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WO2025238587A1 - Combination of anti-b7-h3 antibody-drug conjugate and androgen receptor signaling inhibitor - Google Patents

Combination of anti-b7-h3 antibody-drug conjugate and androgen receptor signaling inhibitor

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Publication number
WO2025238587A1
WO2025238587A1 PCT/IB2025/055075 IB2025055075W WO2025238587A1 WO 2025238587 A1 WO2025238587 A1 WO 2025238587A1 IB 2025055075 W IB2025055075 W IB 2025055075W WO 2025238587 A1 WO2025238587 A1 WO 2025238587A1
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WIPO (PCT)
Prior art keywords
antibody
amino acid
pharmaceutical product
drug conjugate
product according
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/IB2025/055075
Other languages
French (fr)
Inventor
Jun Hasegawa
Chiharu Hattori
Mei TANG
Kentaro Imai
Christian H. Poehlein
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.)
Daiichi Sankyo Co Ltd
Merck Sharp and Dohme LLC
Original Assignee
Daiichi Sankyo Co Ltd
Merck Sharp and Dohme LLC
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Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd, Merck Sharp and Dohme LLC filed Critical Daiichi Sankyo Co Ltd
Publication of WO2025238587A1 publication Critical patent/WO2025238587A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K47/6869—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 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/6835—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
    • A61K47/6849—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 receptor, a cell surface antigen or a cell surface determinant
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present disclosure relates to a pharmaceutical product, wherein an anti-B7-H3 antibody- drug conjugate and an androgen receptor signaling inhibitor are administered in combination, and/or a method of treatment or prevention, wherein an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination to a subject.
  • Antibody-drug conjugates in which a cytotoxic drug is conjugated to an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cancer cells are expected to selectively deliver the cytotoxic drug to cancer cells and kill the cancer cells.
  • ADCs Antibody-drug conjugates in which an exatecan derivative (a DNA topoisomerase I inhibitor) is conjugated to an anti-B7-H3 antibody have been reported (Patent Reference 1).
  • Patent Reference 1 WO2014/057687 Summary Technical Problem Attorney Docket No.
  • Androgen receptor a steroid hormone receptor
  • Androgen receptor signaling inhibitors such as abiraterone, which can inhibit production of androgen in organs including testes and adrenal glands, and tumor cells by inhibiting CYP17, and enzalutamide, apalutamide and darolutamide, which act as antagonists of androgen receptor, are known.
  • Patent Reference 1 does not describe any test result showing a combined effect of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor, or any scientific basis for suggesting such combination.
  • Patent Reference 1 Whilst demand exists for a pharmaceutical product and method of treatment or prevention which can exert a further superior antitumor effect by using an anti-B7-H3 antibody-drug conjugate such as those described in Patent Reference 1 in combination with another anti-cancer agent having a different mechanism of action, test results or Attorney Docket No.
  • the present inventors conceived that the excellent effects of the combined administration could be generalized and expanded to any combination of an anti- B7-H3 antibody-drug conjugate in which a DNA topoisomerase I inhibitor is conjugated to an anti-B7-H3 antibody and an androgen receptor signaling inhibitor.
  • the present disclosure provides the following: [0010] Attorney Docket No.
  • a pharmaceutical product comprising (an effective amount of) an anti-B7-H3 antibody-drug conjugate (as an active ingredient) and (an effective amount of) an androgen receptor signaling inhibitor (as an active ingredient) for administration in combination; [2] The pharmaceutical product according to [1], wherein a drug in the anti-B7-H3 antibody-drug conjugate is a topoisomerase I inhibitor; [3] The pharmaceutical product according to [2], wherein the drug represented by the following formula is released to express an antitumor activity: ; [4] The pharmaceutical product according to [2], wherein an antitumor compound represented by the following formula is conjugated to an anti-B7-H3 antibody through a linker with the nitrogen atom of the amino group at position 1 as the connecting position: Attorney Docket No.
  • a in the formula represents a connecting position to the anti-B7-H3 antibody or functional fragment thereof;
  • a pharmaceutical product comprising (an effective amount of) an anti-B7-H3 antibody-drug conjugate (as an active ingredient) and (an effective amount of) an androgen receptor signaling inhibitor (as an active ingredient) for administration in combination, wherein the anti-B7-H3 antibody-drug conjugate comprises an anti- B7-H3 antibody or a functional fragment thereof conjugated to the drug-linker represented by the formula shown in [7] via the thioether bond, wherein A in the formula represents a connecting position to the anti-B7- H3 antibody or functional fragment thereof.
  • a CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2
  • a CDRL2 consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2
  • a CDRL3 consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2
  • a CDRH1 consisting of an amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 1
  • a CDRH2 consisting of an amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 1
  • a CDRH3 consisting of an amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 1
  • a CDRL1 consisting of an amino acid sequence of amino acid residues 44 to 53 of SEQ ID NO: 2
  • a CDRL2 consisting of an amino acid sequence of amino acid residues 69 to 75 of SEQ ID NO: 2
  • a CDRL3 consist
  • n is in the range from 3 to 5, and wherein the anti-B7-H3 antibody comprises a heavy chain comprising (or consisting of) an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain comprising (or consisting of) an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2;
  • An anti-B7-H3 antibody-drug conjugate or a pharmaceutical composition comprising the anti-B7-H3 antibody-drug conjugate, for use in treating or preventing cancer in combination with an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [58]; [61] The anti-B7-H3 antibody-drug conjugate or the pharmaceutical composition for the use according to [60], by separate simultaneous or sequential administration in combination with the androgen receptor signaling inhibitor; [62] The anti-B7-H3 antibody-drug conjugate or the pharmaceutical composition for the use according to [60] or [61], wherein the cancer is as defined in any one of [33] to [39] and [58]; [63] An androgen receptor signaling inhibitor or a pharmaceutical composition comprising the androgen receptor signaling inhibitor, for use in treating or preventing cancer in combination with an anti-B7-H3
  • 122622-0241 21 inhibitor are as defined in any one of [1] to [62], and wherein the cancer is as defined in any one of [33] to [39] and [58];
  • a method of treating or preventing cancer comprising administering an anti-B7-H3 antibody-drug conjugate as defined in any one of [1] to [62] to a subject in need thereof; and administering an androgen receptor signaling inhibitor as defined in any one of [1] to [62] to the subject; [71] The method according to [45], wherein the cancer is as defined in any one of [33] to [39] and [58]; [72] A kit comprising (a) a first composition comprising an anti-B7-H3 antibody-drug conjugate and (b) a second composition comprising an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [62]; and [73] The kit according to [
  • prostate cancer in the present disclosure may be described as follows: (i) metastatic castration-resistant prostate cancer or metastatic high-risk castration-sensitive prostate cancer Attorney Docket No. 122622-0241 22 when the androgen receptor signaling inhibitor is abiraterone acetate; (ii) castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis when the androgen receptor signaling inhibitor is enzalutamide; (iii) metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer when the androgen receptor signaling inhibitor is apalutamide; or (iv) non-metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer in combination with docetaxel when the androgen receptor signaling inhibitor is darolutamide.
  • the present disclosure provides a pharmaceutical product with an excellent antitumor effect and/or safety, wherein an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination, and/or a method of treatment or prevention with an excellent antitumor effect and/or safety, wherein the anti-B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are administered in combination to a subject.
  • the combined administration of a preferred anti-B7-H3 antibody-drug conjugate of the present disclosure such as ifinatamab deruxtecan in combination with an androgen receptor signaling inhibitor such as enzalutamide is advantageous in terms of safety while exerting an improved antitumor effect over vobramitamab duocarmazine (MGC018) in combination with the same androgen receptor signaling inhibitor.
  • Figure 1 shows tumor volumes after initial treatment in mice administered with vehicle control, anti-B7-H3 antibody-drug conjugate (1), enzalutamide, or a combination of anti-B7-H3 antibody-drug conjugate (1) and enzalutamide, in a patient derived xenograft (PDX) model.
  • Figure 2 shows tumor volumes after initial treatment in mice administered with vehicle control, anti-B7-H3 antibody-drug conjugate (1), abiraterone acetate, or a combination of anti-B7-H3 antibody-drug conjugate (1) and abiraterone acetate, in a patient derived xenograft (PDX) model.
  • the terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.
  • the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise.
  • Attorney Docket No. 122622-0241 27 The term “about” or “approximately” indicates and encompasses the designated value ⁇ 10%.
  • the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first composition” and “second composition” are used to distinguish two compositions.
  • anti-B7-H3 antibody-drug conjugates examples include, but are not limited to, vobramitamab duocarmazine (MGC018), mirzotamab clezutoclax (ABBV-155), BAT8009, HS-20093, MHB088C, 7MW3711, and DB-1311.
  • MCC018 vobramitamab duocarmazine
  • ABBV-155 mirzotamab clezutoclax
  • BAT8009 mirzotamab clezutoclax
  • HS-20093, MHB088C 7MW3711
  • DB-1311 Anti-B7-H3 antibody-drug Attorney Docket No.
  • 122622-0241 28 conjugates are also described in WO2014/057687, WO2023/061457, US11,685,742B2, US20210347894A, US20220233708A, WO2024/022372, WO2022/117040, WO2024/061306, WO2024/037503, WO2024/052685, WO2024/052684, WO2023/236949, US20240148892A, WO2023/241663, WO2024/140935, US20240108745A1 WO2022/170971), WO2024/140932, WO2024/140935, WO2024/211235, and WO25087323, each of which incorporated herein by reference in its entirety.
  • the anti-B7-H3 antibody-drug conjugate is an antibody-drug conjugate in which a drug- linker represented by the following formula: wherein A in the formula represents a connecting position to an anti-B7-H3 antibody or a functional fragment thereof, is conjugated to the anti-B7-H3 antibody or functional fragment thereof via a thioether bond.
  • a drug- linker represented by the following formula: wherein A in the formula represents a connecting position to an anti-B7-H3 antibody or a functional fragment thereof, is conjugated to the anti-B7-H3 antibody or functional fragment thereof via a thioether bond.
  • the drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the anti-B7- H3 antibody.
  • a thiol group in other words, the sulfur atom of a cysteine residue
  • the drug-linker includes exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component.
  • exatecan IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,3,9,12
  • Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula: Attorney Docket No. 122622-0241 30 [0020]
  • the anti-B7-H3 antibody-drug conjugate can also be represented by the following formula: wherein, the drug-linker is conjugated to an anti-B7-H3 antibody or a functional fragment thereof via a thioether bond.
  • the meaning of n may be the same as what is called the average number of conjugated drug molecules per antibody molecule (DAR; Drug-to-Antibody Ratio). In this context, n indicates the average number of drug molecules (or units of the drug-linker) conjugated per antibody molecule in a composition of antibody-drug conjugate molecules.
  • n may be an integer representing the number of drug molecules (or units of the drug-linker) conjugated per antibody molecule in an anti-B7-H3 antibody-drug conjugate molecule.
  • the anti-B7-H3 antibody-drug conjugate is cleaved Attorney Docket No. 122622-0241 31 at the linker portion to release the compound represented by the following formula: [0022]
  • the aforementioned compound is inferred to be the original source of the antitumor activity of the anti-B7-H3 antibody-drug conjugate.
  • the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan.
  • ifinatamab deruxtecan is an antibody-drug conjugate (ADC) comprising the anti-B7- H3 antibody immunoglobulin G1 monoclonal antibody ifinatamab, which is covalently linked to deruxtecan.
  • ADC antibody-drug conjugate
  • ifinatamab deruxtecan exerted potent antitumor activity in high B7-H3 expressing tumors with an acceptable pharmacokinetic and safety profile (Yamato, M., et. al., (2022). Mol Cancer Ther; 21(4), 635-646).
  • the anti- B7-H3 antibody-drug conjugate is ifinatamab govitecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab rezetecan.
  • the anti- B7-H3 antibody-drug conjugate is ifinatamab samrotecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab brengitecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab tirumotecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab adizutecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab tocentecan.
  • the anti- B7-H3 antibody-drug conjugate is ifinatamab sesutecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab pamirtecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab repodatecan.
  • the drug-linker part is already made available to the public as follows: Govitecan is described, e.g., in WHO Drug Information, Proposed INN List 113; Attorney Docket No.
  • anti-B7-H3 antibody or a functional fragment thereof refers to an antibody or a Attorney Docket No. 122622-0241 34 functional fragment thereof respectively each of which binds specifically to B7-H3 (B cell antigen #7 homolog 3; PD-l3; CD276), and preferably has an activity of internalization in B7-H3-expressing cells by binding to B7-H3.
  • B7-H3 one of the B7 family members expressed in antigen-presenting cells as a co-stimulator, is considered to act on receptors on T cells and enhance or suppress immune effect.
  • B7-H3 is a single transmembrane protein and has two variants.
  • B7-H3 variant 1 (4Ig-B7-H3) contains two each of V- or C- like Ig domains
  • B7-H3 variant 2 (2Ig-B7-H3) contains one each of V- or C -like Ig domains. Amino acid sequences of these variants are known in the art.
  • the amino acid sequence of human 4Ig- B7-H3 is for example shown in UniProt accession number Q5ZPR3-1 (2004-11-23 v1) or GenBank accession number: NP_001019907.1.
  • the N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP_001019907.1.
  • the amino acid sequence of human 2Ig-B7- H3 is for example shown in UniProt accession number Q5ZPR3-2, or GenBank accession number: NP_001316557.1 or NP_079516.1.
  • the anti-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate may be derived from any species such as a human, a rat, a mouse, or a rabbit.
  • the anti-B7-H3 antibody or functional fragment thereof is derived from species other than human species, it is preferably chimerized or humanized using a known technique.
  • the anti-B7-H3 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.
  • Examples of an anti-B7-H3 antibody include, but not limited to, M30-H1-L4 described in WO2014/057687 or those described in WO2024/061306 or CN117603916A.
  • the term "functional fragment" of an antibody is also called “antigen-binding fragment” of an antibody, and is used to mean a partial fragment of the antibody having binding activity against an antigen, and includes, but not limited to, Fab, F(ab') 2 , scFv, a diabody, a linear antibody and a multi-specific antibody formed from antibody fragments.
  • Fab' which is a monovalent fragment of antibody variable Attorney Docket No. 122622-0241 36 regions obtained by treating F(ab') 2 under reducing conditions, is also included in the antigen-binding fragment of an antibody.
  • the antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has antigen-binding ability.
  • These antigen-binding fragments include not only those obtained by treating a full-length molecule of an antibody protein with an appropriate enzyme, but proteins produced in appropriate host cells using a genetically engineered antibody gene.
  • the anti-B7-H3 antibody or functional fragment thereof preferably has the characteristic of being able to target cancer cells, or possesses, for example, the property of being able to recognize a cancer cell, the property of being able to bind to a cancer cell, the property of being internalized in a cancer cell, or cytocidal activity against cancer cells.
  • the binding activity of the anti-B7-H3 antibody or functional fragment thereof against cancer cells can be confirmed using flow cytometry, for example.
  • the internalization of the antibody into tumor cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) Attorney Docket No. 122622-0241 37 binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol.
  • a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, or spheroid growth, for example.
  • the antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining changes in the cancer cells.
  • Attorney Docket No. 122622-0241 38 [0031] Since the compound conjugated in the anti-B7-H3 antibody-drug conjugate exerts an antitumor effect when released, it is preferred but not essential that the anti-B7-H3 antibody itself or functional fragment thereof has an antitumor effect.
  • the anti-B7-H3 antibody or functional fragment thereof has the property of being internalized to migrate into cancer cells.
