-3.80 (m, 7H), 3.77 (s, 3H), 3.54-3.45 (m, 1H), 2.90 (d, J=10.9 Hz, 1H), 2.43 (t, .7=7.1 Hz, 2H), 2.05-2.00 (m, 2H), 1.72-1.38 (m, 12H); 13C NMR (150 MHz, DMSO-A) § 168.9, 168.8, 168.1, 168.1, 160.8, 159.6, 155.3, 149.8, 148.7, 137.3, 132.7, 128.9, 127.2, 127.0, 125.8, 124.6, 122.8, 122.7, 122.3, 122.1, 120.4, 118.8, 116.4, 114.0, 113.8, 110.4, 104.7, 94.3, 83.4, 68.1, 65.6, 62.0, 55.7, 54.8, 51.0, 39.5, 38.2, 36.5, 36.1, 31.7, 30.5, 30.2, 24.9, 24.8, 24.5, 22.6, 22.6, 18.9, 17.8; MS (ES+): m/z = 867 (M+H) +; LCMS (Method B): tR = 4.17 min. [00864] 4-(4-(4-(4-(((6u.S')-5-((Allvlo\v)carbonvl)-2-metho\v-l 2-o\o-6-((tetrahvdro-
2ZZ-pyran-2-yl)oxy)-5,6,6a,7,8,9,10,12-octahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3- yl)oxy)butanamido)-l-methyl-LH-pyrrol-2-carboxamido)phenyl)-l-methyl-l/Z-pyrrol-2- carboxylic acid (24)
[00865] A solution of allyl (6a5)-2-methoxy-3-(4-((5-((4-(5-(methoxycarbonyl)-l-methyl- lZf-pyrrol-3-yl)phenyl)carbamoyl)-l-methyl-lZ7-pyrrol-3-yl)amino)-4-oxobutoxy)-12-oxo-6- ((tetrahydro-2Z7-pyran-2-yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2- a][l,4]diazepin-5(12Z7)-carboxylate (23) (600 mg, 0.69 mmol) in 1,4-dioxane (10 mL) was charged with an aqueous solution of sodium hydroxide (1 M, 10 mL) and the resulting mixture was stirred at room temperature for 18 h, then concentrated in vacuo. Water (100 mL) was then added, and the mixture was acidified to pH = 5, with dropwise addition of glacial acetic acid. After extracting with ethyl acetate (2 x 100 mL), the combined organic extracts were concentrated to give the title compound (558 mg, 97%) as a cream solid (mixture of diastereomers).
[00866] 1 H NMR (600 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.89 (s, 1H), 9.78 (s, 1H), 7.68 (d,
J=8.1 Hz, 2H), 7.54-7.44 (m, 3H), 7.22 (s, 1H), 7.14 (d, .7=2.0 Hz, 1H), 7.06 (d, .7=4.3 Hz, 1H), 6.98-6.77 (m, 2H), 6.14 (d, J=9.9 Hz, 1H), 5.83-5.75 (m, 1H), 5.24-4.91 (m, 3H), 4.69-4.35 (m, 2H), 4.18-3.93 (m, 3H), 3.88 (s, 3H), 3.86-3.69 (m, 8H), 3.56-3.44 (m, 1H), 2.89 (dd, .7=23.0, 10.8 Hz, 1H), 2.44 (t, J=6.9 Hz, 2H), 2.04 (dp, J=20.8, 6.9 Hz, 2H), 1.76-1.29 (m, 12H); 13C NMR (150 MHz, DMSO-^H 169.3, 168.6, 168.5, 162.4, 160.1, 155.3, 149.8, 149.2, 149.0, 137.7, 133.2, 129.7, 127.7, 126.9, 125.0, 123.8, 123.2, 122.9, 122.6, 120.9, 119.2, 117.0, 114.5, 114.2, 110.8, 105.2, 99.7, 94.7, 88.0, 83.9, 68.5, 68.3, 66.0, 63.2, 62.5, 56.2, 55.4, 38.7, 37.0, 36.6, 32.2, 30.6, 25.4, 25.2, 23.1, 19.6, 18.3; MS (ES+): m/z = 853 (M+H) +; LCMS (Method B): tR = 3.83 min.
[00867] Allyl (6«5)-3-(4-((5-((4-(5-((4-aminophenyl)carbamoyl)-l-methyl-l/f-pyrrol- 3-yl)phenyl)carbamoyl)-l-methyl-l/Z-pyrrol-3-yl)ammo)-4-oxobutoxy)-2-methoxy-12- oxo-6-((tetrahydro-2ZZ-pyran-2-yl)oxy)-6,6a,7,8,9,10-hexahydrobenzo[e]pyrido[l,2- a] [l,4]diazepin-5(12ZZ)-carboxylate (25) [00868] A solution of 4-(4-(4-(4-(((6aS)-5-((allyloxy)carbonyl)-2-methoxy-12-oxo-6- ((tetrahydro-2Zf-pyran-2-yl)oxy)-5,6,6a,7,8,9, 10, 12-octahydrobenzo[e]pyrido[l ,2- a] [ 1 ,4] diazepin-3 -yl)oxy)butanamido)- 1 -methyl- 1 //-pyrro I -2-carboxami do)phcny I )- 1 - methyl- lZf-pyrrol-2-carboxylic acid (24) (210 mg, 0.246 mmol) in A,A-dimethylformamide (8 mL) was charged with 4-(dimethylamino)pyridine (90 mg, 0.74 mmol) and N-(3- dimethylaminopropyl)-A'-ethylcarbodiimide hydrochloride (118 mg, 0.615 mmol), and stirred for 30 min at room temperature. To the resulting mixture, 1 ,4-benzenediamine (40 mg, 0.370 mmol) was added and stirred for a further 18 h. The reaction mixture was then diluted into a saturated aqueous solution of sodium hydrogen carbonate (100 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were concentrated in vacuo. Purification by flash column chromatography (silica), eluting with methanol/ dichloromethane (from 0% to 20%), gave the title compound (110 mg, 47%) as a cream solid (mixture of diastereomers).
[00869] 1 H NMR (600 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.78 (s, 1H), 9.48 (s, 1H), 7.70 (d,
.7=8.6 Hz, 2H), 7.48 (d, .7=8.5 Hz, 2H), 7.39 (d, J=1.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.30 (d, J=1.8 Hz, 1H), 7.23-7.20 (m, 1H), 7.06 (d, J=4.1 Hz, 1H), 6.97-6.94 (m, 1H), 6.80 (s, 1H), 6.57-6.52 (m, 2H), 6.03 (d, J=10.0 Hz, 1H), 5.81-5.72 (m, 1H), 5.26-4.95 (m, 3H), 4.92 (s, 2H), 4.64-4.36 (m, 2H), 4.14-3.95 (m, 3H), 3.89 (s, 3H), 3.83 (dd, J=6.0, 2.4 Hz, 6H), 3.81- 3.70 (m, 1H), 3.55-3.34 (m, 2H), 3.00-2.82 (m, 1H), 2.44 (t, .7=7.0 Hz, 2H), 2.09-1.99 (m, 2H), 1.94-1.35 (m, 12H); 13C NMR (150 MHz, DMSO-d6) δ 169.4, 168.6, 160.1, 159.7, 149.2, 145.1, 137.5, 133.2, 128.8, 127.1, 125.1, 124.8, 123.2, 122.6, 122.4, 122.3, 121.0, 119.2, 117.0, 114.3, 110.9, 110.8, 110.1, 105.2, 99.7, 94.7, 88.0, 83.9, 68.5, 68.3, 66.0, 63.2, 56.2, 55.4, 38.7, 38.6, 36.8, 36.6, 32.2, 32.1, 30.9, 30.6, 25.4, 25.2, 24.9, 23.1, 23.0, 19.6, 19.4, 18.3; MS (ES+): m/z = 943 (M+H)+; LCMS (Method B): ZR = 3.45 min.