  • the anti-B7-H3 antibody or functional fragment thereof can be obtained by a procedure known in the art.
  • the antigen can be obtained by a procedure known in the art, such as by genetically engineering host cells to produce a gene encoding the antigenic protein.
  • the anti-B7-H3 antibody or functional fragment thereof is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human Attorney Docket No. 122622-0241 39 antibody.
  • These antibodies can be produced using a known method.
  • modified variants of the anti-B7-H3 antibody are also included.
  • the modified variant refers to a variant obtained by subjecting the anti-B7-H3 antibody or functional fragment thereof to chemical or biological modification.
  • Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, and variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain.
  • Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell.
  • an antibody labeled so as to enable the detection or isolation of the antibody or an antigen for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.
  • a modified variant of the antibody is useful for improving the stability and blood retention of the antibody, reducing the Attorney Docket No. 122622-0241 40 antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.
  • a modified variant of the antibody is useful for improving the stability and blood retention of the antibody, reducing the Attorney Docket No. 122622-0241 40 antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.
  • by regulating the modification of a glycan which is linked to the anti-B7-H3 antibody or functional fragment thereof for example, glycosylation, defucosylation
  • an anti- B7-H3 antibody or a functional fragment thereof in which the modification of a glycan is regulated are also included.
  • antigen-binding affinity and the effector function for example, complement activation or antibody-dependent cellular cytotoxicity
  • anti-B7-H3 antibodies subjected to such modification or functional fragments thereof are also included.
  • variants in which one or two amino acids have been deleted at either or both of the carboxyl termini of the heavy chains, and variants obtained by amidation of the deletion variants are also included.
  • the type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody or functional fragment thereof is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved.
  • the ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-B7-H3 antibody and the culture conditions; however, in some embodiments, an anti-B7-H3 antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody can be preferably exemplified.
  • the anti-B7-H3 antibody provided herein may undergo post-translational modifications as known in the art.
  • post-translational modifications include, but are not limited to, chemical modifications, Attorney Docket No. 122622-0241 42 such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art. See, Liu, et. al., J. Pharma. Sci. vol. 97, no. 7, pp. 2426-2447 (2008).
  • an N-terminal E or Q of an anti-B7- H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid.
  • a C-terminal K of anti-B7-H3 antibody provided herein is removed.
  • an N-terminal E or Q of an anti-B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the anti-B7-H3 antibody (e.g., heavy chain C-terminal amino acid) is removed.
  • the present disclosure includes any of the above described post-translational modifications of any of the anti-B7-H3 antibodies provided herein.
  • the light chain from any vertebrate species can be assigned to one of two types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the sequence of its constant domain.
  • the heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): Attorney Docket No. 122622-0241 43 IgA, IgD, IgE, IgG, and IgM. These classes are also designated ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function.
  • a drug-linker intermediate for use in the production of the antibody-drug conjugate is represented by the following formula: [0040]
  • the drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L- phenylalanyl-N-[(2- ⁇ [(1S,9S)-9-ethyl-5-fluoro-9-hydroxy- 4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H- Attorney Docket No.
  • the anti-B7-H3 antibody-drug conjugate can be produced by reacting the above-described drug-linker intermediate and an anti-B7-H3 antibody or a functional fragment thereof having a thiol group (alternatively referred to as a sulfhydryl group).
  • an anti-B7-H3 antibody or a functional fragment thereof having a thiol group alternatively referred to as a sulfhydryl group.
  • the anti-B7-H3 antibody or functional fragment thereof having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)).
  • a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA)
  • TCEP tris(2- carboxyethyl)phosphine hydrochloride
  • EDTA ethylenediamine tetraacetic acid
  • an antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.
  • the average number of conjugated drug molecules per antibody molecule in the antibody-drug conjugate can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).
  • anti-B7-H3 antibody-drug conjugate may refer to an antibody-drug conjugate in which the antibody or a functional fragment thereof in Attorney Docket No. 122622-0241 46 the antibody-drug conjugate is an anti-B7-H3 antibody or a functional fragment thereof.
  • the anti-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate (i-1) comprises a CDRH1 comprising or consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising or consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising or consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising or consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising or consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising or consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2; (i-2) comprises a CDRH1 comprising or consisting of an amino acid sequence consisting of amino acid
  • the average number of units of the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is 2 to 8, preferably 3 to 5, more preferably 3.5 to 4.5, and even more preferably about 4.
  • the number of the drug or the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is an integer in the range from 2 to 8, preferably 2, 4, 6, or 8, and most preferably 4.
  • the anti-B7-H3 antibody-drug conjugate can be produced with reference to WO2014/057687, WO2017/002776 or WO2022/014698.
  • the anti-B7-H3 antibody-drug conjugate produced is ifinatamab deruxtecan. 5. Androgen receptor signaling inhibitor [0050] As used herein, “androgen receptor signaling inhibitor” refers to a drug that has the function of Attorney Docket No.
  • an “androgen synthesis inhibitor” refers to a drug that has an inhibitory effect on androgen synthesis (e.g., A Jacob et al., Cancers (Basel). 2021, 13(21)).
  • an “androgen receptor antagonist” refers to a drug that acts by blocking the androgen binding site of androgen receptor (e.g., A Jacob et al., Cancers (Basel). 2021, 13(21)).
  • the androgen receptor signaling inhibitor are, but not limited to, abiraterone (a CYP17 inhibitor), enzalutamide, apalutamide, darolutamide, or pharmaceutically acceptable salts of these.
  • an androgen receptor signaling inhibitor may be present in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt includes either an acid addition salt or a salt with a base, but may be preferably an acid addition salt, examples of which can include lower alkanesulfonates such as camsilate (camphorsulfonate), methanesulfonate, trifluoromethanesulfonate, and Attorney Docket No.
  • lower alkanesulfonates such as camsilate (camphorsulfonate), methanesulfonate, trifluoromethanesulfonate, and Attorney Docket No.
  • 122622-0241 50 ethanesulfonate; arylsulfonates such as tosylate (p- toluenesulfonate), and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and hydrosulfate; hydrohalic acid salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, decanoate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate, and aspartate.
  • arylsulfonates such as tosylate (p- toluenesulfonate), and benzenesulfonate
  • inorganic acid salts such as phosphate, nitrate, perchlorate, and hydrosulfate
  • the androgen receptor signaling inhibitor or pharmaceutically acceptable salts thereof may also be present in the form of a solvate.
  • the solvate may be a solvate of a pharmaceutically acceptable salt of the androgen receptor signaling inhibitor.
  • the androgen receptor signaling inhibitor is an androgen synthesis inhibitor.
  • the androgen synthesis inhibitor is a CYP17 inhibitor.
  • the CYP17 inhibitor is abiraterone or a pharmaceutically acceptable salt thereof, for example abiraterone acetate or abiraterone decanoate, in particular abiraterone acetate.
  • the androgen receptor signaling inhibitor is an androgen receptor antagonist.
  • the androgen receptor antagonist is selected from the group consisting of enzalutamide, Attorney Docket No. 122622-0241 51 apalutamide, darolutamide, and pharmaceutically acceptable salts thereof.
  • the androgen receptor antagonist is enzalutamide. 6.
  • Medicament and Methods of Treatment [0054] In one aspect, described in the following are a pharmaceutical product and a method of treatment or prevention according to the present invention, wherein an anti—B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination, separately, sequentially, or concurrently, for example.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure may be those in which the anti—B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are separately contained as active components in different formulations and are administered simultaneously or at different times, or may be those in which the anti—B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are contained as active components in a single formulation and administered.
  • the anti—B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor may be administered at different intervals when the anti—B7-H3 Attorney Docket No. 122622-0241 52 antibody-drug conjugate and the androgen receptor signaling inhibitor are separately contained as active ingredients in different formulations.
  • the term "pharmaceutical product” refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing cancer, preferably cancer expressing androgen receptor and/or B7- H3.
  • the pharmaceutical product and method of treatment or preventing of the present disclosure can be used for treating or preventing prostate cancer or breast cancer (including triple- negative androgen receptor-positive breast cancer).
  • Attorney Docket No. 122622-0241 53 In one embodiment, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing prostate cancer.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing prostate cancer selected from the group consisting of castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, non- metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, metastatic high- risk castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, hormone-sensitive prostate cancer, and metastatic hormone-sensitive prostate cancer optionally in combination with docetaxel.
  • prostate cancer selected from the group consisting of castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, non- metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, metastatic high- risk castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, hormone-sensitive prostate cancer, and metastatic hormone-sensitive prostate cancer optionally in combination with docetaxel
  • the prostate cancer is metastatic castration- resistant prostate cancer or metastatic high-risk castration-sensitive prostate cancer, and the androgen receptor signaling inhibitor is abiraterone acetate;
  • the prostate cancer is castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or non-metastatic castration- sensitive prostate cancer with biochemical Attorney Docket No.
  • the androgen receptor signaling inhibitor is enzalutamide
  • the prostate cancer is metastatic castration- sensitive prostate cancer or non-metastatic castration-resistant prostate cancer, and the androgen receptor signaling inhibitor is apalutamide
  • the prostate cancer is non-metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer in combination with docetaxel, and the androgen receptor signaling inhibitor is darolutamide.
  • the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan, and the androgen receptor signaling inhibitor is abiraterone or a pharmaceutically acceptable salt thereof, for example abiraterone acetate or abiraterone decanoate, in particular abiraterone acetate.
  • the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan, and the androgen receptor signaling inhibitor is enzalutamide, apalutamide, darolutamide, or a pharmaceutically acceptable salts thereof, in particular enzalutamide.
  • the anti-B7-H3 antibody-drug conjugate can be preferably used in the case that B7-H3 expression is Attorney Docket No. 122622-0241 55 found in the cancer, as determined by examining the type of cancer and tumor markers.
  • the presence or absence of B7-H3 tumor markers can be checked by, for example, collecting tumor tissue from a cancer patient, and subjecting the formalin fixed paraffin embedded specimen (FFPE) to an examination at a gene product (protein) level, such as an immunohistochemistry (IHC) method, a flow cytometry, a western blot method, or an examination at a gene transcription level, such as an in situ hybridization method (ISH), a quantitative PCR method (q-PCR), or a microarray analysis; alternatively, it can also be checked by collecting cell-free blood circulating tumor DNA (ctDNA) from a cancer patient and subjecting to an examination which uses a method such as next-generation sequencing (NGS).
  • FFPE formalin fixed paraffin embedded specimen
  • IHC immunohistochemistry
  • ISH in situ hybridization method
  • q-PCR quantitative PCR method
  • NGS next-generation sequencing
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can be preferably used for mammals, and can be more preferably used for humans. In some embodiments, the human is an adult (e.g., 18 years old or greater). [0061] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for a maintenance therapy. In other embodiments, the pharmaceutical product and method Attorney Docket No. 122622-0241 56 of treatment or prevention of the present disclosure may be used for the purpose of preventing the recurrence of a tumor after initial chemotherapy. Therefore, in one embodiment, “preventing cancer” means preventing the recurrence of cancer or tumor.
  • maintenance therapy is used to mean treatment that is given to help prevent cancer from coming back after it has disappeared following an initial therapy.
  • the term is defined on the basis of “maintenance therapy” in the following reference: NCI Dictionaries, “maintenance therapy”, NCI Dictionary of Cancer Terms [online]. National Cancer Institute [retrieved on 2023-04-10]. Retrieved from ⁇ cancer.gov/publications/dictionaries/cancer- terms/def/maintenance-therapy>.
  • the antitumor effect of the pharmaceutical product and method of treatment or prevention can be confirmed by, for example, generating a model in which cancer cells are transplanted to a test animal, and measuring reduction in tumor volume, life-prolonging effects due to applying the pharmaceutical product and method of treatment or prevention. Furthermore, comparison with the antitumor effect of single administration of each of the anti-B7-H3 antibody-drug conjugate and the androgen Attorney Docket No. 122622-0241 57 receptor signaling inhibitor can provide confirmation of the combined effect of the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor.
  • the antitumor effect of the pharmaceutical product and method of treatment or prevention of the present disclosure can be confirmed, in a clinical study, with the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, WHO's evaluation method, Macdonald's evaluation method, measurement of body weight, and other methods; and can be determined by indicators such as Complete response (CR), Partial response (PR), Progressive disease (PD), Objective response rate (ORR), Duration of response (DoR), Progression-free survival (PFS), or Overall survival (OS).
  • RECIST Response Evaluation Criteria in Solid Tumors
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can retard growth of cancer cells, suppress their proliferation, or can Attorney Docket No. 122622-0241 58 kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or can achieve an improvement in the quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and method of treatment or prevention do not accomplish the killing of cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells. Furthermore, the pharmaceutical product and method of treatment or prevention can show a sustained antitumor effect.
  • QOL quality of life
  • the pharmaceutical product and method of treatment or prevention of the present disclosure are not associated with severe body weight loss.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues.
  • the pharmaceutical product of the present disclosure includes a pharmaceutical composition containing at least one pharmaceutically Attorney Docket No. 122622-0241 59 suitable ingredient.
  • the pharmaceutically suitable ingredient can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration or the like of the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor.
  • the anti-B7-H3 antibody-drug conjugate can be administered as a pharmaceutical product containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as Polysorbate 80 or 20.
  • a buffer such as a histidine buffer
  • an excipient such as sucrose or trehalose
  • a surfactant such as Polysorbate 80 or 20.
  • the pharmaceutical product containing the anti-B7-H3 antibody-drug conjugate can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.
  • the pharmaceutical product or composition containing the anti-B7-H3 antibody-drug conjugate is an aqueous injection
  • it can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.
  • the pharmaceutical product or composition containing the anti-B7-H3 antibody-drug conjugate is a lyophilized injection
  • it can be preferably dissolved in water for injection, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.
  • Examples of the administration route which may be used to administer the pharmaceutical product of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular, or intraperitoneal routes; and preferably include an intravenous route.
  • the anti-B7-H3 antibody-drug conjugate can be administered to a human once at intervals of 1 to 180 days, and can be preferably administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, and can be even more preferably administered once every 3 weeks.
  • the anti-B7-H3 antibody-drug conjugate can be administered at a dose of about 0.001 to 100 mg/kg, and can be preferably administered at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 6.4 mg/kg, Attorney Docket No. 122622-0241 61 8 mg/kg, 12 mg/kg, or 16 mg/kg, and can be more preferably administered at a dose of 8 to 12 mg/kg, preferably, 8 mg/kg or 12 mg/kg once every 3 weeks.
  • 8 to 12 mg/kg, preferably 12 mg/kg or 8 mg/kg, of the anti-B7-H3 antibody-drug conjugate is intravenously administered once every three weeks.
  • the dosage amount of an androgen receptor signaling inhibitor is not particularly limited as long as it is an effective amount for treating or preventing a target disease and appropriately selected depending on the age, body weight, symptom, health condition and disease progression of the patient.
  • the frequency of administration is not particularly limited and can be appropriately selected depending on the purpose. For example, the dosage amount per day is administered once a day or divided into a plurality of doses and administered separately.
  • an agent e.g., those described herein individually or in combination
  • a therapeutically effective amount of an agent, including a therapeutic agent can be an amount necessary for (i) reduction, delay or amelioration of the Attorney Docket No.
  • a “therapeutically effective amount” of a substance/molecule/agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance/molecule/agent, to elicit a desired response in the individual.
  • a therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance/molecule/agent are outweighed by the therapeutically beneficial effects.
  • the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.
  • the androgen receptor signaling inhibitor is orally administered once a day or twice a day.