[00870] (5)-A-(4-ammophenyl)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12- hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepm-3-yl)oxy)butanamido)-l-methyl-l/Z- pyrrol-2-carboxamido)phenyl)-l-methyl-LH-pyrrol-2-carboxamide (26)
[00871] A solution of allyl (6a5)-3-(4-((5-((4-(5-((4-aminophenyl)carbamoyl)-l-methyl- lZf-pyrrol-3-yl)phenyl)carbamoyl)-l-methyl-lZf-pyrrol-3-yl)amino)-4-oxobutoxy)-2- methoxy-12-oxo-6-((tetrahydro-2Zf-pyran-2-yl)oxy)-6,6a,7,8,9,10- hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-5(12Z/)-carboxylate (25) (250 mg, 0.265 mmol) in dichloromethane (3 mL) was charged with tetrakis(triphenylphosphine)palladium(0) (15 mg, 5mol%), and pyrrolidine (26 μL, 0.32 mmol) and the resulting mixture was stirred at room temperature for 20 min, before being subjected to strong vacuum for 30 min. The resulting residue was then purified by flash column chromatography (silica), eluting with methanol/di chloromethane (from 0% to 10%) to give the title compound (118 mg, 59%) as a cream solid.
[00872] [a]D 23 = 85° (c 0.143, DMSO); 1 H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.78
(s, 1H), 9.48 (s, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.70 (d, .7=8.6 Hz, 2H), 7.48 (d, .7=8.6 Hz, 2H), 7.39 (d, .7=1.5 Hz, 1H), 7.33 (d, .7=8.7 Hz, 2H), 7.30 (d, J=1.5 Hz, 1H), 7.27 (s, 1H), 7.21 (d, 7=1.4 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 6.80 (s, 1H), 6.53 (d, 7=8.7 Hz, 2H), 4.86 (s, 2H), 4.13 (dt, J=9.6, 6.3 Hz, 1H), 4.07- 3.97 (m, 2H), 3.88 (s, 3H), 3.83 (d, 7=5.1 Hz, 6H), 3.72 (dt, 7=8.4, 4.1 Hz, 1H), 3.16-3.08 (m, 1H), 2.44 (t, 7=7.4 Hz, 2H), 2.07- 2.02 (m, 3H), 1.89-1.59 (m, 5H); 13C NMR (150 MHz, DMSO-d6) δ 168.9, 166.3, 164.7, 159.6, 159.2, 150.2, 147.2, 144.8, 139.9, 137.0, 129.7, 128.2, 126.7, 124.7, 124.4, 122.7, 122.1, 121.9, 121.8, 120.7, 120.5, 118.8, 113.7, 111.4, 109.6, 109.5, 104.8, 67.8, 55.6, 49.3, 36.3, 36.2, 31.9, 24.7, 23.7, 22.6, 17.7; MS (ES+): m/z = 757 (M+H)+; LCMS (Method A): tR = 5.80 min; HRMS (El, m/z): calculated for C42H45N8O6+ (M+H)+ 757.3457 found 757.3457.
[00873] V-(4-((.S')-2-((.S')-2-(6-(2,5-Dioxo-2,5-dihvdro-l //-pvrrol-l-vl)hexanamido)-3- methylbutanamido)propanamido)phenyl)-4-(4-(4-(4-(((A)-2-methoxy-l 2-oxo- 6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3-yl)oxy)butanamido)-l- methyl-17/-pyrrol-2-carboxamido)phenyl)-l-methyi-17/-pyrrol-2-carboxamide (27)
[00874] A solution of (>S')-/V-(4-aminophcnyl)-4-(4-(4-(4-((2-mcthoxy-l 2-oxo- 6a, 7, 8, 9, 10, 12-hexahydrobenzo[e]pyrido[ 1 ,2-zz] [ 1 ,4]diazepin-3-yl)oxy)butanamido)-l - mcthyl-l /7-pyrrol-2-carboxamido)phcnyl)-l -methyl- l //-pyrrol-2-carboxamidc (26) (200 mg, 0.264 mmol), in dichloromethane (3 mL) and methanol (300 μL) was cooled to 0 °C, then charged with 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (98 mg, 0.396 mmol) and (6- (2,5-dioxo-2,5-dihydro-l //-pyrrol-l -yl)hcxanoyl)-L-valyl-L-alaninc (106 mg, 0.277 mmol). The resulting mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. Purification by flash column chromatography (silica), eluting with methanol/dichloromethane (from 0% to 10%) gave the title compound (150 mg, 51%) as a white solid.
[00875] [a]D 22 = 85° (c 0.200, DMSO); 1 H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.84
(s, 1H), 9.79 (s, 2H), 8.12 (d, J=1.0 Hz, 1H), 8.00 (d, J=5.7 Hz, 1H), 7.81 (d, .7=8.6 Hz, 1H), 7.71 (d, .7=8.7 Hz, 2H), 7.65 (d, ,7=9.0 Hz, 2H), 7.54 (d, ,7=9.0 Hz, 2H), 7.49 (d, .7=8.6 Hz, 2H), 7.44 (d, ,7=1.5 Hz, 1H), 7.38 (d, ,7=1.7 Hz, 1H), 7.27 (s, 1H), 7.22 (t, ,7=1.7 Hz, 1H), 6.99 (s, 2H), 6.97 (d, ,7=1.6 Hz, 1H), 6.80 (s, 1H), 4.42-4.35 (m, 1H), 4.17 (dd, ,7=8.6, 6.9 Hz, 1H), 4.14-3.93 (m, 4H), 3.91 (s, 3H), 3.83 (d, J=5.7 Hz, 6H), 3.74-3.65 (m, 3H), 3.37 (t, .7=7.1 Hz, 2H), 3.15-3.08 (m, 1H), 2.47-2.42 (m, 2H), 2.21-1.93 (m, 4H), 1.90-1.73 (m, 2H), 1.60-1.44 (m, 4H), 1.31 (d, ,7=7.1 Hz, 3H), 1.22-1.14 (m, 4H), 0.85 (dd, ,7=23.3, 6.8 Hz, 6H); 13C NMR (150 MHz, DMSO-d6) δ 172.3, 171.0, 171.0, 170.7, 168.9, 166.3, 164.7, 159.6, 159.5, 150.7, 150.2, 147.1, 139.9, 137.1, 134.8, 134.4, 129.5, 126.2, 125.3, 124.4, 122.7, 122.1, 121.9, 120.7,
120.5, 120.3, 119.3, 111.4, 110.3, 109.5, 104.8, 67.8, 57.5, 55.9, 55.6, 49.3, 48.9, 39.5, 37.0,
36.5, 36.2, 34.9, 31.9, 30.4, 27.7, 25.8, 24.9, 23.7, 22.6, 19.2, 18.2, 18.0, 17.7; MS (ES+): m/z = 1121 (M+H)+; LCMS (Method B): fe = 3.57 min; HRMS (ESI, m/z): calc, for C6OH7ONHOII+ (M+H)+ 1120.5250 found 1120.5257.
[00876] m/7-Butvl ((2.S')-l-(((2.S')-l-(((LS'.9.S')-9-ethvl-5-nuoro-9-hvdro\v-4-methvl- 10,13-dioxo-2,3,9,10,12,13,13a,14-octahydro-lZ/-benzo[<fe]pyrano[3',4':5,6]indeno[l,2- Z>]quinolm-l-yl)ammo)-l-oxopropan-2-yl)ammo)-3-methyl-l-oxobutan-2-yl)carbamate (28)
[00877] A solution of (tert-butoxycarbonyl)-Z-valyl-Z-alanine (54.7 mg, 0.19 mmol), exatecan mesylate (100 mg, 0.19 mmol) and A/A-diisopropylcthylaininc (100 μL, 0.57 mmol) in A,A-dimethylformamide (3 mL) was charged with HATU (80 mg, 0.19 mmol) and the resulting mixture was stirred for 10 min at room temperature, whereupon it was concentrated in vacuo, to give the title compound, which was used in the subsequent step without any further purification.
[00878] (2.S')-2-Amino-V-((2.S')-l -((( ES'.9.S')-9-ethvl-5-nuoro-9-hvdro\v-4-inethvl-l 0,13- dioxo-2,3,9,10,12,13,13a,14-octahydro-EH-benzo[<fe]pyrano[3',4':5,6]indeno[l,2- Z>]quinolm-l-yl)ammo)-l-oxopropan-2-yl)-3-methylbutanamide trifluoroacetate (29)
[00879] tert-Butyl ((2S)-l-(((2S)-l-(((15,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,12,13,13a,14-octahydro-lZf-benzo[t/e]pyrano[3',4':5,6]indeno[l,2-6]quinolin- l-yl)amino)-l-oxopropan-2-yl)amino)-3 -methyl- l-oxobutan-2-yl)carbamate (28) (134 mg, crude) was solubilised into trifluoroacetic acid (1.5 mL) and dichloromethane (3 mL) and the resulting mixture was stirred for 15 min, whereupon it was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in water/acetonitrile) and lyophilised to give the title compound (96 mg, 71%, two steps).
[00880] l-(3-(2,5-Dioxo-2,5-dihydro-lZZ-pyrrol-l-yl)propanamido)-7V-((25)-l-(((25)-l- (((15,95)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14- octahydro-lZZ-benzo[<Ze]pyrano[3',4':5,6]mdeno[l,2-6]qumolm-l-yl)ammo)-l- oxopropan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)-3,6,9,12,15,18,21,24- octaoxaheptacosan-27-amide (30)
[00881] A solution of l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-3-oxo- 7,10,13,16,19,22,25,28-octaoxa-4-azahentriacontan-31-oic acid (46 mg, 0.078 mmol) in N,N- dimethylformamide (2 mL) was charged with A,A-diisopropylethylamine (47 μL, 0.27 mmol) and HATU (30 mg, 0.079 mmol). After stirring for 1 min at room temperature, (25)-2-amino- A-((25)-l-(((15,95)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14- octahydro-lZf-benzo[t/e]pyrano[3',4':5,6]indeno[l,2-6]quinolin-l-yl)amino)-l-oxopropan-2- yl)-3-methylbutanamide trifluoroacetate (29) (56 mg, 0.078 mmol) was added and stirring was continued for another 10 min. The resulting mixture was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in water/ acetonitrile) and the pure fractions lyophilised to give the title compound (60 mg, 65%) as a yellow solid.
[00882] 1 H NMR (400 MHz, CDCh) 7.61-7.60 (m, 2H), 7.42 (d, .7=8.0 Hz, 1H), 7.04 (d, .7=8.0 Hz, 1H), 6.94 (d, .7=8.0 Hz, 1H), 6.69 (s, 2H), 6.48 (br s, 1H), 5.74 (d, J=12.0 Hz, 1H),
5.56-5.55 (m, 1H), 5.47 (d, J=\ 6.0 Hz, 1H), 5.28 (d, J=12.0 Hz, 1H), 5.04 (d, J=16.0 Hz, 1H),
4.57-4.54 (m, 1H), 3.96 (t, .7=4.0 Hz, 1H), 3.83-3.80 (m, 3H), 3.63-3.59 (m, 29H), 3.52 (t, .7=4.0 Hz, 2H), 3.40 (q, .7=4.0 Hz, 2H), 3.26-3.22 (m, 1H), 3.11-3.05 (m, 1H), 2.56-2.52 (m, 3H), 2.40-2.33 (m, 6H), 2.28-2.13 (m, 3H), 1.93-1.84 (m, 2H), 1.47 (d, J=8.0 Hz, 3H), 1.03 (t,J=6.0 Hz, 3H), 0.91 (t, .7=6.0 Hz, 6H); MS (ES+): m/z = 1180.5 (M+H)+; LCMS (5 min): tR = 1.87 min; HPLC (15 min): 8.91 min (99.1% purity, 220 nm).
[00883] (9ZZ-Fluoren-9-yl)methyl ((2.S)-l-(((2.S')-l-((4-(((((l.S'.9.S)-9-ethyl-5-lluoro-9- hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14-octahydro-lZf- benzo[<fe]pyrano[3',4':5,6]mdeno[l,2-/>]qumolin-l- yl)carbamoyl)oxy)methyl)phenyl)ammo)-l-oxopropan-2-yl)ammo)-3-methyl-l- oxobutan-2-yl)carbamate (31) [00884] A solution of (9//-fluorcn-9-yl)mcthyl ((5)-3-methyl-l-(((5)-l-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxopropan-2-yl)amino)- 1 -oxobutan-2- yl)carbamate (141 mg, 0.21 mmol) in A\A'-diincthylforinainidc (3 mL) was charged with exatecan mesylate (100 mg, 0.19 mmol), l-hydroxy-7-azabenzotriazole (10 mg, 0.073 mmol) and A'.A'-diisopropylcthylaminc (83 μL, 0.48 mmol), and then stirred at room temperature for 6 h. The resulting mixture was employed in the subsequent step without any further manipulations.
[00885] 4-((5)-2-((5)-2-Amino-3-methylbutanamido)propanamido)benzyl ((LS',9.S')-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14-octahydro-lZZ- benzo[<Ze]pyrano[3',4':5,6]indeno[l,2-b]qumolm-l-yl)carbamate trifluoroacetate (32)
[00886] The reaction mixture containing (9//-fluorcn-9-yl (methyl ((25)-l-(((25)-l-((4- (((((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14- octahydro- lZ/-benzo[flte]pyrano[3', 4':5,6]indeno[ l,2-6]quinolin-l - yl)carbamoyl)oxy)methyl)phenyl)amino)- 1 -oxopropan-2-yl)amino)-3-methyl- 1 -oxobutan-2- yl)carbamate (31) (184 mg, crude) in AyV-dinicthylforinainidc (3 mL) was charged with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.18 mL, 1.20 mmol) dropwise, and then stirred for 10 min, before it was purified by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in water/acetonitrile) and lyophilised to give the title compound (89 mg, 54%, two steps).