  • the androgen receptor signaling inhibitor is abiraterone acetate orally administered once a day, optionally 1,000 mg orally administered once a day, and Attorney Docket No.
  • the prostate cancer is metastatic castration-resistant prostate cancer or metastatic high-risk castration- sensitive prostate cancer;
  • the androgen receptor signaling inhibitor is enzalutamide orally administered once a day, optionally 160 mg orally administered once a day, and the prostate cancer is metastatic castration-resistant prostate cancer;
  • the androgen receptor signaling inhibitor is apalutamide orally administered once a day, optionally 240 mg orally administered once a day, and the prostate cancer is metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer; or
  • the androgen receptor signaling inhibitor is darolutamide orally administered twice a day, optionally 600 mg orally administered twice a day, and the prostate cancer is non-metastatic castration-resistant prostate cancer.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure may further contain a cancer therapeutic agent other than the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor.
  • the pharmaceutical product and method of treatment or prevention can also be administered in Attorney Docket No. 122622-0241 64 combination with another cancer therapeutic agent, thereby enhancing the antitumor effect.
  • Other cancer therapeutic agents to be used for such purpose may be administered to a subject simultaneously, separately, or sequentially with the pharmaceutical product, or may be administered with varying each dosage interval.
  • Such cancer therapeutic agents are not limited as long as they have antitumor activity, and can be selected from the group consisting of irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, cabazitaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur-gimeracil-oteracil combination, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine-tipiracil combination, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, triptorelin, histrelin
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can also be used in combination with Attorney Docket No. 122622-0241 65 radiotherapy.
  • a cancer patient may receive radiotherapy before and/or after or simultaneously with receiving therapy with the pharmaceutical product.
  • the pharmaceutical product and method of treatment or prevention of the present disclosure can also be used as an adjuvant chemotherapy in combination with a surgical procedure.
  • the pharmaceutical product may be administered for the purpose of diminishing the size of a tumor before a surgical procedure (referred to as pre-operative adjuvant chemotherapy or neoadjuvant therapy), or may be administered after a surgical procedure for the purpose of preventing the recurrence of a tumor (referred to as post-operative adjuvant chemotherapy or adjuvant therapy).
  • pre-operative adjuvant chemotherapy or neoadjuvant therapy a surgical procedure for the purpose of preventing the recurrence of a tumor
  • post-operative adjuvant chemotherapy or adjuvant therapy referred to as post-operative adjuvant chemotherapy or adjuvant therapy
  • the terms “administration in combination with” and “administered in combination” are used to represent a form of drug administration in which a plurality of active ingredients are contained or encapsulated in different preparations and administered simultaneously (a person skilled in the Attorney Docket No. 122622-0241 66 art would naturally understand that “simultaneously” or “at the same time” may be or may not be at about the same time) or separately or sequentially in any order at different times, or both contained or encapsulated in the same preparation and administered, unless the context otherwise requires and unless technically inconsistent.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9.
  • a nested sub-range of an exemplary range of 1 to 50 may Attorney Docket No. 122622-0241 67 comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
  • the term “dosing cycle” refers to a period of treatment followed by an optional period of rest (no treatment) that is repeated on a regular schedule. The period of treatment may include a single drug or a combination of drugs. In some embodiments, the dosing cycle does not include a period of rest.
  • a dosing cycle as described herein may be about 3 weeks or 21 days long.
  • Day 1 is the first day of a dosing cycle.
  • Day 1 of Cycle 1 is the first day of the first dosing cycle.
  • the terms “subject” or “patient” are used interchangeably and mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human (e.g., an adult human, i.e., greater than or equal to 18 years of age).
  • the subject has a disease or condition that can be treated with an agent provided herein.
  • the disease or condition is a cancer.
  • the cancer is prostate cancer.
  • the cancer Attorney Docket No. 122622-0241 68 castration-resistant prostate cancer (CRPC).
  • the cancer is metastatic castration- resistant prostate cancer (mCRPC).
  • CRPC castration-resistant prostate cancer
  • mCRPC metastatic castration- resistant prostate cancer
  • prostate cancer is a form of cancer wherein cells of the prostate gland grow uncontrolled.
  • Adenocarcinoma prostate cancer is a type of prostate cancer that starts in the gland cells that produce prostate fluid.
  • Small cell prostate cancer (SCPC) is a type of prostate cancer that develops from neuroendocrine cells of the prostate.
  • SCPC Small cell prostate cancer
  • Small cell and adenocarcinoma prostate cancers can be differentiated by visual examination of cells under a microscope or radiographically, among others.
  • “Adenocarcinoma without small cell” refers to a prostate cancer where the tumor is composed of adenocarcinoma cells without significant presence of small cell carcinoma.
  • Adenocarcinoma of the prostate can be assessed using the Gleason grading system to determine its aggressiveness based on the appearance of the cancer cells.
  • Attorney Docket No. 122622-0241 69 adenocarcinoma may show some features of neuroendocrine differentiation, but if the predominant cell type is adenocarcinoma and does not have a significant “small cell” component, it would still be considered “adenocarcinoma without small cell.”
  • the term “castration-resistant prostate cancer” or “CRPC” refers to prostate cancer that continues to grow even when testosterone levels are low or at castrate levels. CRPC can be diagnosed when a blood test shows rising prostate-specific antigen (PSA) levels and low testosterone levels.
  • PSA prostate-specific antigen
  • the term “metastatic castration-resistant prostate cancer” or “mCRPC” refers to prostate cancer that has spread to other parts of the body and continues to grow even when testosterone levels are low or at castrate levels.
  • the methods provided herein are for treating a cancer.
  • the cancer is a prostate cancer.
  • the method provided herein is for treating non-metastatic prostate cancer (nmHSPC).
  • the method provided herein is for treating metastatic hormone-sensitive prostate cancer (mHSPC).
  • the method provided herein is for treating non-metastatic castration-resistant prostate Attorney Docket No. 122622-0241 70 cancer (nmCRPC).
  • the method provided herein is for treating metastatic castration-resistant prostate cancer (mCRPC).
  • mCRPC metastatic castration-resistant prostate cancer
  • the subject is docetaxel na ⁇ ve. In some embodiments of the methods provided herein, the subject is docetaxel na ⁇ ve in treatment of mCRPC.
  • the methods provided herein may be used to treat a patient that has one or all of the following criteria: Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology; Have prostate cancer progression while on androgen deprivation therapy (ADT; or post bilateral orchiectomy) within 6 months before Screening, as optionally determined by one of the following: a. Clinical disease progression and prostate- specific antigen (PSA) progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of ⁇ 1 week between each assessment where the PSA value at Screening should be ⁇ 1 ng/mL; Attorney Docket No.
  • PSA prostate-specific antigen
  • the therapies disclosed herein reduce the growth of tumor cells in vivo. Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art.
  • Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., CT or MRI) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like.
  • administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor.
  • administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50- Attorney Docket No. 122622-0241 73 100%, about 75-100% or about 90-100%.
  • administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100%.
  • the subject is a human subject.
  • the human subject is an adult, i.e., greater than or equal to 18 years of age.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 4.8 mg/kg to 12 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 4.8 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 4.8 mg/kg.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 6.4 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 6.4 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug Attorney Docket No. 122622-0241 74 conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 8 mg/kg.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 8 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 10 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 10 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 12 mg/kg.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 12 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose ranging from about 4 mg/kg to about 12 mg/kg.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered to a subject with cancer once every three weeks as an intravenous dosage form which comprises the therapeutically effective amount of the antibody-drug conjugate (e.g., ifinatamab deruxtecan), wherein the therapeutically effective amount may be about 5 to 3000 mg, about 5 to 2500 mg, about 5 to 2000 mg, about 5 to about 1500 mg, about 5 to about 1000 mg, about 10 to Attorney Docket No.
  • 122622-0241 75 about 3000 mg, about 10 to about 2500 mg, about 10 to about 2000 mg, about 10 to about 1500 mg, about 10 to about 1000 mg, about 25 to about 2500 mg, about 25 to about 2000 mg, about 25 to about 1500 mg, about 25 to about 1000 mg, about 50 to about 2500 mg, about 50 to about 2000 mg, about 50 to about 1500 mg, about 50 to about 1000 mg, about 50 to about 950 mg, about 50 to about 900 mg, about 50 to about 850 mg, about 50 to about 800 mg, about 50 to about 750 mg, about 50 to about 700 mg, about 50 to about 650 mg, about 50 to about 600 mg, about 50 to about 550 mg, about 50 to about 500 mg, about 50 to about 450 mg, about 50 to about 400 mg, about 50 to about 350 mg, about 50 to about 300 mg, about 50 to about 250 mg, about 100 to about 2500 mg, about 100 to about 2000 mg, about 100 to about 1500 mg, about 100 to about 1000 mg, about 100 to about 950 mg, about 100 to about 900
  • 122622-0241 76 about 150 to about 650 mg, about 150 to about 600 mg, about 150 to about 550 mg, about 150 to about 500 mg, about 150 to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 150 to about 300 mg, about 150 to about 250 mg, about 200 to about 1000 mg, about 200 to about 950 mg, about 200 to about 900 mg, about 200 to about 850 mg, about 200 to about 800 mg, about 200 to about 750 mg, about 200 to about 700 mg, about 200 to about 650 mg, about 200 to about 600 mg, about 200 to about 550 mg, about 200 to about 500 mg, about 200 to about 450 mg, about 200 to about 400 mg, about 200 to about 350 mg, about 200 to about 300 mg, about 200 to about 250 mg, about 250 to about 1000 mg, about 250 to about 950 mg, about 250 to about 900 mg, about 250 to about 850 mg, about 250 to about 800 mg, about 250 to about 750 mg, about 250 to about 700 mg, about 250 to about 650 mg,
  • the dose of the ADC administered to the subject may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about Attorney Docket No.
  • 122622-0241 78 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395
  • the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every three weeks.
  • the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered twenty-two (22) days after the first dose of the antibody-drug conjugate.
  • the second dose of the antibody-drug conjugate is administered on Day 22 of the dosing cycle.
  • the antibody-drug conjugate e.g., ifinatamab deruxtecan
  • the antibody-drug conjugate is administered intravenously.
  • the antibody-drug conjugate e.g., ifinatamab deruxtecan
  • the antibody-drug conjugate is administered via a 90 ⁇ 10 minutes IV fusion.
  • the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 30 ⁇ 5 minutes IV Attorney Docket No.
  • an effective amount of any one or more of drugs selected from the group consisting of antihistamines, acetaminophen, and corticosteroids is administered to prevent or ameliorate infusion-related reaction (IRR).
  • a dose of the antibody-drug conjugate administered is reduced from about 12 mg/kg to about 10 mg/kg, or from about 10 mg/kg to about 8 mg/kg.
  • the androgen receptor antagonist in the present disclosure is enzalutamide, for example, relevant to any method as disclosed herein, enzalutamide is administered orally once per day.
  • enzalutamide is administered at a dose of about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg or about 240 mg per day. In one embodiment, enzalutamide is administered at a dose of about 160 mg per day such as four 40 mg capsules or tablets per day. In some further or alternative Attorney Docket No. 122622-0241 82 embodiments, for example, relevant to any method as disclosed herein, enzalutamide is administered at a dose of 40 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg per day.
  • enzalutamide is administered at a dose of 160 mg per day such as four 40 mg capsules or tablets per day.
  • the androgen receptor antagonist in the present disclosure is abiraterone acetate
  • abiraterone acetate is administered orally once per day.
  • abiraterone acetate is administered at a dose of about 500 mg to about 2000 mg such as about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg or about 2000 mg per day.
  • abiraterone acetate is administered at a dose of about 1000 mg such as two 500 mg tablets or four 250 mg tablets per day.
  • abiraterone acetate is administered at a dose of 500 mg to 2000 mg such as 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg or 2000 mg per day.
  • abiraterone acetate is administered at a dose of 1000 mg such as two 500 mg tablets or four 250 mg tablets per day.
  • prednisone or an equivalent dose of prednisolone is optionally also administered orally.
  • prednisone or an equivalent dose of prednisolone may be administered at a dose of about 5 mg or up to about 10 mg/day such as about 10 mg per day or per approved product label in this case.
  • prednisone or an equivalent dose of prednisolone may be administered at a dose of 5 mg or up to 10 mg/day such as 10 mg per day or per approved product label in this case.
  • Prednisolone may only be used when prednisone is unavailable.
  • the patient may receive only one type of medication (either prednisone or prednisolone) throughout the treatment.
  • prednisone or prednisolone may be administered with abiraterone acetate according to local/institutional guidelines.
  • Examples [0102] the present disclosure is specifically described in view of the examples shown below. In some embodiments, those skilled in the art will naturally understand that the embodiments described in the following examples may be extended and generalized Attorney Docket No. 122622-0241 84 to be also implemented in the detailed description of the present disclosure, as long as they are not technically contradictory and consistent with the context. However, the present disclosure is not limited to these.
  • Example 1 Production of anti-B7-H3 antibody-drug conjugate (1)
  • an anti-B7-H3 antibody namely, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2
  • an anti-B7-H3 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A in the formula represents a connecting position to the anti-B7-H3 antibody, is conjugated to the anti-B7- Attorney Docket No.
  • anti-B7-H3 antibody-drug conjugate (1) which is also known as ifinatamab deruxtecan
  • the average number of units of the drug-linker conjugated per antibody molecule in anti-B7-H3 antibody-drug conjugate (1) was 4 by a HPLC method.
  • Example 2 Antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and enzalutamide in a patient derived xenograft (PDX) model PDX tumor (NOp.1567) derived from a patient with castration resistant prostate cancer (CRPC) was provided from National Institutes of Biomedical Innovation, Health and Nutrition. Male NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, The Jackson Laboratory Japan, Inc.) were subcutaneously implanted with a fragment of NOp.1567 PDX tumors, which were maintained in host mice.
  • PDX patient derived xenograft
  • CRPC castration resistant prostate cancer
  • Table 1 Group Dosing Group Compound Dose No schedule Vehicle 1 Soln.
  • a - Q2W x 2 control Attorney Docket No. 122622-0241 86 Soln.
  • a - Q2W x 2 3 Enzalutamide Enzalutamide 50 mg/kg QD x 3 weeks *1 Anti-B7-H3 Anti-B7-H3 antibody- antibody-drug 3 mg/kg Q2W x 2 4 drug conjugate (1) conjugate + Enzalutamide 50 mg/kg QD x 3 weeks *1 Enzalutamide *1: Except for Saturday, Sunday, and the final day of the study [0106] The volume to administer each compound was calculated from the individual body weight measured on the day of dosing. Anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln.
  • B as a vehicle control of enzalutamide was administered orally to mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) at 10 mL/kg on days 0, 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, and 18.
  • the 0.3 mg/mL dosing solution of anti-B7-H3 antibody-drug conjugate (1) was administered intravenously to mice in Group 2 (anti-B7-H3 antibody- drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + enzalutamide) at 10 mL/kg on days 0 and 14.
  • the 5 mg/mL dosing solution of enzalutamide was administered orally to mice in Group 3 (enzalutamide) and Group 4 (anti-B7-H3 antibody-drug conjugate + enzalutamide) at 10 mL/kg on days 0, 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, and 18. [0108] Tumor length and tumor width were measured with a digital caliper.
  • Tumor volumes in the groups are shown in Figure 1.
  • the data represents mean tumor volume ⁇ standard error of the mean (SEM).