[00887] 4-((25,55)-37-(2,5-Dioxo-2,5-dihydro-lZZ-pyrrol-l-yl)-5-isopropyl-2-methyl-
4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl
((15,95)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,12,13,13a,14- octahydro-lZZ-benzo[<fe]pyrano[3',4':5,6]mdeno[l,2-b]qumolm-l-yl)carbamate (33)
[00888] A solution of l-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-3-oxo- 7,10,13,16,19,22,25,28-octaoxa-4-azahentriacontan-31-oic acid (37 mg, 0.062 mmol) in N,N- dimethylformamide (2 mL) was charged with A,A-diisopropylethylamine (0.039 mL, 0.22 mmol) and HATU (24 mg, 0.063 mmol), and the resulting mixture was stirred for 1 min at room temperature, before adding 4-((5)-2-((5)-2-amino-3- methylbutanamido)propanamido)benzyl ((15,95)-9-ethyl-5-fluoro-9-hydroxy-4-methyl- 10,13-dioxo-2,3,9,10,12,13,13a,14-octahydro-lZ7-benzo[t/e]pyrano[3',4':5,6]indeno[l,2- b] quinolin- 1 -yl)carbamate trifluoroacetate (32) (54 mg, 0.062 mmol) and stirring for a further 10 min. Purification by reverse-phase preparative HPLC (0.1% trifluoroacetic acid in water/acetonitrile) followed by lyophilisation, gave the title compound (57 mg, 69%) as a yellow solid.
[00889] 1 H NMR (400 MHz, CDCh) 8.61 (s, 1H), 7.63-7.54 (m, 4H), 7.30 (s, 2H), 7.12 (s,
1H), 7.02 (s, 1H), 6.67 (s, 2H), 6.45 (s, 1H), 5.69 (d, J=12.0 Hz, 1H), 5.50-5.31 (m, 4H), 5.20 (d, .7=8.0 Hz, 1H), 5.08 (d, .7=8.0 Hz, 1H), 4.62 (br s, 1H), 4.23 (br s, 1H), 3.84-3.70 (m, 4H), 3.67-3.59 (m, 28H), 3.49 (t, .7=4.0 Hz, 2H), 3.37 (q, .7=4.0 Hz, 2H), 3.16 (br s, 2H), 2.68-2.65 (m, 1H), 2.49-2.46 (m, 3H), 2.41 (s, 3H), 2.35-2.27 (m, 3H), 1.90 (br s, 5H), 1.42 (d, .7=8.0 Hz, 3H), 1.04-1.00 (m, 9H); MS (ES+): m/z = 1329.8 (M+H)+; LCMS (5 min): tR = 2.05 min; HPLC (15 min): 10.48 min (100% purity, 220 nm).
[00890] 4-((785,815,845,895,925)-78-
((2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- T etracosaoxatriheptacontan-73-yl)carbamoyl)-81 -(3-(((5)- 1 -(((5)- 1 -((4-((((((5)-4, 11 -diethyl- 9-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-lZf-pyrano[3',4':6,7]indolizino[l ,2-6]quinolin-4- yl)oxy)carbonyl)oxy)methyl)phenyl)amino)-l-oxopropan-2-yl)amino)-3-methyl-l-oxobutan- 2-yl)amino)-3-oxopropyl)-89-isopropyl-92-methyl-75, 80, 83,87, 90-pentaoxo-84-(4-(3-tosyl- 2-(tosylmethyl)propanoyl)benzamido)- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-
74,79,82,88,9 l-pentaazatrinonacontan-93-amido)benzyl ((5)-4,l l-diethyl-9-hydroxy-3,14- dioxo-3,4,12,14-tetrahydro-lZf-pyrano[3',4':6,7]indolizino[l,2-6]quinolin-4-yl) carbonate
[00891] A solution of 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl
((S)-4, 11 -diethyl-9-hydroxy-3 , 14-dioxo-3 ,4,12,14-tetrahydro- 1 H- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-4-yl) carbonate (41 mg, 0.00576 mmol) and (785, 815, 845)-78-((2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71- tetracosaoxatriheptacontan-73-yl)carbamoyl)-81-(2-carboxyethyl)-75,80,83-trioxo-84-(4-(3- tosyl-2-(tosylmethyl)propanoyl)benzamido)-
2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-
74,79,82-triazaheptaoctacontan-87-oic acid (80 mg, 0.00264 mmol) in N,N- dimethylformamide (2 mL) was cooled to 0 °C. HATU (26 mg, 0.00687 mmol) was then added, followed by NMM (17.5 μL, 0.00158 mmol). The resulting mixture was stirred for 45 min at 0 °C, then concentrated in vacuo. Purification by Gilson preparative HPLC (Phenomenex, Luna 5 pm C18(2) 100 A, LC Column 150 x 21.2 mm) using gradient method: 14-70% Water- MeCN (0.05% formic acid), followed by lyophilisation, gave the title compound (52.5 mg, 45%) as a yellow solid.
[00892] Theoretical exact mass: 4413.1; found: 2207.55 (M+2H)2+, 1472.03 (M+3H)3+, 1104.28 (M+4H)4+. [00893] HPLC (14 min): 7.70 min (97.8% purity, 254 nm).
[00894] (9ZZ-Fluoren-9-yl)methyl ((.S')-l-(((.S')-l-((4-(4-(4-(4-(4-(((.S')-2-metho\y-12-o\o-
6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3-yl)oxy)butanamido)-l- methyl-LH-pyrrole-2-carboxamido)phenyl)-l-methyl-l/Z-pyrrole-2- carboxamido)phenyl)ammo)-l-oxopropan-2-yl)ammo)-3-methyl-l-oxobutan-2- yl)carbamate (35)
[00895] A mixture consisting of (((9Zf-fluoren-9-yl)methoxy)carbonyl)-£-valyl-£-alanine (325 mg, 0.793 mmol) and ethyl l,2-dihydro-2-ethoxyquinoline-l -carboxylate (326 mg, 1.32 mmol) in A,A-dimethylformamide (20 mL) was stirred at room temperature for 1 h before adding (5)-A-(4-aminophenyl)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12- hexahydrobenzo[e]pyrido[ 1 ,2-a] [ 1 ,4]diazepin-3-yl)oxy)butanamido)- 1 -methyl-lZf-pyrrol-2- carboxamido)phenyl)-l -methyl- lZf-pyrrol-2-carboxamide (26) (500 mg, 0.661 mmol) and stirring the resulting mixture at 0 °C for 5 h, then warming to room temperature and stirring for a further 13 h. After the reaction was judged to be complete by LCMS, the reaction mixture was diluted into dichloromethane/methyl tert-butyl ether (1:8, 200 mL) and stirred for a further 1 h before filtering under reduced pressure. The filter cake was dried under strong vacuum, to give the title compound (500 mg, 66%) as a yellow solid, which was employed in the subsequent step without further purification.
[00896] MS (ES+): m/z = 1149 (M+H)+; LCMS (Method F): tR = 3.92 min.
[00897] A-(4-((5)-2-((5)-2-Amino-3-methylbutanamido)propanamido)phenyl)-4-(4-(4-(4- (((5)-2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3- yl)oxy)butanamido)- 1 -methyl- 1 //-pyrrolc-2-carboxamido)phcnyl )- 1 -methyl- 1 //-pyrrolc-2- carboxamide (36)
[00898] A mixture consisting of (9//-tluorcn-9-yl)mcthyl ((5)-l-(((5)-l-((4-(4-(4-(4-(4- (((5)-2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[l,2-a][l,4]diazepin-3- yl)oxy)butanamido)- 1 -methyl- 1 //-pyrrolc-2-carboxamido)phcnyl )- 1 -methyl- I //-pyrrolc-2- carboxamido)phenyl)amino)- 1 -oxopropan-2-yl)amino)-3-methyl- 1 -oxobutan-2-yl)carbamate (35) (500 mg, 0.435 mmol) and piperidine (111 mg, 1.31 mmol) in A,A-dimethylformamide (10 mL) was stirred at room temperature for 16 h, before LCMS showed consumption of starting material. After dilution into dichloromethane/methyl tert-butyl ether (1:8, 200 mL), the residue was stirred for 1 h before filtration under reduced pressure. The filter cake was then dried under reduced pressure, to give the title compound (400 mg, 99%) as a yellow solid.
[00899] MS (ES+): m/z = 927 (M+H)+; LCMS (Method F): tR = 2.81 min.
[00900] (S)-A5-((S)- 1 -(((5)- 1 -((4-(4-(4-(4-(4-(((5)-2-Methoxy- 12-oxo-6a,7,8,9, 10,12- hexahydrobenzo[e]pyrido[ 1 ,2-a] [ 1 ,4]diazepin-3-yl)oxy)butanamido)- 1 -methyl- 1 //-pyrrolc-2- carboxamido)phenyl)- 1 -methyl- 1 //-pyrrolc-2-carboxamido)phcnyl )amino)- 1 -oxopropan-2- yl)amino)-3-methyl-l-oxobutan-2-yl)-2-(4-(3-tosyl-2-(tosylmethyl)propanoyl)benzamido)- A1 -(2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68,71- tetracosaoxatriheptacontan-73-yl)pentanediamide (37)
[00901] A solution of (5)-75-oxo-76-(4-(3-tosyl-2-(tosylmethyl)propanoyl)benzamido)- 2,5,8,l l,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-74- azanonaheptacontan-79-oic acid (85 mg, 0.05 mmol) and A-(4-((5)-2-((5)-2-amino-3- methylbutanamido)propanamido)phenyl)-4-(4-(4-(4-(((5)-2-methoxy-12-oxo-6a,7,8,9,10,12- hexahydrobenzo[e]pyrido[ 1 ,2-a] [ 1 ,4]diazepin-3-yl)oxy)butanamido)- 1 -methyl-lZf-pyrrole-2- carboxamido)phenyl)-l -methyl- lZf-pyrrole-2-carboxamide (36) (51 mg, 0.055 mmol) in N,N- dimethylformamide (2 mL) was cooled to 0 °C and charged with HATU (27 mg, 0.07 mmol) and NMM (16.5 μL, 0.15 mmol), then stirred at this temperature for 1 h. The reaction mixture was purified by reverse-phase chromatography using Gilson preparative HPLC (Phenomenex, Luna 5 pm C18(2) 100 A, LC Column 150 x 21.2 mm) using gradient method: 14-70% Water- MeCN (no modifier), followed by lyophilisation, to give the title compound (64 mg, 49%) as a white solid.
[00902] Theoretical exact mass: 2607.2; found: 1304.6 (M+2H)2+, 870.1 (M+3H)3+, 652.8 (M+4H)4+. [00903] HPLC (14 min): 7.46 min (97.6% purity, 254 nm).
[00904] Compound numbers and structure are shown below in Table 5.
Table 5: Compound numbers and structure.
Example 2: Conjugation to mAb and in vivo efficacy
Conjugation of Payload to Antibody
[00905] This Example provides a non-limiting method for preparing ADCs of the disclose by conjugating a mAb to a compound of the disclosure (a compound of formula (III) such as a compound from Table 5, e.g. compound 30). 21.5 mg IgGl antibody (8.0 mg/ml in PBS) is charged with EDTA to a final concentration of 2 mM. Reduction is attained by adding 1.27 molar equivalents TCEP (10 mM in water) and incubating for 2 hours at 20°C. After 1.5 hours, a reduction in-process test conjugation with an established payload (e.g., Mal- vcMMAE) is performed, and analyzed by HIC to test for the reduction level. As the target reduction level had not been reached, another 0.1 molar equivalents TCEP are added and the reduction time extended by 1 hour. After 0.5 hours, a second in-process test is run. After confirmation of the desired reduction level, 20% (v/v) Propylene glycol is added to the reduced antibody followed by 6.4 molar equivalents desired linker/payload (a compound of formula (III) such as a compound from Table 5, e.g. compound 30) (10 mM stock in DMSO). The solution is incubated for 1 hour at rt. The reaction is quenched by adding 6.4 molar equivalents N-acetylcysteine (10 mM in water). The ADC is buffer exchanged via G25 into PBS and washed by dead-end filtration (Vivaspin-20, 30 kDa MWCO, 0.0006 m2) for 10 DVs. Samples are taken for analysis by HIC, SEC, PLRP, free toxin linker, Endosafe, and the concentration is determined using a SEC calibration curve. Aliquotting is carried out under laminar flow, and the product is stored at -80°C. Only disposable, sterile and pyrogen/DNA/RNA-free plasticware is used.
Antigen Binding Affinity (FACS)
[00906] Test samples are prepared in FACS buffer (PBS, 1% BSA, 0. 1% NaNs) and studies are performed with a 10 pg/mL starting concentration and 3-fold 8-point serial dilution. Antigen positive cells are seeded at a density of lx 105 per well of a 96-well assay plate (BD 351177), and samples added at 100 μL per well. Assay plates are incubated on ice for 30 mins.
[00907] After 30 minutes, assay plates are centrifuged, supernatant is discarded and cells are washed with FACS buffer. 100 μL of 1 :800 Goat pAb Anti-Human IgG (Fc-specific)-PE are added per well. Assay plates are then incubated on ice for a further 30mins.
[00908] At this time point, assay plates are centrifuged, supernatant is discarded and cells are washed with FACS buffer. 100 μL of BD Cellfix (diluted 1: 10) in water is added per well. Data readout consists of fluorescence and is measured using a cytometer (e.g. Thermo Fisher Attune NxT Focusing cytometer).
In vivo Efficacy
[00909] Antitumour activity of the selected ADCs is assessed in tumour xenograft models (both cancer-derived and patient-derived) obtained by inoculation of the relevant cell-line (e.g., MDA-MB-231) in mice.