  • SEM standard error of the mean
  • TGIs in Group 2 anti-B7-H3 antibody-drug conjugate
  • Group 3 enzalutamide
  • Group 4 anti-B7-H3 antibody- drug conjugate + enzalutamide
  • mice Male NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, The Jackson Laboratory Japan, Inc.) are subcutaneously implanted with a fragment of NOp.1567 PDX tumors, which are maintained in host mice. When the tumor volume reaches approximately 200 to 300 mm 3 , tumor-bearing mice are assigned to four groups as shown in Table 2 (day 0):
  • 4 conjugate + Abiraterone Abiraterone 0.5% in acetate 4 weeks acetate diet [0112] The volume to administer each compound is calculated from the individual body weight measured on the day of dosing.
  • Anti-B7-H3 antibody-drug conjugate (1) is diluted with Soln. A (10 mmol/L histidine buffer (pH5.9) containing 9% sucrose and 0.02% polysorbate 20) to prepare a 0.3 mg/mL dosing solution.
  • Abiraterone acetate is manufactured by a method known to a person skilled in the art or commercially available abiraterone acetate can be purchased. Abiraterone acetate is thoroughly mixed with a gamma-ray irradiated powdered FR- 2 diet (Funabashi Farm Co., Ltd) at a concentration of 0.5% (w/w). [0113] Attorney Docket No. 122622-0241 91 Soln. A as a vehicle control of anti-B7-H3 antibody-drug conjugate (1) is administered intravenously to mice in Group 1 (vehicle control) and Group 3 (abiraterone acetate) at 10 mL/kg on days 0 and 14.
  • the 0.3 mg/mL dosing solution of anti-B7-H3 antibody-drug conjugate (1) is administered intravenously to mice in Group 2 (anti-B7-H3 antibody-drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) at 10 mL/kg on days 0 and 14.
  • Mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) are fed a gamma-ray irradiated powdered FR-2 diet without abiraterone acetate for 4 weeks.
  • mice in Group 3 (abiraterone acetate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) are fed a gamma-ray irradiated powdered FR-2 diet containing 0.5% (w/w) abiraterone acetate for 4 weeks.
  • Tumor length and tumor width are measured with a digital caliper.
  • Example 4 Antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and abiraterone acetate in a PDX model
  • Anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln. A to prepare a 0.3 mg/mL dosing solution.
  • Abiraterone acetate (ZYTIGA®) was purchased from Janssen Pharmaceutical K.K. which is commercially available. Abiraterone acetate was ground and thoroughly mixed with a gamma-ray-irradiated powdered FR-2 diet (Funabashi Farm Co., Ltd) at a concentration of 0.5% (w/w). [0118] Attorney Docket No. 122622-0241 94 Soln.
  • a as a vehicle control of anti-B7-H3 antibody-drug conjugate (1) was administered intravenously to mice in Group 1 (vehicle control) and Group 3 (abiraterone acetate) at 10 mL/kg on days 0 and 14.
  • the 0.3 mg/mL dosing solution of anti-B7-H3 antibody- drug conjugate (1) was administered intravenously to mice in Group 2 (anti-B7-H3 antibody-drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) at 10 mL/kg on days 0 and 14.
  • mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) were fed a gamma-ray-irradiated powdered FR-2 diet without abiraterone acetate from day 0 to day 28 as a control for abiraterone acetate treatment.
  • Mice in Group 3 (abiraterone acetate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) were fed the gamma-ray irradiated powdered FR-2 diet containing 0.5% (w/w) abiraterone acetate from day 0 to day 28.
  • Group 2 anti-B7-H3 antibody-drug conjugate
  • Group 3 abiraterone acetate
  • Group 4 anti-B7-H3 antibody-drug conjugate + abiraterone acetate
  • Example 5 Clinical trial protocol to evaluate the safety and efficacy of Ifinatamab Deruxtecan (I-DXd)-based Attorney Docket No. 122622-0241 96 treatment combinations or Ifinatamab Deruxtecan alone in participants with Metastatic Castration-resistant Prostate Cancer (mCRPC) This is a Phase 1/2 open-label umbrella study of of ifinatamab deruxtecan (referred to throughout this Example as I-DXd) -based treatment combinations or as monotherapy in participants with metastatic castration- resistant prostate cancer (mCRPC).
  • the study consists of multiple treatment arms. There will be two monotherapy treatment arms (Arms 1 (docetaxel) and 2 (I-DXd)) that will enroll participants into the Efficacy Phase of the study at the majority of sites. There will be one combination treatment arm of I-DXd plus abiraterone acetate or enzalutamide(referred to throughout this Example as androgen receptor pathway inhibitors (ARPI); Arm 4) that will initiate and enroll participants into the Safety Lead-in Phase at separate selected sites, followed by the Efficacy Phase.
  • Primary Objectives (1) To evaluate the safety and tolerability for each treatment arm. (2) To estimate the prostate-specific antigen (PSA) response rate for each treatment arm.
  • PSA prostate-specific antigen
  • At least 80 participants will be enrolled in each of the monotherapy treatment arms. Monotherapy treatment arms will continue enrolling participants when combination treatment arm is open and enrolling, so enrollment is expected to be approximately 120 participants per monotherapy treatment arm. Approximately 60 participants will be enrolled in the combination treatment arm. [0128] In the Safety Lead-in Phase, approximately 10 participants will be enrolled in the combination treatment arm. If the combination treatment arm moves from the Safety Lead-in Phase into the Efficacy Phase, the number of enrolled participants in the combination Attorney Docket No.
  • treatment arm will be approximately 60 participants including the participants enrolled in the Safety Lead-in and the Efficacy Phases together (i.e., ⁇ 10 participants at the RP2D in Safety Lead-in plus ⁇ 50 participants in Efficacy Phase).
  • Participants with bone-only disease will be eligible to enter the study, but the number of participants with bone-only disease will be capped at 50% of the enrollment per treatment arm.
  • Study Groups, Design and Dosages [0130] Participants are assigned to one of three arms (Arm 1, Arm 2 and Arm 4) and treated according to Table 4 below:
  • Prednisone is the preferred steroid to be used in the study.
  • Prednisolone should Attorney Docket No. 122622-0241 101 only be used when prednisone is unavailable. Participants should receive only one type of medication (either prednisone or prednisolone) throughout the entire study.
  • Prednisone/prednisolone will be administered with abiraterone acetate according to local/institutional guidelines. [0132] Study treatment will follow a 21-day cycle.
  • Docetaxel and prednisone/prednisolone will be prepared and administered as per the corresponding approved product label(s).
  • the recommended dose of docetaxel for mCRPC is 75 mg/m 2 q3w as a 1-hour IV infusion for a maximum of 10 cycles.
  • the recommended premedication is dexamethasone 8 mg po (orally) at 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.
  • the dose may deescalate to 8 mg/kg q3w and backfill to approximately 10 participants, if needed.
  • the BOIN design will be followed to confirm the RP2D.
  • the initial dose of I-DXd will be infused for 90 ⁇ 10 minutes. If there is no infusion-related reaction (IRR) during or after the initial dose, the subsequent doses of I-DXd may be infused for 30 ⁇ 5 minutes.
  • IRR infusion-related reaction
  • a 2- or 3-drug combination regimen e.g., corticosteroids with either a 5-HT3 receptor antagonist (e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g., aprepitant, casopitant, netupitant, or rolapitant) as well as other drugs as indicated) according to local or standard practice guidelines.
  • a 5-HT3 receptor antagonist e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron
  • NK-1 receptor antagonist e.g., aprepitant, casopitant, netupitant, or rolapitant
  • the drug is prepared based on the participant’s baseline body weight, defined as the last measurement before the first dose.
  • the dose must be recalculated if the participant’s weight changes by ⁇ 10% from baseline. After the recalculation, the updated participant’s weight will be used as the new baseline Attorney Docket No. 122622-0241 106 weight.
  • the site may follow local institutional policy for recalculating dose based on weight changes of less than 10%.
  • the entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 2 out of 3 participants at this dose level develop a DLT, the dose will be deescalated to the next lower dose level but may be reescalated at a later time if the lower dose is well tolerated. If 3 out of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be deescalated, if allowed per Attorney Docket No. 122622-0241 107 protocol, and the current dose will not be explored further.
  • Dose finding will follow the BOIN design with a target DLT rate of 30%, dose escalation DLT-rate boundary of 23.6%, and dose de-escalation DLT-rate boundary of 35.9%. Dose-escalation and de-escalation decisions are based on the BOIN design and depend on the number of participants enrolled and number of participants with at least 1 DLT observed at the current dose level. [0143] If a dose de-escalation decision is made before 10 participants have completed enrollment at the starting dose, the enrollment at this dose level will be halted and a new set of participants will be enrolled and treated at the next lower dose level.
  • abiraterone acetate will be administered as dose of 1000 mg (two 500 mg tablets or four 250 mg tablets) po qd with prednisone/prednisolone 5 mg orally bid. Participants are advised to swallow the abiraterone acetate tablet as a single dose whole with water at the same time each day on empty stomach. Participants should not eat food 2 hours before and 1 hour after taking abiraterone acetate. Refer to local guidelines and regulations for more details. After discontinuation, participants should complete prednisone/prednisolone taper per investigator’s discretion.
  • enzalutamide will be administered at a dose of 160 mg (four 40 mg capsules/tablets) po qd with or without food. Participants are advised to swallow the enzalutamide capsule whole and do not chew, dissolve, or open the capsules. Refer to local guidelines and regulations for more details.
  • Target Population [0148] Participants must be at least 18 years of age with mCRPC. An individual is eligible for inclusion in the Attorney Docket No. 122622-0241 110 study if the individual meets all of the following criteria: • Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology.
  • PSA prostate-specific antigen
  • ARPIs androgen receptor pathway inhibitors
  • nmHSPC non-metastatic hormone-sensitive prostate cancer
  • mHSPC metastatic hormone-sensitive prostate cancer
  • nmCRPC non-metastatic castration-resistant prostate cancer
  • Participants who have received at most 2 prior ARPIs are not eligible for Arm 4.
  • Grade 4 nonhematologic toxicity (not based on laboratory value) • Hematologic toxicity: • Grade 4 thrombocytopenia of any duration • Grade ⁇ 3 thrombocytopenia associated with clinically significant bleeding, regardless of duration • Grade ⁇ 3 thrombocytopenia lasting >7 days • Grade 4 anemia of any duration • Grade 4 lymphocyte count decreased lasting ⁇ 14 days • Any other Grade 4 hematologic toxicity lasting >7 days • Febrile neutropenia Grade 3 or Grade 4: • Grade 3 is defined as absolute neutrophil count (ANC) ⁇ 1000/mm 3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ⁇ 38 degrees C (100.4 degrees F) for more than 1 hour • Grade 4 is defined as ANC ⁇ 1000/mm 3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ⁇ 38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated Attorney Docket No.
  • ANC absolute neutrophil count
  • Table 7 Docetaxel Dose Reduction Guidelines (Arm 1) Drug Dose/Potency Regimen Initial 75 mg/m 2 every 3 weeks docetaxel dose Dose reduction 60 mg/m 2 Every 3 weeks 5.6 Dose Modification of I-DXd (Arm 2 and Arm 4) [0154] No dose modification of I-DXd is required for Grade 1 or Grade 2 events, unless specified. For Grade 3 or Grade 4 events, monitoring (including local laboratory Attorney Docket No. 122622-0241 117 tests when appropriate) will be performed frequently and at an interval of no greater than 7 days until the adverse event (AE) is determined to be resolving or back to baseline.
  • AE adverse event
  • the participant can resume treatment with I-DXd at a dose level as outlined in Table 8. Once the dose of I-DXd has been reduced because of toxicity, all subsequent doses should be administered at that lower dose level unless further dose reduction is required. More than 2 dose reductions are not allowed and participants cannot reduce the dose of I-DXd below 8 mg/kg. The participant will be withdrawn from the study treatment if further toxicity meeting the requirement for dose reduction occurs. Once the dose of I-DXd is reduced, no dose reescalation is permitted.

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Abstract

In some aspects, a pharmaceutical product comprising an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor for administration in combination is provided.