[00910] Maximum tolerated dose (MTD) of the relevant ADCs is established on 6-8 CD1 mice (or equivalent) at multiple concentrations on a single dose basis. Once the single dose MTD is determined, an efficacy study is initiated at doses under the maximum tolerated dose. [00911] Briefly, tumours are implanted onto the flank of the mice using a 23-gauge needle, and are randomly assigned to groups (e.g., control or ADC). After implantation, tumours are measured 3 times per week using digital calipers. The length and width of the tumour is measured and volume calculated using the following formula: volume = (length x width2)/2. The bodyweight of all mice on the study is measured and recorded 3 times per week. Mice are observed daily and any signs of distress or changes to general condition (e.g., starred fur, lack of movement, difficulty breathing). Specific criteria are set for early termination, and this only occurs if tumour volume exceeded 1500mm3, weight loss of>15% occurred or animals become compromised (e.g., inability to eat/drink). [00912] Mice are housed in IVC cages (5 mice per cage) with individual mice identified by ear punch. Cages, bedding and water are sanitized before use. Animals are provided with Com- o-cobs enrichment bedding to provide environment enrichment and nesting material. All animals have free access to a standard certified commercial diet and water. The animal holding room is maintained as follows: room temperature at 20-24°C, humidity at 30-70% and a 12h light/dark cycle used. Cages are changed once a week with food and water replaced when necessary. All procedures are carried out under the guidelines of the Animal (Scientific Procedures) Act 1986.
[00913] A major focus of this study is to develop a treatment for cancer, including but not limited to cancer types that are known to overexpress specific antigens, such as the ones listed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B.
Example 3: In vitro data for Compound 30 _
[00914] Despite free payloads being approximately equivalent in potency (FIG IB), trastuzumab-Compound 30 ADC was found to be less potent in HER2+++ line than T-Dxd ADC (FIG. 1A and FIG. 1C). Although not wishing to be bound by any particular theory, this result supports a slow cleavage mechanism of action for the Compound 30.
[00915] FIG. 2 illustrates experimental data demonstrating that in vivo efficacy shows more prolonged/ sustained regressions with trastuzumab-Compound 30 ADC compared to Enhertu®. JIMT-1 CDX in vivo efficacy (HER2+). While not wishing to be bound by any particular theory, this result supports a slower release mechanism of action for Compound 30. In a non-limiting example, levels of free payload are assessed in both trastuzumab- Compound 30 and trastuzumab-Dxd cohorts.
Example 4: In vivo efficacy of an ADC including Compound 30 and targeting PTK7.
[00916] An ADC that includes an anti-PTK7 mAb conjugated to Compound 30 was found to exhibit in vivo efficacy in the MDA-MB-486 breast cancer model. FIG. 3 shows a plot demonstrating that in a MD-468 breast cancer model in mice, an ADC that includes an anti- PTK7 mAb conjugated to Compound 30 (Targeted ADC) was effective at preventing an increase in tumor volume at 42 days after treatment. In contrast, treatment with phosphate buffered saline (PBS) or a B12-targeted mAb conjugated to Compound 30 (DAR 8) did not prevent an increase in tumor volume. Accordingly, ADCs targeting PTK7 and including compounds of the disclosure (e.g. Compound 30) are useful for treating cancers associated with PTK7.
[00917] A number of patent and non-patent publications are cited herein in order to describe the state of the art to which this disclosure pertains.
[00918] While certain embodiments of the present disclosure have been described and/or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present disclosure is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope and spirit of the appended claims.
[00919] Moreover, as used herein, the term “about” means that amounts, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such.
[00920] Furthermore, the transitional terms “comprising”, “consisting essentially of’ and “consisting of’, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term “consisting of’ excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term “consisting essentially of’ limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. All compounds, compositions, formulations, and methods described herein that embody the present disclosure can, in alternate embodiments, be more specifically defined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of.”
[00921] It is to be understood that the embodiments of the disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that can be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure can be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described.
[00922] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the disclosure being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

WE HEREBY CLAIM: l.An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen as disclosed in Tables 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B;
L is a linker of the formula -R*-LI-LA-;
R* is a reactive moiety;
Li is -[CH2]i-3-C(O)NH-;
LA is -[CH2CH2O]P-(CH2)I-5-C(O)-XAA-, wherein p is an integer from 5 to 10, and XAA is an amino acid sequence having 2 to 5 amino acid moieties; n is an integer from 1 to 20;
|— [CH2]2-C(O)NH-— |
2. The antibody-drug conjugate of claim 1, wherein Li is
3. The antibody-drug conjugate of claim 1 or 2, wherein p is 7 or 8.
4. The antibody-drug conjugate of any one of claims 1-3, wherein p is 8.
5. The antibody-drug conjugate of any one of claims 1-4, wherein R* is selected from a succinimide, an oxime, a heterocycle (e.g. triazolyl or isoxazolidinyl), an amide, and a thioether, an alkenyl phosphorous group, and an alkyl phosphorous group, optionally R* is a succinimide.
6. The antibody-drug conjugate of any one of claims 1-5, wherein XAA is an amino acid sequence having 2 amino acid moieties.
7. The antibody-drug conjugate of claim 6, wherein XAA is selected from Vai-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gin, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Vai-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.
8. The antibody-drug conjugate of claim 6 or 7, wherein XAA is valine-alanine.
9. The antibody-drug conjugate of any one of claims 1-5, wherein XAA is an amino acid sequence having 3 amino acid moieties.
10. The antibody drug conjugate of claim 9, wherein XAA is selected from alanine-alanine- alanine, valine-alanine-alanine, glutamic acid-valine-citrulline, and valine-lysine-glycine.
11. The antibody-drug conjugate of any one of claims 1-5, wherein XAA is an amino acid sequence having 4 amino acid moieties.
12. The antibody drug conjugate of claim 11, wherein XAA is selected from glycine-glycine- phenylalanine-glycine, glutamic acid-aspartic acid-phenylalanine-tryptophan, glycine- phenylalanine-leucine-glycine, and alanine-leucine-alanine-leucine.
13. The antibody-drug conjugate of any one of claims 1-12, wherein LA is -[CLLCLLOJp-
(CH2)I-3-C(O)-XAA-.
14. The antibody-drug conjugate of any one of claims 1-13, wherein LA is -[CFLCFhOJp-
(CH2)2-C(O)-XAA-.
15. The antibody-drug conjugate of any one of claims 1-14, wherein the linker L has the formula:
16. The antibody-drug conjugate of any one of claims 1-16, wherein D is
17. The antibody-drug conjugate of any one of claims 1-16, wherein L-D has the formula:
18. The antibody-drug conjugate of any one of claims 1-17, wherein n is an integer from 4 to 8.
19. The antibody-drug conjugate of claim 18, wherein n is 4.
20. The antibody-drug conjugate of claim 18, wherein n is 8.
21. The antibody-drug conjugate of any one of claims 1-20, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and (c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 1-393 or 1002-1050; and
(ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 394-786 or 1051-1085.
22. The antibody-drug conjugate of any one of claims 1-21, wherein the tumor-associated antigen is protein tyrosine kinase 7 (PTK7).
23. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 1002-1050; and
(ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 1051-1085.
24. The antibody-drug conjugate of any one of claims 1-21, wherein the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
25. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 229-236; and
(ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 622-629.
26. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VH comprises an amino acid sequence as set forth in SEQ ID NO: 229; and
(ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1), (b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VL comprises an amino acid sequence as set forth in SEQ ID NO: 622.
27. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002- 1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
28. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
29. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
30. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622.
31. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
32. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
33. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
34. The antibody-drug conjugate of any one of claims 1-21, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 622.
35. The antibody-drug conjugate of any one of claims 1-34, wherein the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
36. The antibody-drug conjugate of any one of claims 1-35, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1061-1083.
37. The antibody-drug conjugate of any one of claims 1-35, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1061-1083.
38. The antibody-drug conjugate of any one of claims 1-37, wherein the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
39. The antibody-drug conjugate of any one of claims 1-38, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
40. The antibody-drug conjugate of any one of claims 1-39, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
41. The antibody-drug conjugate of any one of claims 1-39, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
42. The antibody-drug conjugate of any one of claims 1-38, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1086-1107.
43. The antibody-drug conjugate of any one of claims 1-42, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107.
44. The antibody-drug conjugate of any one of claims 1-42, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
45. The antibody-drug conjugate of any one of claims 1-38, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
46. The antibody-drug conjugate of any one of claims 1-45, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 824.
47. The antibody-drug conjugate of any one of claims 1-45, wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
48. A pharmaceutical composition comprising the antibody drug conjugate of any one of claims 1-47; and a pharmaceutically acceptable carrier.
49. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the antibody drug conjugate of any one of claims 1-47, or the pharmaceutical composition of claim 48.
50. The method of claim 49, wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, headneck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi’s sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin’s disease, non-Hodgkin’s lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma, acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, brain cancer, breast cancer, triple-negative breast cancer (TNBC), bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing’s tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilm’s tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin’s disease, multiple myeloma, non-Hodgkin’s lymphoma, polycythemia vera, and Waldenstrom’s macroglobulinemia.
51. The method of claim 49 or 50, wherein the cancer in a colon cancer.
52. The method of claim 49 or 50, wherein the cancer is a HER2 -positive cancer.
53. The method of claim 52, wherein the HER2 -positive cancer in a breast cancer, an ovarian cancer, a bladder cancer, a pancreatic cancer, a stomach cancer, an esophageal cancer, a uterine cancer, and endometrial carcinoma, a colon cancer, a non-small cell lung cancer, and cervical cancer, or a head-and-neck cancer.
54. The method of claim 49 or 50, wherein the cancer in a PTK7 -positive cancer.
55. The method of claim 54, wherein the PTK7 -positive cancer is a breast cancer, a colorectal cancer, an esophageal squamous cell carcinoma, a gastric cancer, a leukemia, a neuroblastoma, or an ovarian cancer.
56. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds protein a tumor-associated antigen as disclosed in Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B;
D comprises a drug moiety; n is an integer from 1 to 20; and
L has the formula:
57. The antibody-drug conjugate of claim 56, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) that comprises:
(a) a VH complementarity determining region one (HCDR1),
(b) a VH complementarity determining region two (HCDR2), and
(c) a VH complementarity determining region three (HCDR3), wherein HCDR1-3 individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VH comprises an amino acid sequence as set forth in any one of SEQ ID NO: 1-393 or 1002-1050; and
(ii) a light chain variable region (VL) that comprises:
(a) a VL complementarity determining region one (LCDR1),
(b) a VL complementarity determining region two (LCDR2), and
(c) a VL complementarity determining region three (LCDR3), wherein the LCDRs individually comprise between 0, 1, 2, 3, 4, or 5 substitutions, wherein the VL comprises an amino acid sequence as set forth in any one of SEQ ID NO: 394-786 or 1051-1085.
58. The antibody-drug conjugate of claim 56 or 57, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
59. The antibody-drug conjugate of any one of claims 56-58, wherein the tumor-associated antigen is protein tyrosine kinase 7 (PTK7).
60. The antibody-drug conjugate of any one of claims 56-59, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
61. The antibody-drug conjugate of any one of claims 56-58, wherein the tumor-associated antigen is PTK7.
62. The antibody-drug conjugate of any one of claims 56-61, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
63. The antibody-drug conjugate of any one of claims 56-61, wherein the antibody or binding fragment thereof comprises a VH that comprises three HCDR individually comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NOs: 787 (HCDR1), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3), and/or a VL that comprises three LCDR individually comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
64. The antibody-drug conjugate of any one of claims 56-61, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622.
65. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
66. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
67. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
68. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787. a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789, and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
69. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787. a HCDR2 of SEQ ID NO: 788, a HCDR3 of SEQ ID NO: 789, and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
70. The antibody-drug conjugate of any one of claims 56-64, wherein the antibody or binding fragment thereof comprises: (i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 622.
71. The antibody-drug conjugate of any one of claims 56-58, wherein the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
72. The antibody-drug conjugate of any one of claims 56-58, wherein the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
73. The antibody-drug conjugate of any one of claims 56-58, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1086-1107.
74. The antibody-drug conjugate of claim 73, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107.
75. The antibody-drug conjugate of claim 73, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1086-1107.
76. The antibody-drug conjugate of any one of claim 73, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107.
77. The antibody-drug conjugate of any one of claims 56-58, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
78. The antibody-drug conjugate of any one of claim 77, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
79. The antibody-drug conjugate of claim 77, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
80. The antibody-drug conjugate of claim 77, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
81. The antibody-drug conjugate of claim 77, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
82. The antibody-drug conjugate of claim 77 wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 824.
83. The antibody-drug conjugate of any one of claims 56-82, wherein the drug moiety
84. The antibody-drug conjugate of any one of claims 56-83, wherein the drug moiety is
85. The antibody-drug conjugate of any one of claims 56-84, wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
86. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; n is an integer from 1 to 20; and
L-D has the formula:
87. The antibody-drug conjugate of claim 86, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
88. The antibody-drug conjugate of claim 86 or 87, wherein the tumor-associated antigen is protein tyrosine kinase 7 (PTK7).
89. The antibody-drug conjugate of any one of claims 86-88, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
90. The antibody-drug conjugate of claim 86 or 87, wherein the tumor-associated antigen is epidermal growth factor receptor 2 (HER2).
91. The antibody-drug conjugate of any one of claims 86-90, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
92. The antibody-drug conjugate of any one of claims 86-91, wherein the antibody or binding fragment thereof comprises a VH comprising three HCDR individually comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787 (HCDR1), SEQ ID NO: 788 (HCDR2), and SEQ ID NO: 789 (HCDR3), and/or a VL comprising three LCDR individually comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790 (LCDR1), SEQ ID NO: 791 (LCDR2), and SEQ ID NO: 792 (LCDR3).
93. The antibody-drug conjugate of any one of claims 86-91, wherein the antibody or binding fragment thereof comprises a VH that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 229, and/or a VL that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 622.
94. The antibody-drug conjugate of any one of claims 86-93, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-393 or 1002-1050; and
(ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 394-786 or 1051-1085.
95. The antibody-drug conjugate of claim 94, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085.
96. The antibody-drug conjugate of claim 94, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 229-236, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 622-629.
97. The antibody-drug conjugate of claim 94, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789; and/or
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
98. The antibody-drug conjugate of claim 94, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and/or
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
99. The antibody-drug conjugate of claim 94, wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 229, and (ii) a light chain variable region (VL) comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 622.
100. The antibody-drug conjugate of any one of claims 86-94, wherein the antibody is selected from a monoclonal antibody, polyclonal antibody, a nanobody, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, and a human antibody.