Description

Attorney Docket No. 122622-0241 1 COMBINATION OF ANTI-B7-H3 ANTIBODY-DRUG CONJUGATE AND ANDROGEN RECEPTOR SIGNALING INHIBITOR Technical Field [0001] In some aspects, the present disclosure relates to a pharmaceutical product, wherein an anti-B7-H3 antibody- drug conjugate and an androgen receptor signaling inhibitor are administered in combination, and/or a method of treatment or prevention, wherein an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination to a subject. Background [0002] Prostate cancer is the most common cancer in men worldwide. When prostate cancer progresses despite androgen deprivation therapy (ADT) alone, it is called castration-resistant prostate cancer (CRPC). Approximately 10% to 20% of prostate cancer patients develop metastatic castration-resistant prostate cancer (mCRPC) within 5 years. Even though the 5-year survival rate of patients with localized prostate cancer is high, the prognosis for those patients, who develop CRPC within that 5-year follow-up period, is poor. While the standards of care have improved over the years, current Attorney Docket No. 122622-0241 2 standards of care still fail to meet the need for effective therapies to improve treatment of prostate cancer in general and mCRPC in particular. Accordingly, there is a need in the art for new therapies, including, for example, combination therapies for the treatment of prostate cancer. Provided herein are solutions to these and other problems in the art. [0003] Antibody-drug conjugates (ADCs) in which a cytotoxic drug is conjugated to an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cancer cells are expected to selectively deliver the cytotoxic drug to cancer cells and kill the cancer cells. [0004] Antibody-drug conjugates in which an exatecan derivative (a DNA topoisomerase I inhibitor) is conjugated to an anti-B7-H3 antibody have been reported (Patent Reference 1). Citation List Patent Literature [0005] Patent Reference 1: WO2014/057687 Summary Technical Problem Attorney Docket No. 122622-0241 3 [0006] Androgen receptor, a steroid hormone receptor, is a ligand-activated nuclear transcription factor that plays key role in the pathogenesis of prostate cancer. A therapeutic strategy of disrupting androgen receptor signaling associated with prostate cancer growth has led to the development of drugs that inhibit androgen synthesis enzymes or block androgen receptor. Androgen receptor signaling inhibitors (ARSIs) such as abiraterone, which can inhibit production of androgen in organs including testes and adrenal glands, and tumor cells by inhibiting CYP17, and enzalutamide, apalutamide and darolutamide, which act as antagonists of androgen receptor, are known. However, the therapeutic benefit of these drugs is often short-lived due to development of drug resistance. Patent Reference 1 does not describe any test result showing a combined effect of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor, or any scientific basis for suggesting such combination. [0007] Whilst demand exists for a pharmaceutical product and method of treatment or prevention which can exert a further superior antitumor effect by using an anti-B7-H3 antibody-drug conjugate such as those described in Patent Reference 1 in combination with another anti-cancer agent having a different mechanism of action, test results or Attorney Docket No. 122622-0241 4 scientific basis that demonstrate or suggest an excellent antitumor effect and/or safety of a combination of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are not yet known or well elucidated. Solution to Problem [0008] In some aspects, the present inventors, as a result of diligent studies, have surprisingly found that combined administration of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor unexpectedly exhibits an excellent antitumor effect and/or safety, and thereby completed the present invention. In further preferred non-limiting embodiments, the present inventors conceived that the excellent effects of the combined administration could be generalized and expanded to any combination of an anti- B7-H3 antibody-drug conjugate in which a DNA topoisomerase I inhibitor is conjugated to an anti-B7-H3 antibody and an androgen receptor signaling inhibitor. [0009] Thus, in some embodiments, the present disclosure provides the following: [0010] Attorney Docket No. 122622-0241 5 [1] A pharmaceutical product comprising (an effective amount of) an anti-B7-H3 antibody-drug conjugate (as an active ingredient) and (an effective amount of) an androgen receptor signaling inhibitor (as an active ingredient) for administration in combination; [2] The pharmaceutical product according to [1], wherein a drug in the anti-B7-H3 antibody-drug conjugate is a topoisomerase I inhibitor; [3] The pharmaceutical product according to [2], wherein the drug represented by the following formula is released to express an antitumor activity: ; [4] The pharmaceutical product according to [2], wherein an antitumor compound represented by the following formula is conjugated to an anti-B7-H3 antibody through a linker with the nitrogen atom of the amino group at position 1 as the connecting position: Attorney Docket No. 122622-0241 6 ; [5] The pharmaceutical product according to [4], wherein the antitumor compound is conjugated to the anti-B7-H3 antibody through the linker via a thioether bond which is formed at a disulfide bond moiety present in the anti-B7- H3 antibody; [6] The pharmaceutical product according to [4] or [5], wherein the linker comprises a tetrapeptide residue of -Gly-Gly-Phe-Gly-; [7] A pharmaceutical product comprising (an effective amount of) an anti-B7-H3 antibody-drug conjugate (as an active ingredient) and (an effective amount of) an androgen receptor signaling inhibitor (as an active ingredient) for administration in combination, wherein the anti-B7-H3 antibody-drug conjugate is an antibody- drug conjugate in which a drug-linker represented by the following formula is conjugated to an anti-B7-H3 antibody or a functional fragment thereof via a thioether bond: Attorney Docket No. 122622-0241 7 wherein A in the formula represents a connecting position to the anti-B7-H3 antibody or functional fragment thereof; [8] A pharmaceutical product comprising (an effective amount of) an anti-B7-H3 antibody-drug conjugate (as an active ingredient) and (an effective amount of) an androgen receptor signaling inhibitor (as an active ingredient) for administration in combination, wherein the anti-B7-H3 antibody-drug conjugate comprises an anti- B7-H3 antibody or a functional fragment thereof conjugated to the drug-linker represented by the formula shown in [7] via the thioether bond, wherein A in the formula represents a connecting position to the anti-B7- H3 antibody or functional fragment thereof. [9] The pharmaceutical product according to any one of [1] to [8], wherein the androgen receptor signaling inhibitor is an androgen synthesis inhibitor or an androgen receptor antagonist; Attorney Docket No. 122622-0241 8 [10] The pharmaceutical product according to [9], wherein the androgen synthesis inhibitor is a CYP17 inhibitor; [11] The pharmaceutical product according to [10], wherein the CYP17 inhibitor is abiraterone or a pharmaceutically acceptable salt thereof; [12] The pharmaceutical product according to [10] or [11], wherein the CYP17 inhibitor is abiraterone acetate or abiraterone decanoate; [13] The pharmaceutical product according to [12], wherein the CYP17 inhibitor is abiraterone acetate and wherein the pharmaceutical product further optionally comprises prednisone or prednisolone in combination; [14] The pharmaceutical product according to [9], wherein the androgen receptor antagonist is selected from the group consisting of enzalutamide, apalutamide, darolutamide, and pharmaceutically acceptable salts thereof; [15] The pharmaceutical product according to [14], wherein the androgen receptor antagonist is enzalutamide; [16] The pharmaceutical product according to any one of [1] to [15], wherein the anti-B7-H3 antibody or functional fragment thereof comprises (i) a CDRH1 comprising an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising an amino acid sequence consisting of amino Attorney Docket No. 122622-0241 9 acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2; or (ii) a CDRH1 comprising an amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising an amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising an amino acid sequence of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising an amino acid sequence of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising an amino acid sequence of amino acid residues 108 to 116 of SEQ ID NO: 2; [17] The pharmaceutical product according to any one of [1] to [16], wherein the anti-B7-H3 antibody or functional fragment thereof comprises (I) a CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID Attorney Docket No. 122622-0241 10 NO: 1, a CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2; or (II) a CDRH1 consisting of an amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 consisting of an amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 consisting of an amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 consisting of an amino acid sequence of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 consisting of an amino acid sequence of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 consisting of an amino acid sequence of amino acid residues 108 to 116 of SEQ ID NO: 2; [18] The pharmaceutical product according to any one of [1] to [17], wherein the anti-B7-H3 antibody or functional fragment thereof comprises a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 2. Attorney Docket No. 122622-0241 11 [19] The pharmaceutical product according to any one of [1] to [18], wherein the anti-B7-H3 antibody or functional fragment thereof comprises a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 2; [20] The pharmaceutical product according to any one of [1] to [19], wherein the anti-B7-H3 antibody comprises a heavy chain comprising or consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain comprising or consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2; [21] The pharmaceutical product according to any one of [1] to [20], wherein the anti-B7-H3 antibody is an IgG1; [22] The pharmaceutical product according to any one of [1] to [21], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2; [23] The pharmaceutical product according to any one of [1] to [22], wherein a lysine residue is deleted from Attorney Docket No. 122622-0241 12 each of the carboxyl termini of both of the heavy chains of the anti-B7-H3 antibody; [24] The pharmaceutical product according to any one of [1] to [23], wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range from 3 to 5, and more preferably from 3.5 to 4.5; [25] The pharmaceutical product according to any one of [1] to [23], wherein the number of units of the drug- linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is an integer in the range from 2 to 8, preferably 2, 4, 6, or 8, and most preferably 4; [26] The pharmaceutical product according to any one of [1] to [23], wherein the anti-B7-H3 antibody-drug conjugate is represented by the following formula: wherein ‘Antibody’ in the formula represents the anti-B7- H3 antibody or functional fragment thereof conjugated to the drug-linker via a thioether bond and n represents the average number of units of the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug Attorney Docket No. 122622-0241 13 conjugate, wherein n is in the range from 3 to 5, and wherein the anti-B7-H3 antibody comprises a heavy chain comprising (or consisting of) an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain comprising (or consisting of) an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2; [27] The pharmaceutical product according to any one of [1] to [23], wherein the anti-B7-H3 antibody-drug conjugate is represented by the formula shown in [26], wherein ‘Antibody’ in the formula is an anti-B7-H3 antibody or a functional fragment thereof and each drug- linker represented by the structure shown within the bracket in the formula is conjugated to the anti-B7-H3 antibody or functional fragment thereof via a thioether bond, and n represents the average number of units of the drug-linker conjugated per antibody molecule in the anti- B7-H3 antibody-drug conjugate; [28] The pharmaceutical product according to any one of [1] to [23], wherein the anti-B7-H3 antibody-drug conjugate is represented by the formula shown in [26], wherein ‘Antibody’ in the formula is an anti-B7-H3 antibody or a functional fragment thereof conjugated to the drug-linker via a thioether bond, and n represents drug-to-antibody ratio; Attorney Docket No. 122622-0241 14 [29] The pharmaceutical product according to any one of [1] to [28], wherein the anti-B7-H3 antibody-drug conjugate is ifinatamab deruxtecan; [30] The pharmaceutical product according to any one of [1] to [29], wherein the anti-B7-H3 antibody or functional fragment thereof is an anti-B7-H3 antibody; [31] The pharmaceutical product according to any one of [1] to [30], wherein the anti-B7-H3 antibody or functional fragment thereof is an antibody comprising two heavy chains and two light chains; [32] The pharmaceutical product according to any one of [1] to [31], wherein the product is a combined preparation comprising the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor, for separate simultaneous or sequential administration; [33] The pharmaceutical product according to any one of [1] to [32], wherein the product is for treating or preventing cancer; [34] The pharmaceutical product according to [33], wherein the cancer is cancer expressing androgen receptor and/or B7-H3; [35] The pharmaceutical product according to [33] or [34], wherein the cancer is prostate cancer or breast cancer; [36] The pharmaceutical product according to [35], wherein the cancer is prostate cancer; Attorney Docket No. 122622-0241 15 [37] The pharmaceutical product according to any one of [1] to [36], wherein the pharmaceutical product further comprises another cancer therapeutic agent for administration in combination with the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor defined in any one of [1] to [31]; [38] The pharmaceutical product according to any one of [33] to [37], wherein the cancer is prostate cancer selected from the group consisting of castration- resistant prostate cancer, metastatic castration- resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer, castration- sensitive prostate cancer, metastatic castration- sensitive prostate cancer, metastatic high-risk castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, hormone-sensitive prostate cancer, and metastatic hormone-sensitive prostate cancer; [39] The pharmaceutical product according to [38], wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC); [40] The pharmaceutical product according to any one of [33] to [39], wherein the androgen receptor signaling inhibitor is abiraterone acetate or enzalutamide; Attorney Docket No. 122622-0241 16 [41] The pharmaceutical product according to any one of [1] to [40], wherein the antibody-drug conjugate is to be administered at a dose of about 4.8 mg/kg to 12 mg/kg; [42] The pharmaceutical product according to any one of [1] to [41], wherein the antibody-drug conjugate is to be administered at a dose of about 4.8 mg/kg, about 6.4 mg/kg, about 8 mg/kg, about 10 mg/kg, or about 12 mg/kg; [43] The pharmaceutical product according to [42], wherein the antibody-drug conjugate is to be administered at a dose of about 8 mg/kg; [44] The pharmaceutical product according to [42], wherein antibody-drug conjugate is to be administered at a dose of about 10 mg/kg; [45] The pharmaceutical product according to [42], wherein the antibody-drug conjugate is to be administered at a dose of about 12 mg/kg; [46] The pharmaceutical product according to any one of [1] to [45], wherein the antibody-drug conjugate is to be administered once every three weeks; [47] The pharmaceutical product according to any one of [1] to [46], wherein the antibody-drug conjugate is to be administered intravenously; [48] The pharmaceutical product according to any one of [1] to [47], wherein the antibody-drug conjugate is to be administered via a 90 ± 10 minutes IV fusion; [49] The pharmaceutical product according to [48], wherein the antibody-drug conjugate is to be administered Attorney Docket No. 122622-0241 17 via a 30 ± 5 minutes IV fusion if there is no (substantial) infusion-related reaction (IRR) during or after the initial dose of the antibody-drug conjugate administration; [50] The pharmaceutical product according to any one of [1] to [49], wherein before each dose of the anti-B7-H3 antibody-drug conjugate administration, an effective amount of any one or more of drugs selected from the group consisting of antihistamines, acetaminophen, and corticosteroids is to be administered to prevent or ameliorate infusion-related reaction (IRR); [51] The pharmaceutical product according to any one of [1] to [42] and [44] to [50], wherein if a dose reduction is required due to the toxicity of the antibody-drug conjugate administration, a dose of the antibody-drug conjugate administered is reduced from about 12 mg/kg to about 10 mg/kg, or from about 10 mg/kg to about 8 mg/kg; [52] The pharmaceutical product according to any one of preceding clauses including [40], wherein enzalutamide is to be administered orally once per day; [53] The pharmaceutical product according to any one of preceding clauses including [52], wherein enzalutamide is to be administered at a dose of 160 mg , optionally wherein enzalutamide is to be administered as four 40 mg capsules or tablets; Attorney Docket No. 122622-0241 18 [54] The pharmaceutical product according to any one of preceding clauses including [40], wherein abiraterone acetate is to be administered orally once per day; [55] The pharmaceutical product according to any one of preceding clauses including [54], wherein abiraterone acetate is to be administered at a dose of 1000 mg, optionally wherein abiraterone acetate is to be administered as two 500 mg tablets or four 250 mg tablets; [56] The pharmaceutical product according to any one of preceding clauses including [40], [54] or [55], wherein prednisone or an equivalent dose of prednisolone is to be further administered orally; [57] The pharmaceutical product according to any one of preceding clauses including [40] and [54] to [56], wherein prednisone or an equivalent dose of prednisolone is to be further administered at a dose of up to 10 mg, optionally wherein prednisone or an equivalent dose of prednisolone is to be administered as 5 mg or 10 mg per day or per approved product label; [58] The pharmaceutical product according to any one of [33] to [35], wherein the cancer is androgen receptor- positive breast cancer or triple-negative androgen receptor-positive breast cancer; [59] A pharmaceutical product as defined in any one of [1] to [58], for use in treating or preventing cancer; Attorney Docket No. 122622-0241 19 [60] An anti-B7-H3 antibody-drug conjugate or a pharmaceutical composition comprising the anti-B7-H3 antibody-drug conjugate, for use in treating or preventing cancer in combination with an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [58]; [61] The anti-B7-H3 antibody-drug conjugate or the pharmaceutical composition for the use according to [60], by separate simultaneous or sequential administration in combination with the androgen receptor signaling inhibitor; [62] The anti-B7-H3 antibody-drug conjugate or the pharmaceutical composition for the use according to [60] or [61], wherein the cancer is as defined in any one of [33] to [39] and [58]; [63] An androgen receptor signaling inhibitor or a pharmaceutical composition comprising the androgen receptor signaling inhibitor, for use in treating or preventing cancer in combination with an anti-B7-H3 antibody-drug conjugate, wherein the anti-B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [62]; [64] The androgen receptor signaling inhibitor or the pharmaceutical composition for the use according to [63], Attorney Docket No. 122622-0241 20 by separate simultaneous or sequential administration in combination with the anti-B7-H3 antibody-drug conjugate; [65] The androgen receptor signaling inhibitor or the pharmaceutical composition for the use according to [63] or [64], wherein the cancer is as defined in any one of [33] to [39] and [58]; [66] Use of an anti-B7-H3 antibody-drug conjugate for the preparation of a medicament for treating or preventing cancer, by administration in combination with an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [62]; [67] Use of an androgen receptor signaling inhibitor for the preparation of a medicament for treating or preventing cancer, by administration in combination with an anti-B7-H3 antibody-drug conjugate, wherein the anti- B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [62]; [68] The use according to [66] or [67], wherein the cancer is as defined in any one of [33] to [39] and [58]; [69] A pharmaceutical combination of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor, for use in the treatment or prevention of cancer, wherein the anti-B7-H3 antibody- drug conjugate and the androgen receptor signaling Attorney Docket No. 122622-0241 21 inhibitor are as defined in any one of [1] to [62], and wherein the cancer is as defined in any one of [33] to [39] and [58]; [70] A method of treating or preventing cancer comprising administering an anti-B7-H3 antibody-drug conjugate as defined in any one of [1] to [62] to a subject in need thereof; and administering an androgen receptor signaling inhibitor as defined in any one of [1] to [62] to the subject; [71] The method according to [45], wherein the cancer is as defined in any one of [33] to [39] and [58]; [72] A kit comprising (a) a first composition comprising an anti-B7-H3 antibody-drug conjugate and (b) a second composition comprising an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of [1] to [62]; and [73] The kit according to [72], for use in treating or preventing cancer, wherein the cancer is optionally as defined in any one of [33] to [39] and [58]. [0011] Further embodiments of the prostate cancer in the present disclosure may be described as follows: (i) metastatic castration-resistant prostate cancer or metastatic high-risk castration-sensitive prostate cancer Attorney Docket No. 122622-0241 22 when the androgen receptor signaling inhibitor is abiraterone acetate; (ii) castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis when the androgen receptor signaling inhibitor is enzalutamide; (iii) metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer when the androgen receptor signaling inhibitor is apalutamide; or (iv) non-metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer in combination with docetaxel when the androgen receptor signaling inhibitor is darolutamide. Advantageous Effects of Invention [0012] In some embodiments, the present disclosure provides a pharmaceutical product with an excellent antitumor effect and/or safety, wherein an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination, and/or a method of treatment or prevention with an excellent antitumor effect and/or safety, wherein the anti-B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are administered in combination to a subject. Attorney Docket No. 122622-0241 23 Without wishing to be bound by any theory, in preferred embodiments, the combined administration of a preferred anti-B7-H3 antibody-drug conjugate of the present disclosure such as ifinatamab deruxtecan in combination with an androgen receptor signaling inhibitor such as enzalutamide is advantageous in terms of safety while exerting an improved antitumor effect over vobramitamab duocarmazine (MGC018) in combination with the same androgen receptor signaling inhibitor. Brief Description of Drawing [0013] [Figure 1] Figure 1 shows tumor volumes after initial treatment in mice administered with vehicle control, anti-B7-H3 antibody-drug conjugate (1), enzalutamide, or a combination of anti-B7-H3 antibody-drug conjugate (1) and enzalutamide, in a patient derived xenograft (PDX) model. [Figure 2] Figure 2 shows tumor volumes after initial treatment in mice administered with vehicle control, anti-B7-H3 antibody-drug conjugate (1), abiraterone acetate, or a combination of anti-B7-H3 antibody-drug conjugate (1) and abiraterone acetate, in a patient derived xenograft (PDX) model. [Figure 3] In and for Figure 3: AE=adverse event; ARPI=androgen receptor pathway inhibitors; DLT=dose- limiting toxicity; ECOG=Eastern Cooperative Oncology Attorney Docket No. 122622-0241 24 Group; mCRPC=metastatic castration-resistant prostate cancer; N=total number of participants; PSA=prostate- specific antigen; RP2D=recommended Phase 2 dose; TPC=treatment of physician’s choice. a. For any combination treatment arm that moves from the Safety Lead-in Phase into the Efficacy Phase, the number of enrolled participants in the treatment arm will include those who were enrolled in the Safety Lead-in and Efficacy Phases. In the Safety Lead-in Phase, approximately 10 participants will be enrolled and in the Efficacy Phase, approximately 50 participants will be enrolled in each combination treatment arm. b. Participants enrolled in the Safety Lead-in Phase will be allocated to a treatment arm. Total number of participants (N) enrolled will depend on DLT evaluation. c. Participants will be randomly assigned during the Efficacy Phase by prespecified stratification factor with a randomization ratio of 1:2 for monotherapy and combination treatment arms. For example, when there are 2 monotherapy arms and 2 combination treatment arms open for enrollment in the Efficacy Phase, the randomization ratio will be 1:1:2:2 for the 2 monotherapy arms and 2 combination treatment arms. d. The number of participants with bone-only disease will be capped at 50% of the enrollment per treatment arm. e. At study start, participants will be randomly assigned to the Efficacy Phase in Arms 1 and 2 and will be Attorney Docket No. 122622-0241 25 allocated at separate selected sites to the Safety Lead- in Phase in Arm 4. Each combination treatment arm begins the Efficacy Phase at other study sites after the Safety Lead-in Phase is completed. Once at least one combination treatment arm has entered the Efficacy Phase, new participants will be randomized (ie, not allocated) to all open treatment arms at study sites enrolling the Efficacy Phase. Arm 1 and Arm 2 will be continue to remain open for enrollment anytime that a combination treatment arm is in the Efficacy Phase. f. Dose escalation during the Safety Lead-in will be for I-DXd. The combination product will be given at the recommended dose. g. Participants entering Arm 4 Safety Lead-in will be monitored for receipt of abiraterone acetate and I-DXd or enzalutamide and I-DXd for sufficient number of each ARPI. i. Total number of participants (N) in the combination arms will be ~60 participants inclusive of participants from the Safety Lead-in Phase (~10 participants at the RP2D) and participants from the Efficacy Phase (~50 participants). j. ARPI will include abiraterone acetate plus prednisone/prednisolone or enzalutamide as TPC selected based on whichever ARPI was not last received by the participant. Attorney Docket No. 122622-0241 26 Description of Embodiments [0014] Hereinafter, preferred modes for carrying out the present disclosure are described. The embodiments described below are given merely for illustrating examples of typical embodiments of the present disclosure and are not intended to limit the scope of the present invention. 1. General [0015] Unless otherwise defined, terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. As used herein, the terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated. As used herein, the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise. Attorney Docket No. 122622-0241 27 The term “about” or “approximately” indicates and encompasses the designated value ± 10%. In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first composition” and “second composition” are used to distinguish two compositions. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” 2nd Ed., Thomas Sorrell, University Science Books, Sausalito: 2006, and “March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference. 2. Anti-B7-H3 antibody-drug conjugate [0016] Anti-B7-H3 antibody-drug conjugates used in the present disclosure are known in the art. Examples of such anti-B7-H3 antibody-drug conjugates include, but are not limited to, vobramitamab duocarmazine (MGC018), mirzotamab clezutoclax (ABBV-155), BAT8009, HS-20093, MHB088C, 7MW3711, and DB-1311. Anti-B7-H3 antibody-drug Attorney Docket No. 122622-0241 28 conjugates are also described in WO2014/057687, WO2023/061457, US11,685,742B2, US20210347894A, US20220233708A, WO2024/022372, WO2022/117040, WO2024/061306, WO2024/037503, WO2024/052685, WO2024/052684, WO2023/236949, US20240148892A, WO2023/241663, WO2024/140935, US20240108745A1 WO2022/170971), WO2024/140932, WO2024/140935, WO2024/211235, and WO25087323, each of which incorporated herein by reference in its entirety. [0017] In some embodiments, the anti-B7-H3 antibody-drug conjugate is an antibody-drug conjugate in which a drug- linker represented by the following formula: wherein A in the formula represents a connecting position to an anti-B7-H3 antibody or a functional fragment thereof, is conjugated to the anti-B7-H3 antibody or functional fragment thereof via a thioether bond. [0018] Attorney Docket No. 122622-0241 29 As used herein, the partial structure consisting of a linker and a drug in an antibody-drug conjugate is referred to as a "drug-linker". In some embodiments, the drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the anti-B7- H3 antibody. [0019] In some embodiments, the drug-linker includes exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component. Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula: Attorney Docket No. 122622-0241 30 [0020] In some embodiments, the anti-B7-H3 antibody-drug conjugate can also be represented by the following formula: wherein, the drug-linker is conjugated to an anti-B7-H3 antibody or a functional fragment thereof via a thioether bond. The meaning of n may be the same as what is called the average number of conjugated drug molecules per antibody molecule (DAR; Drug-to-Antibody Ratio). In this context, n indicates the average number of drug molecules (or units of the drug-linker) conjugated per antibody molecule in a composition of antibody-drug conjugate molecules. Alternatively, in a different context, n may be an integer representing the number of drug molecules (or units of the drug-linker) conjugated per antibody molecule in an anti-B7-H3 antibody-drug conjugate molecule. [0021] In some embodiments, after migrating into cancer cells, the anti-B7-H3 antibody-drug conjugate is cleaved Attorney Docket No. 122622-0241 31 at the linker portion to release the compound represented by the following formula: [0022] In some embodiments, the aforementioned compound is inferred to be the original source of the antitumor activity of the anti-B7-H3 antibody-drug conjugate. In preferred embodiments, the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan. As used herein, the term “ifinatamab deruxtecan” is an antibody-drug conjugate (ADC) comprising the anti-B7- H3 antibody immunoglobulin G1 monoclonal antibody ifinatamab, which is covalently linked to deruxtecan. In pre-clinical models, ifinatamab deruxtecan exerted potent antitumor activity in high B7-H3 expressing tumors with an acceptable pharmacokinetic and safety profile (Yamato, M., et. al., (2022). Mol Cancer Ther; 21(4), 635-646). Ifinatamab and ifinatamab deruxtecan are described, e.g., in WHO Drug Information, Vol. 36, No. 3, 2022 (Recommended INN: List 88). Deruxtecan is also described, e.g., in WHO Drug Information, Vol. 30, No. 4, 2016 (Proposed INN List 116). Attorney Docket No. 122622-0241 32 [0023] In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab govitecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab rezetecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab samrotecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab brengitecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab tirumotecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab adizutecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab tocentecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab sesutecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab pamirtecan. In some alternative preferred embodiments, the anti- B7-H3 antibody-drug conjugate is ifinatamab repodatecan. In each of the above anti-B7-H3 antibody-drug conjugates, the drug-linker part is already made available to the public as follows: Govitecan is described, e.g., in WHO Drug Information, Proposed INN List 113; Attorney Docket No. 122622-0241 33 Rezetecan is described, e.g., in WHO Drug Information, Proposed INN List 127; Samrotecan is described, e.g., in WHO Drug Information, Proposed INN List 129; Brengitecan is described, e.g., in WHO Drug Information, Proposed INN List 129; Tirumotecan is described, e.g., in WHO Drug Information, Proposed INN List 129; Adizutecan is described, e.g., in WHO Drug Information, Proposed INN List 130; Tocentecan is described, e.g., in WHO Drug Information, Proposed INN List 130; Sesutecan is described, e.g., in WHO Drug Information, Proposed INN List 130; Pamirtecan is described, e.g., in WHO Drug Information, Proposed INN List 131; or Repodatecan is described, e.g., in WHO Drug Information, Proposed INN List 132. A person skilled in the art will readily understand that any anti-B7-H3 antibody including those described herein can be connected to any of the above drug-linker to produce an anti-B7-H3 antibody-drug conjugate. 3. Antibody in the anti-B7-H3 antibody-drug conjugate [0024] As used herein, the term "anti-B7-H3 antibody" or a functional fragment thereof refers to an antibody or a Attorney Docket No. 122622-0241 34 functional fragment thereof respectively each of which binds specifically to B7-H3 (B cell antigen #7 homolog 3; PD-l3; CD276), and preferably has an activity of internalization in B7-H3-expressing cells by binding to B7-H3. [0025] B7-H3, one of the B7 family members expressed in antigen-presenting cells as a co-stimulator, is considered to act on receptors on T cells and enhance or suppress immune effect. B7-H3 is a single transmembrane protein and has two variants. B7-H3 variant 1 (4Ig-B7-H3) contains two each of V- or C- like Ig domains, and B7-H3 variant 2 (2Ig-B7-H3) contains one each of V- or C -like Ig domains. Amino acid sequences of these variants are known in the art. The amino acid sequence of human 4Ig- B7-H3 is for example shown in UniProt accession number Q5ZPR3-1 (2004-11-23 v1) or GenBank accession number: NP_001019907.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP_001019907.1. The amino acid sequence of human 2Ig-B7- H3 is for example shown in UniProt accession number Q5ZPR3-2, or GenBank accession number: NP_001316557.1 or NP_079516.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP_001316557.1 or NP_079516.1. B7-H3 protein has a very Attorney Docket No. 122622-0241 35 limited expression on normal tissues because of its post- transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types. [0026] In some embodiments, the anti-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate may be derived from any species such as a human, a rat, a mouse, or a rabbit. In cases when the anti-B7-H3 antibody or functional fragment thereof is derived from species other than human species, it is preferably chimerized or humanized using a known technique. The anti-B7-H3 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. Examples of an anti-B7-H3 antibody include, but not limited to, M30-H1-L4 described in WO2014/057687 or those described in WO2024/061306 or CN117603916A. [0027] As used herein, the term "functional fragment" of an antibody is also called "antigen-binding fragment" of an antibody, and is used to mean a partial fragment of the antibody having binding activity against an antigen, and includes, but not limited to, Fab, F(ab')2, scFv, a diabody, a linear antibody and a multi-specific antibody formed from antibody fragments. In some embodiments, Fab', which is a monovalent fragment of antibody variable Attorney Docket No. 122622-0241 36 regions obtained by treating F(ab')2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. The antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has antigen-binding ability. These antigen-binding fragments include not only those obtained by treating a full-length molecule of an antibody protein with an appropriate enzyme, but proteins produced in appropriate host cells using a genetically engineered antibody gene. [0028] In some embodiments, the anti-B7-H3 antibody or functional fragment thereof preferably has the characteristic of being able to target cancer cells, or possesses, for example, the property of being able to recognize a cancer cell, the property of being able to bind to a cancer cell, the property of being internalized in a cancer cell, or cytocidal activity against cancer cells. [0029] The binding activity of the anti-B7-H3 antibody or functional fragment thereof against cancer cells can be confirmed using flow cytometry, for example. The internalization of the antibody into tumor cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) Attorney Docket No. 122622-0241 37 binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used. [0030] The antitumor activity of the anti-B7-H3 antibody or functional fragment thereof can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, or spheroid growth, for example. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining changes in the cancer cells. Attorney Docket No. 122622-0241 38 [0031] Since the compound conjugated in the anti-B7-H3 antibody-drug conjugate exerts an antitumor effect when released, it is preferred but not essential that the anti-B7-H3 antibody itself or functional fragment thereof has an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is preferred that the anti-B7-H3 antibody or functional fragment thereof has the property of being internalized to migrate into cancer cells. [0032] In some embodiments, the anti-B7-H3 antibody or functional fragment thereof can be obtained by a procedure known in the art. [0033] The antigen can be obtained by a procedure known in the art, such as by genetically engineering host cells to produce a gene encoding the antigenic protein. [0034] In some embodiments, the anti-B7-H3 antibody or functional fragment thereof is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human Attorney Docket No. 122622-0241 39 antibody. These antibodies can be produced using a known method. [0035] In some embodiments, for the anti-B7-H3 antibody, modified variants of the anti-B7-H3 antibody are also included. The modified variant refers to a variant obtained by subjecting the anti-B7-H3 antibody or functional fragment thereof to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, and variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant. Such a modified variant of the antibody is useful for improving the stability and blood retention of the antibody, reducing the Attorney Docket No. 122622-0241 40 antigenicity thereof, detecting or isolating an antibody or an antigen, and so on. [0036] Further, by regulating the modification of a glycan which is linked to the anti-B7-H3 antibody or functional fragment thereof (for example, glycosylation, defucosylation), it is possible to enhance antibody- dependent cellular cytotoxic activity. As examples of the technique for regulating the modification of a glycan of antibodies, techniques disclosed for example in WO99/54342, WO00/61739, WO02/31140, WO2007/133855, and WO2013/120066, are known. In some embodiments, an anti- B7-H3 antibody or a functional fragment thereof in which the modification of a glycan is regulated are also included. [0037] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence do not affect Attorney Docket No. 122622-0241 41 the antigen-binding affinity and the effector function (for example, complement activation or antibody-dependent cellular cytotoxicity) of the antibody. Therefore, in some embodiments, anti-B7-H3 antibodies subjected to such modification or functional fragments thereof are also included. In other embodiments, variants in which one or two amino acids have been deleted at either or both of the carboxyl termini of the heavy chains, and variants obtained by amidation of the deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated) are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody or functional fragment thereof is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-B7-H3 antibody and the culture conditions; however, in some embodiments, an anti-B7-H3 antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody can be preferably exemplified. In some embodiments, the anti-B7-H3 antibody provided herein may undergo post-translational modifications as known in the art. Examples of post-translational modifications include, but are not limited to, chemical modifications, Attorney Docket No. 122622-0241 42 such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art. See, Liu, et. al., J. Pharma. Sci. vol. 97, no. 7, pp. 2426-2447 (2008). Other types of modifications include noncovalent interaction, conformational heterogeneity, and aggregation. Id. In some embodiments, an N-terminal E or Q of an anti-B7- H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of anti-B7-H3 antibody provided herein is removed. In other embodiments, an N-terminal E or Q of an anti-B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the anti-B7-H3 antibody (e.g., heavy chain C-terminal amino acid) is removed. The present disclosure includes any of the above described post-translational modifications of any of the anti-B7-H3 antibodies provided herein. [0038] The light chain from any vertebrate species can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the sequence of its constant domain. The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): Attorney Docket No. 122622-0241 43 IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and µ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. As isotypes of the anti-B7-H3 antibody, for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified. 