101. The antibody-drug conjugate of any one of claims 86-95, wherein the binding fragment thereof is selected from an antibody fragment, a Fab, a Fab', a Fab'-SH, a F(ab')2, a Fv, a single chain Fv, and fusion protein comprising the antigen-binding portion of an antibody.
102. The antibody-drug conjugate of any one of claims 86-96, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1086-1107.
103. The antibody-drug conjugate of claim 92, wherein the binding fragment comprises a ScFv that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107.
104. The antibody-drug conjugate of any one of claims 86-96, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 793-811 or 1086-1107.
105. The antibody-drug conjugate of claim 104, wherein the binding fragment is a single chain variable fragment (ScFv) comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107.
106. The antibody-drug conjugate of any one of claims 86-96, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
107. The antibody-drug conjugate of claim 106, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
108. The antibody-drug conjugate of claim 106, wherein the binding fragment comprises a nanobody that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence as set forth in SEQ ID NO: 824.
109. The antibody-drug conjugate of any one of claims 86-96, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 812-841 or 1108-1111.
110. The antibody-drug conjugate of claim 109, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
111. The antibody-drug conjugate of claim 109, wherein the binding fragment is a nanobody comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 824.
112. The antibody-drug conjugate of any one of claims 86-110, wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) ranging from about 1 to about 10, optionally wherein the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally DAR is about 4, optionally DAR is about 8.
113. The antibody-drug conjugate of any one of claims 84-111, wherein n is an integer from 1 to 10, 2 to 8, or 4 to 8, optionally n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, optionally n is 4 or 8, optionally n is 4, optionally n is 8.
114. An antibody-drug conjugate having any one of formula 1030-1064 or 1101-1118, wherein Ab comprises an antibody that specifically binds a tumor-associated antigen selected from Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B, or antigen binding fragment thereof.
115. An antibody-drug conjugate of any one of embodiments (I)-(XVII).
116. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; n is 1;
L-D has the formula:
117. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from Tables 1, 2, 3, or 4; n is 4;
L-D has the formula:
118. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A, or 4B; n is 8;
L-D has the formula:
119. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from any one of Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A or 4B; n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) that binds any one of the targets set forth in Table 1, 2 A, or 2B, and
(ii) a light chain variable region (VL) that binds any one of the targets set forth in Table 1, 2A, or 2B;
(B) a single chain variable fragment (ScFv) that binds any one of the targets set forth in Table 1, 3 A, or 3B or
(C) a nanobody that binds any one of the targets set forth in Table 1, 4A, or 4B.
120. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds protein tyrosine kinase 7 (PTK7); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NOs: 1051-1085;
(B) a single chain variable fragment (ScFv) comprising an amino acid sequence as set forth in SEQ ID NOs: 1086-1107 or
(C) a nanobody comprising an amino acid sequence as set forth in SEQ ID NOs: 1108- 1111.
121. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-236; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629;
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
122. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ
ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
123. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
124. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 1;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO:229; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
125. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from any one of Table 1A, IB, 2A, 2B, 2C, 3A, 3B, 4A or 4B; n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) that binds any one of the targets set forth in
Table 1A, IB, 2A, 2B, or 2C, and
(ii) a light chain variable region (VL) that binds any one of the targets set forth in Table 1A, IB, 2A, 2B, or 2C;
(B) a single chain variable fragment (ScFv) that binds any one of the targets set forth in Table 1A, IB, 3A, or 3B; or
(C) a nanobody that binds any one of the targets set forth in Table 1A, IB, 4A, or 4B.
126. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds protein tyrosine kinase 7 (PTK7); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 1002-1050, and
(ii) a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 1051-1085;
(B) a single chain variable fragment (ScFv) comprising an amino acid sequence as set forth in SEQ ID NO: 1086-1107; or
(C) a nanobody comprising an amino acid sequence as set forth in SEQ ID NO: 1108-1111.
127. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-236; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629;
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
128. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ
ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
129. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
130. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 4;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO:229; and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
131. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen selected from Table 1, 2, 3, or 4; n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(C):
(A) (i) a heavy chain variable region (VH) that binds any one of the targets set forth in
Table 1A, IB, 2A, 2B, or 2C, and
(ii) a light chain variable region (VL) that binds any one of the targets set forth in Table 1A, IB, 2A, 2B, or 2C;
(B) a single chain variable fragment (ScFv) that binds any one of the targets set forth in Table 1A, IB, 3A, or 3B; or
(C) a nanobody that binds any one of the targets set forth in Table 1A, IB, 4A, or 4B.
132. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds protein tyrosine kinase 7 (PTK7); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 1002-1050, and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 1051-1085; or
(B) a single chain variable fragment (ScFv) amino acid sequence as set forth in any one of SEQ ID NOs: 1086-1107; or
(C) a nanobody of amino acid sequence as set forth in any one of SEQ ID NOs: 1108-1111.
133. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises any one of (A)-(B):
(A) (i) a heavy chain variable region (VH) of amino acid sequence as set forth in any one of SEQ ID NOs: 229-622, and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in any one of SEQ ID NOs: 622-629; or
(B) a nanobody of amino acid sequence as set forth in SEQ ID NO: 824.
134. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ
ID NO: 787, a HCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 788, and a HCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 790, a LCDR2 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 791, and a LCDR3 comprising 0, 1, 2, 3, 4, or 5 amino acid substitutions relative to SEQ ID NO: 792.
135. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) comprising: a HCDR1 of SEQ ID NO: 787, a HCDR2 of SEQ ID NO: 788, and a HCDR3 of SEQ ID NO: 789; and
(ii) a light chain variable region (VL) comprising: a LCDR1 of SEQ ID NO: 790, a LCDR2 of SEQ ID NO: 791, and a LCDR3 of SEQ ID NO: 792.
136. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I): Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is 8;
L-D has the formula: wherein the antibody or binding fragment thereof comprises:
(i) a heavy chain variable region (VH) of amino acid sequence as set forth in SEQ ID NO: 229, and
(ii) a light chain variable region (VL) of amino acid sequence as set forth in SEQ ID NO: 622.
137. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen;
L is a linker of the formula -R*-LI-LA-;
R* is a reactive moiety;
Li is -[CH2]i-3-C(O)NH-;
LA is -[CH2CH2O]P-(CH2)I-5-C(O)-XAA-, wherein p is an integer from 5 to 10, and
XAA is an amino acid sequence having 2 to 5 amino acid moieties; n is an integer from 1 to 20;
138. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds a tumor-associated antigen; n is an integer from 1 to 20; and L-D has the formula:
139. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds protein tyrosine kinase 7 (PTK7); n is an integer from 1 to 20; and
L-D has the formula:
140. An antibody-drug conjugate having formula (I):
Ab-[L-D]n formula (I) wherein in formula (I):
Ab is an antibody or binding fragment thereof that binds epidermal growth factor receptor 2 (HER2); n is an integer from 1 to 20; and
L-D has the formula:
141. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the antibodydrug conjugate of any one of claims 86-140.
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WO2026022310A1 (en) * 2024-07-24 2026-01-29 Skymab Biotherapeutics Antibody-drug conjugate comprising an anti-pmel-17 antibody, and uses thereof

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