4. Production of the anti-B7-H3 antibody-drug conjugate [0039] In some embodiments, a drug-linker intermediate for use in the production of the antibody-drug conjugate is represented by the following formula: [0040] In some embodiments, the drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L- phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy- 4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H- Attorney Docket No. 122622-0241 44 benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced with reference to WO2014/057687, WO2015/098099, WO2015/115091, WO2015/155998, or WO2019/044947, for example. [0041] In some embodiments, the anti-B7-H3 antibody-drug conjugate can be produced by reacting the above-described drug-linker intermediate and an anti-B7-H3 antibody or a functional fragment thereof having a thiol group (alternatively referred to as a sulfhydryl group). [0042] The anti-B7-H3 antibody or functional fragment thereof having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained. Attorney Docket No. 122622-0241 45 Further, in some embodiments, by using 2 to 20 molar equivalents of the drug-linker intermediate per the antibody having a sulfhydryl group, an antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced. [0044] The average number of conjugated drug molecules per antibody molecule in the antibody-drug conjugate can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method). [0045] Conjugation between the antibody and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule in the antibody-drug conjugate can be performed with reference to WO2014/057687, WO2017/002776 or WO2022/014698, for example. [0046] As used herein, the term "anti-B7-H3 antibody-drug conjugate" may refer to an antibody-drug conjugate in which the antibody or a functional fragment thereof in Attorney Docket No. 122622-0241 46 the antibody-drug conjugate is an anti-B7-H3 antibody or a functional fragment thereof. [0047] In some embodiments, the anti-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate (i-1) comprises a CDRH1 comprising or consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising or consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising or consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising or consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising or consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising or consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2; (i-2) comprises a CDRH1 comprising or consisting of an amino acid sequence of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising or consisting of an amino acid sequence of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising or consisting of an amino acid sequence of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising or consisting of an Attorney Docket No. 122622-0241 47 amino acid sequence of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising or consisting of an amino acid sequence of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising or consisting of an amino acid sequence of amino acid residues 108 to 116 of SEQ ID NO: 2; (ii-1) comprises a heavy chain variable region comprising or consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 1, and a light chain variable region comprising or consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 2; (ii-2) comprises a heavy chain variable region comprising or consisting of an amino acid sequence of amino acid residues 20 to 141 of SEQ ID NO: 1, and a light chain variable region comprising or consisting of an amino acid sequence of amino acid residues 21 to 128 of SEQ ID NO: 2; (iii-1) comprises a heavy chain comprising or consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain comprising or consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2; or (iii-2) comprises a heavy chain comprising or consisting of an amino acid sequence of amino acid residues 20 to Attorney Docket No. 122622-0241 48 consisting of an amino acid sequence of amino acid residues 21 to 233 of SEQ ID NO: 2. In some embodiments of the anti-B7-H3 antibody or functional fragment thereof, a lysine residue is deleted from each of the carboxyl termini of both of the heavy chains. [0048] In some embodiments, the average number of units of the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is 2 to 8, preferably 3 to 5, more preferably 3.5 to 4.5, and even more preferably about 4. In other embodiments, the number of the drug or the drug-linker conjugated per antibody molecule in the anti-B7-H3 antibody-drug conjugate is an integer in the range from 2 to 8, preferably 2, 4, 6, or 8, and most preferably 4. [0049] In some embodiments, the anti-B7-H3 antibody-drug conjugate can be produced with reference to WO2014/057687, WO2017/002776 or WO2022/014698. In preferred embodiments, the anti-B7-H3 antibody-drug conjugate produced is ifinatamab deruxtecan. 5. Androgen receptor signaling inhibitor [0050] As used herein, “androgen receptor signaling inhibitor” refers to a drug that has the function of Attorney Docket No. 122622-0241 49 inhibiting androgen receptor signaling, and includes, but is not limited to, androgen synthesis inhibitors or androgen receptor antagonists. In some embodiments, an androgen receptor signaling inhibitor may be referred to as a novel hormonal agent. [0051] As used herein, in some aspects, an “androgen synthesis inhibitor” refers to a drug that has an inhibitory effect on androgen synthesis (e.g., A Jacob et al., Cancers (Basel). 2021, 13(21)). As used herein, in some aspects, an “androgen receptor antagonist” refers to a drug that acts by blocking the androgen binding site of androgen receptor (e.g., A Jacob et al., Cancers (Basel). 2021, 13(21)). Examples of the androgen receptor signaling inhibitor are, but not limited to, abiraterone (a CYP17 inhibitor), enzalutamide, apalutamide, darolutamide, or pharmaceutically acceptable salts of these. [0052] In some embodiments, an androgen receptor signaling inhibitor may be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes either an acid addition salt or a salt with a base, but may be preferably an acid addition salt, examples of which can include lower alkanesulfonates such as camsilate (camphorsulfonate), methanesulfonate, trifluoromethanesulfonate, and Attorney Docket No. 122622-0241 50 ethanesulfonate; arylsulfonates such as tosylate (p- toluenesulfonate), and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and hydrosulfate; hydrohalic acid salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, decanoate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate, and aspartate. [0053] In other embodiments, the androgen receptor signaling inhibitor or pharmaceutically acceptable salts thereof may also be present in the form of a solvate. For clarification, the solvate may be a solvate of a pharmaceutically acceptable salt of the androgen receptor signaling inhibitor. In an embodiment, the androgen receptor signaling inhibitor is an androgen synthesis inhibitor. In one such embodiment, the androgen synthesis inhibitor is a CYP17 inhibitor. In more specific embodiments, the CYP17 inhibitor is abiraterone or a pharmaceutically acceptable salt thereof, for example abiraterone acetate or abiraterone decanoate, in particular abiraterone acetate. In another embodiment, the androgen receptor signaling inhibitor is an androgen receptor antagonist. In one such embodiment, the androgen receptor antagonist is selected from the group consisting of enzalutamide, Attorney Docket No. 122622-0241 51 apalutamide, darolutamide, and pharmaceutically acceptable salts thereof. In a more specific embodiment, the androgen receptor antagonist is enzalutamide. 6. Medicament and Methods of Treatment [0054] In one aspect, described in the following are a pharmaceutical product and a method of treatment or prevention according to the present invention, wherein an anti—B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor are administered in combination, separately, sequentially, or concurrently, for example. [0055] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure may be those in which the anti—B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are separately contained as active components in different formulations and are administered simultaneously or at different times, or may be those in which the anti—B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are contained as active components in a single formulation and administered. The anti—B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor may be administered at different intervals when the anti—B7-H3 Attorney Docket No. 122622-0241 52 antibody-drug conjugate and the androgen receptor signaling inhibitor are separately contained as active ingredients in different formulations. [0056] As used herein, in one aspect, the term "pharmaceutical product" refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered. [0057] In preferred embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing cancer, preferably cancer expressing androgen receptor and/or B7- H3. In an embodiment, the pharmaceutical product and method of treatment or preventing of the present disclosure can be used for treating or preventing prostate cancer or breast cancer (including triple- negative androgen receptor-positive breast cancer). Attorney Docket No. 122622-0241 53 In one embodiment, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing prostate cancer. In another embodiment, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for treating or preventing prostate cancer selected from the group consisting of castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, non- metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, metastatic high- risk castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis, hormone-sensitive prostate cancer, and metastatic hormone-sensitive prostate cancer optionally in combination with docetaxel. [0058] In further embodiments: (i) the prostate cancer is metastatic castration- resistant prostate cancer or metastatic high-risk castration-sensitive prostate cancer, and the androgen receptor signaling inhibitor is abiraterone acetate; (ii) the prostate cancer is castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or non-metastatic castration- sensitive prostate cancer with biochemical Attorney Docket No. 122622-0241 54 recurrence at high risk for metastasis, and the androgen receptor signaling inhibitor is enzalutamide; (iii) the prostate cancer is metastatic castration- sensitive prostate cancer or non-metastatic castration-resistant prostate cancer, and the androgen receptor signaling inhibitor is apalutamide; (iv) the prostate cancer is non-metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer in combination with docetaxel, and the androgen receptor signaling inhibitor is darolutamide. In a further embodiment, the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan, and the androgen receptor signaling inhibitor is abiraterone or a pharmaceutically acceptable salt thereof, for example abiraterone acetate or abiraterone decanoate, in particular abiraterone acetate. In a further embodiment, the anti-B7-H3 antibody- drug conjugate is ifinatamab deruxtecan, and the androgen receptor signaling inhibitor is enzalutamide, apalutamide, darolutamide, or a pharmaceutically acceptable salts thereof, in particular enzalutamide. [0059] The anti-B7-H3 antibody-drug conjugate can be preferably used in the case that B7-H3 expression is Attorney Docket No. 122622-0241 55 found in the cancer, as determined by examining the type of cancer and tumor markers. The presence or absence of B7-H3 tumor markers, can be checked by, for example, collecting tumor tissue from a cancer patient, and subjecting the formalin fixed paraffin embedded specimen (FFPE) to an examination at a gene product (protein) level, such as an immunohistochemistry (IHC) method, a flow cytometry, a western blot method, or an examination at a gene transcription level, such as an in situ hybridization method (ISH), a quantitative PCR method (q-PCR), or a microarray analysis; alternatively, it can also be checked by collecting cell-free blood circulating tumor DNA (ctDNA) from a cancer patient and subjecting to an examination which uses a method such as next-generation sequencing (NGS). [0060] The pharmaceutical product and method of treatment or prevention of the present disclosure can be preferably used for mammals, and can be more preferably used for humans. In some embodiments, the human is an adult (e.g., 18 years old or greater). [0061] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure can be used for a maintenance therapy. In other embodiments, the pharmaceutical product and method Attorney Docket No. 122622-0241 56 of treatment or prevention of the present disclosure may be used for the purpose of preventing the recurrence of a tumor after initial chemotherapy. Therefore, in one embodiment, “preventing cancer” means preventing the recurrence of cancer or tumor. [0062] As used herein, the term “maintenance therapy” is used to mean treatment that is given to help prevent cancer from coming back after it has disappeared following an initial therapy. The term is defined on the basis of “maintenance therapy” in the following reference: NCI Dictionaries, “maintenance therapy”, NCI Dictionary of Cancer Terms [online]. National Cancer Institute [retrieved on 2023-04-10]. Retrieved from < cancer.gov/publications/dictionaries/cancer- terms/def/maintenance-therapy>. [0063] The antitumor effect of the pharmaceutical product and method of treatment or prevention can be confirmed by, for example, generating a model in which cancer cells are transplanted to a test animal, and measuring reduction in tumor volume, life-prolonging effects due to applying the pharmaceutical product and method of treatment or prevention. Furthermore, comparison with the antitumor effect of single administration of each of the anti-B7-H3 antibody-drug conjugate and the androgen Attorney Docket No. 122622-0241 57 receptor signaling inhibitor can provide confirmation of the combined effect of the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor. [0064] In addition, the antitumor effect of the pharmaceutical product and method of treatment or prevention of the present disclosure can be confirmed, in a clinical study, with the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, WHO's evaluation method, Macdonald's evaluation method, measurement of body weight, and other methods; and can be determined by indicators such as Complete response (CR), Partial response (PR), Progressive disease (PD), Objective response rate (ORR), Duration of response (DoR), Progression-free survival (PFS), or Overall survival (OS). [0065] The foregoing methods can provide confirmation of superiority in terms of the antitumor effect of the pharmaceutical product and method of treatment or prevention of the present disclosure compared to existing pharmaceutical products and methods of treatment for cancer therapy. [0066] The pharmaceutical product and method of treatment or prevention of the present disclosure can retard growth of cancer cells, suppress their proliferation, or can Attorney Docket No. 122622-0241 58 kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or can achieve an improvement in the quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and method of treatment or prevention do not accomplish the killing of cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells. Furthermore, the pharmaceutical product and method of treatment or prevention can show a sustained antitumor effect. [0067] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure are not associated with severe body weight loss. [0068] The pharmaceutical product and method of treatment or prevention of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues. [0069] In some embodiments, the pharmaceutical product of the present disclosure includes a pharmaceutical composition containing at least one pharmaceutically Attorney Docket No. 122622-0241 59 suitable ingredient. The pharmaceutically suitable ingredient can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration or the like of the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor. For example, the anti-B7-H3 antibody-drug conjugate can be administered as a pharmaceutical product containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as Polysorbate 80 or 20. The pharmaceutical product containing the anti-B7-H3 antibody-drug conjugate can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection. [0070] In the case that the pharmaceutical product or composition containing the anti-B7-H3 antibody-drug conjugate is an aqueous injection, it can be preferably diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified. [0071] Attorney Docket No. 122622-0241 60 In the case that the pharmaceutical product or composition containing the anti-B7-H3 antibody-drug conjugate is a lyophilized injection, it can be preferably dissolved in water for injection, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified. [0072] Examples of the administration route which may be used to administer the pharmaceutical product of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular, or intraperitoneal routes; and preferably include an intravenous route. [0073] In some embodiments, the anti-B7-H3 antibody-drug conjugate can be administered to a human once at intervals of 1 to 180 days, and can be preferably administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, and can be even more preferably administered once every 3 weeks. Also, in further embodiments, the anti-B7-H3 antibody-drug conjugate can be administered at a dose of about 0.001 to 100 mg/kg, and can be preferably administered at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 6.4 mg/kg, Attorney Docket No. 122622-0241 61 8 mg/kg, 12 mg/kg, or 16 mg/kg, and can be more preferably administered at a dose of 8 to 12 mg/kg, preferably, 8 mg/kg or 12 mg/kg once every 3 weeks. In some embodiments, 8 to 12 mg/kg, preferably 12 mg/kg or 8 mg/kg, of the anti-B7-H3 antibody-drug conjugate is intravenously administered once every three weeks. The dosage amount of an androgen receptor signaling inhibitor is not particularly limited as long as it is an effective amount for treating or preventing a target disease and appropriately selected depending on the age, body weight, symptom, health condition and disease progression of the patient. The frequency of administration is not particularly limited and can be appropriately selected depending on the purpose. For example, the dosage amount per day is administered once a day or divided into a plurality of doses and administered separately. [0074] The term “effective amount” or “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., those described herein individually or in combination) that is sufficient to reduce and/or ameliorate the severity and/or duration of a given disease, disorder or condition, and/or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the Attorney Docket No. 122622-0241 62 advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and/or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance/molecule/agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance/molecule/agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance/molecule/agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal. [0075] In some embodiments, for treating or preventing cancer, the androgen receptor signaling inhibitor is orally administered once a day or twice a day. In some embodiments, for treating or preventing prostate cancer: (a) the androgen receptor signaling inhibitor is abiraterone acetate orally administered once a day, optionally 1,000 mg orally administered once a day, and Attorney Docket No. 122622-0241 63 the prostate cancer is metastatic castration-resistant prostate cancer or metastatic high-risk castration- sensitive prostate cancer; (b) the androgen receptor signaling inhibitor is enzalutamide orally administered once a day, optionally 160 mg orally administered once a day, and the prostate cancer is metastatic castration-resistant prostate cancer; (c) the androgen receptor signaling inhibitor is apalutamide orally administered once a day, optionally 240 mg orally administered once a day, and the prostate cancer is metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer; or (d) the androgen receptor signaling inhibitor is darolutamide orally administered twice a day, optionally 600 mg orally administered twice a day, and the prostate cancer is non-metastatic castration-resistant prostate cancer. [0076] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure may further contain a cancer therapeutic agent other than the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor. In other embodiments, the pharmaceutical product and method of treatment or prevention can also be administered in Attorney Docket No. 122622-0241 64 combination with another cancer therapeutic agent, thereby enhancing the antitumor effect. Other cancer therapeutic agents to be used for such purpose may be administered to a subject simultaneously, separately, or sequentially with the pharmaceutical product, or may be administered with varying each dosage interval. Such cancer therapeutic agents are not limited as long as they have antitumor activity, and can be selected from the group consisting of irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, cabazitaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur-gimeracil-oteracil combination, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trifluridine-tipiracil combination, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, triptorelin, histrelin, degarelix, relugolix, bicalutamide, flutamide, nilutamide, sipuleucel-T, radium-223 dichloride, prednisone, letrozole, anastrozole, progesterone formulation, trastuzumab emtansine, trastuzumab, pertuzumab, and lapatinib, for example. [0077] In some embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure can also be used in combination with Attorney Docket No. 122622-0241 65 radiotherapy. For example, a cancer patient may receive radiotherapy before and/or after or simultaneously with receiving therapy with the pharmaceutical product. [0078] In other embodiments, the pharmaceutical product and method of treatment or prevention of the present disclosure can also be used as an adjuvant chemotherapy in combination with a surgical procedure. The pharmaceutical product may be administered for the purpose of diminishing the size of a tumor before a surgical procedure (referred to as pre-operative adjuvant chemotherapy or neoadjuvant therapy), or may be administered after a surgical procedure for the purpose of preventing the recurrence of a tumor (referred to as post-operative adjuvant chemotherapy or adjuvant therapy). [0079] As used herein, the terms “medicament” and “pharmaceutical composition” are used without distinction. [0080] As used herein, in some embodiments, the terms “administration in combination with” and “administered in combination” are used to represent a form of drug administration in which a plurality of active ingredients are contained or encapsulated in different preparations and administered simultaneously (a person skilled in the Attorney Docket No. 122622-0241 66 art would naturally understand that “simultaneously” or “at the same time” may be or may not be at about the same time) or separately or sequentially in any order at different times, or both contained or encapsulated in the same preparation and administered, unless the context otherwise requires and unless technically inconsistent. [0081] As used herein, unless specifically stated otherwise and not limited in particular, and as long as it does not contradict technically and in the context, a term written in the singular form is considered to include the plural form, and vice versa. 7. Dosage regimen [0082] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may Attorney Docket No. 122622-0241 67 comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. [0083] As used herein, the term “dosing cycle” refers to a period of treatment followed by an optional period of rest (no treatment) that is repeated on a regular schedule. The period of treatment may include a single drug or a combination of drugs. In some embodiments, the dosing cycle does not include a period of rest. As one non-limiting example, in some embodiments, a dosing cycle as described herein may be about 3 weeks or 21 days long. As referred to herein, “Day 1” is the first day of a dosing cycle. As referred to herein, “Day 1 of Cycle 1” is the first day of the first dosing cycle. [0084] As used herein, the terms “subject” or “patient” are used interchangeably and mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human (e.g., an adult human, i.e., greater than or equal to 18 years of age). In some embodiments, the subject has a disease or condition that can be treated with an agent provided herein. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer Attorney Docket No. 122622-0241 68 castration-resistant prostate cancer (CRPC). In some embodiments, the cancer is metastatic castration- resistant prostate cancer (mCRPC). [0085] “Cancer” refers to any physiological condition in mammals characterized by unregulated cell growth; in particular, cellular-proliferative disease states. As used herein, “tumor” refers to any neoplastic cell growth or proliferation, whether malignant or benign, and to all pre-cancerous and cancerous cells and tissues. [0086] As used herein, “prostate cancer” is a form of cancer wherein cells of the prostate gland grow uncontrolled. Adenocarcinoma prostate cancer is a type of prostate cancer that starts in the gland cells that produce prostate fluid. Small cell prostate cancer (SCPC) is a type of prostate cancer that develops from neuroendocrine cells of the prostate. Small cell and adenocarcinoma prostate cancers can be differentiated by visual examination of cells under a microscope or radiographically, among others. “Adenocarcinoma without small cell” refers to a prostate cancer where the tumor is composed of adenocarcinoma cells without significant presence of small cell carcinoma. Adenocarcinoma of the prostate can be assessed using the Gleason grading system to determine its aggressiveness based on the appearance of the cancer cells. In certain embodiments, Attorney Docket No. 122622-0241 69 adenocarcinoma may show some features of neuroendocrine differentiation, but if the predominant cell type is adenocarcinoma and does not have a significant “small cell” component, it would still be considered “adenocarcinoma without small cell.” [0087] The term “castration-resistant prostate cancer” or “CRPC” refers to prostate cancer that continues to grow even when testosterone levels are low or at castrate levels. CRPC can be diagnosed when a blood test shows rising prostate-specific antigen (PSA) levels and low testosterone levels. [0088] The term “metastatic castration-resistant prostate cancer” or “mCRPC” refers to prostate cancer that has spread to other parts of the body and continues to grow even when testosterone levels are low or at castrate levels. [0089] In one aspect, the methods provided herein are for treating a cancer. In some embodiments, the cancer is a prostate cancer. In one aspect, the method provided herein is for treating non-metastatic prostate cancer (nmHSPC). In one aspect, the method provided herein is for treating metastatic hormone-sensitive prostate cancer (mHSPC). In one aspect, the method provided herein is for treating non-metastatic castration-resistant prostate Attorney Docket No. 122622-0241 70 cancer (nmCRPC). In one aspect, the method provided herein is for treating metastatic castration-resistant prostate cancer (mCRPC). [0090] In some embodiments of the methods provided herein, the subject is docetaxel naïve. In some embodiments of the methods provided herein, the subject is docetaxel naïve in treatment of mCRPC. [0091] In certain embodiments, the methods provided herein may be used to treat a patient that has one or all of the following criteria: Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology; Have prostate cancer progression while on androgen deprivation therapy (ADT; or post bilateral orchiectomy) within 6 months before Screening, as optionally determined by one of the following: a. Clinical disease progression and prostate- specific antigen (PSA) progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at Screening should be ≥1 ng/mL; Attorney Docket No. 122622-0241 71 b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or without PSA progression; c. Radiographic disease progression in bone based on PCWG-Modified RECIST 1.1, defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression; Have progression under the following conditions if the patient received first generation antiandrogen therapy before enrollment: a. Evidence of progression >4 weeks since last flutamide treatment; b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment; Have current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft-tissue lesion per RECIST 1.1 by CT/MRI; Have received prior treatment with one or two androgen receptor pathway inhibitors (ARPIs; e.g., abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castration- resistant prostate cancer (nmCRPC) or mCRPC and progressed during or after at least 8 weeks of treatment (at least 14 weeks of treatment for the patient with bone progression); Attorney Docket No. 122622-0241 72 Have ongoing androgen deprivation with serum testosterone optionally <50 ng/dL (<1.7 nM); or Have had prior treatment with PARP inhibitor (PARPi) if indicated by local approved regimen or were deemed ineligible to receive PARPi. [0092] In certain embodiments, the therapies disclosed herein reduce the growth of tumor cells in vivo. Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., CT or MRI) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like. [0093] In specific embodiments, administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor. In further embodiments, administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50- Attorney Docket No. 122622-0241 73 100%, about 75-100% or about 90-100%. In further embodiments, administration of the therapies provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100%. [0094] In one embodiment, the subject is a human subject. In one embodiment, the human subject is an adult, i.e., greater than or equal to 18 years of age. [0095] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 4.8 mg/kg to 12 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 4.8 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 4.8 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 6.4 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 6.4 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug Attorney Docket No. 122622-0241 74 conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 8 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 8 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 10 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 10 mg/kg. In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of about 12 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose of 12 mg/kg. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at a dose ranging from about 4 mg/kg to about 12 mg/kg. [0096] In some embodiments, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered to a subject with cancer once every three weeks as an intravenous dosage form which comprises the therapeutically effective amount of the antibody-drug conjugate (e.g., ifinatamab deruxtecan), wherein the therapeutically effective amount may be about 5 to 3000 mg, about 5 to 2500 mg, about 5 to 2000 mg, about 5 to about 1500 mg, about 5 to about 1000 mg, about 10 to Attorney Docket No. 122622-0241 75 about 3000 mg, about 10 to about 2500 mg, about 10 to about 2000 mg, about 10 to about 1500 mg, about 10 to about 1000 mg, about 25 to about 2500 mg, about 25 to about 2000 mg, about 25 to about 1500 mg, about 25 to about 1000 mg, about 50 to about 2500 mg, about 50 to about 2000 mg, about 50 to about 1500 mg, about 50 to about 1000 mg, about 50 to about 950 mg, about 50 to about 900 mg, about 50 to about 850 mg, about 50 to about 800 mg, about 50 to about 750 mg, about 50 to about 700 mg, about 50 to about 650 mg, about 50 to about 600 mg, about 50 to about 550 mg, about 50 to about 500 mg, about 50 to about 450 mg, about 50 to about 400 mg, about 50 to about 350 mg, about 50 to about 300 mg, about 50 to about 250 mg, about 100 to about 2500 mg, about 100 to about 2000 mg, about 100 to about 1500 mg, about 100 to about 1000 mg, about 100 to about 950 mg, about 100 to about 900 mg, about 100 to about 850 mg, about 100 to about 800 mg, about 100 to about 750 mg, about 100 to about 700 mg, about 100 to about 650 mg, about 100 to about 600 mg, about 100 to about 550 mg, about 100 to about 500 mg, about 100 to about 450 mg, about 100 to about 400 mg, about 100 to about 350 mg, about 100 to about 300 mg, about 100 to about 250 mg, about 150 to about 2000 mg, about 150 to about 1500 mg, about 150 to about 1000 mg, about 150 to about 950 mg, about 150 to about 900 mg, about 150 to about 850 mg, about 150 to about 800 mg, about 150 to about 750 mg, about 150 to about 700 mg, Attorney Docket No. 122622-0241 76 about 150 to about 650 mg, about 150 to about 600 mg, about 150 to about 550 mg, about 150 to about 500 mg, about 150 to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 150 to about 300 mg, about 150 to about 250 mg, about 200 to about 1000 mg, about 200 to about 950 mg, about 200 to about 900 mg, about 200 to about 850 mg, about 200 to about 800 mg, about 200 to about 750 mg, about 200 to about 700 mg, about 200 to about 650 mg, about 200 to about 600 mg, about 200 to about 550 mg, about 200 to about 500 mg, about 200 to about 450 mg, about 200 to about 400 mg, about 200 to about 350 mg, about 200 to about 300 mg, about 200 to about 250 mg, about 250 to about 1000 mg, about 250 to about 950 mg, about 250 to about 900 mg, about 250 to about 850 mg, about 250 to about 800 mg, about 250 to about 750 mg, about 250 to about 700 mg, about 250 to about 650 mg, about 250 to about 600 mg, about 250 to about 550 mg, about 250 to about 500 mg, about 250 to about 450 mg, about 250 to about 400 mg, about 250 to about 350 mg, about 250 to about 300 mg, about 300 to about 1000 mg, about 300 to about 950 mg, about 300 to about 900 mg, about 300 to about 850 mg, about 300 to about 800 mg, about 300 to about 750 mg, about 300 to about 700 mg, about 300 to about 650 mg, about 300 to about 600 mg, about 300 to about 550 mg, about 300 to about 500 mg, about 300 to about 450 mg, about 300 to about 400 mg, about 300 to about 350 mg, Attorney Docket No. 122622-0241 77 about 350 to about 1000 mg, about 350 to about 950 mg, about 350 to about 900 mg, about 350 to about 850 mg, about 350 to about 800 mg, about 350 to about 750 mg, about 350 to about 700 mg, about 350 to about 650 mg, about 350 to about 600 mg, about 350 to about 550 mg, about 350 to about 500 mg, about 350 to about 450 mg, about 350 to about 400 mg, about 400 to about 1000 mg, about 400 to about 950 mg, about 400 to about 900 mg, about 400 to about 850 mg, about 400 to about 800 mg, about 400 to about 750 mg, about 400 to about 700 mg, about 400 to about 650 mg, about 400 to about 600 mg, about 400 to about 550 mg, about 400 to about 500 mg, about 400 to about 450 mg, about 450 to about 1000 mg, about 450 to about 950 mg, about 450 to about 900 mg, about 450 to about 850 mg, about 450 to about 800 mg, about 450 to about 750 mg, about 450 to about 700 mg, about 450 to about 650 mg, about 450 to about 600 mg, about 450 to about 550 mg, about 450 to about 500 mg, about 500 to about 1000 mg, about 500 to about 950 mg, about 500 to about 900 mg, about 500 to about 850 mg, about 500 to about 800 mg, about 500 to about 750 mg, about 500 to about 700 mg, about 500 to about 650 mg, about 500 to about 600 mg, or about 500 to about 550 mg. In other words, in some embodiments the dose of the ADC administered to the subject may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about Attorney Docket No. 122622-0241 78 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, Attorney Docket No. 122622-0241 79 about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about Attorney Docket No. 122622-0241 80 2000 mg, or any value in between. A person skilled in the art would understand the appropriate amount of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) considering various factors such as the weight of an patient in need thereof. [0097] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every three weeks. [0098] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered twenty-two (22) days after the first dose of the antibody-drug conjugate. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered on Day 22 of the dosing cycle. [0099] In some embodiments of this disclosure, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered intravenously. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 90 ± 10 minutes IV fusion. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 30 ± 5 minutes IV Attorney Docket No. 122622-0241 81 fusion if there is no substantial infusion-related reaction (IRR) during or after the initial dose of the antibody-drug conjugate administration. In one embodiment, before each dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) administration, an effective amount of any one or more of drugs selected from the group consisting of antihistamines, acetaminophen, and corticosteroids is administered to prevent or ameliorate infusion-related reaction (IRR). In some alternative embodiments, if a dose reduction is required due to the toxicity of the the antibody-drug conjugate (e.g., ifinatamab deruxtecan), a dose of the antibody-drug conjugate administered is reduced from about 12 mg/kg to about 10 mg/kg, or from about 10 mg/kg to about 8 mg/kg. [0100] In some embodiments, wherein the androgen receptor antagonist in the present disclosure is enzalutamide, for example, relevant to any method as disclosed herein, enzalutamide is administered orally once per day. In some further or alternative embodiments, for example, relevant to any method as disclosed herein, enzalutamide is administered at a dose of about 40 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg or about 240 mg per day. In one embodiment, enzalutamide is administered at a dose of about 160 mg per day such as four 40 mg capsules or tablets per day. In some further or alternative Attorney Docket No. 122622-0241 82 embodiments, for example, relevant to any method as disclosed herein, enzalutamide is administered at a dose of 40 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg per day. In one embodiment, enzalutamide is administered at a dose of 160 mg per day such as four 40 mg capsules or tablets per day. [0101] In some embodiments, wherein the androgen receptor antagonist in the present disclosure is abiraterone acetate, for example, relevant to any method as disclosed herein, abiraterone acetate is administered orally once per day. In some further or alternative embodiments, for example, relevant to any method as disclosed herein, abiraterone acetate is administered at a dose of about 500 mg to about 2000 mg such as about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg or about 2000 mg per day. In one embodiment, abiraterone acetate is administered at a dose of about 1000 mg such as two 500 mg tablets or four 250 mg tablets per day. In some further or alternative embodiments, for example, relevant to any method as disclosed herein, abiraterone acetate is administered at a dose of 500 mg to 2000 mg such as 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg or 2000 mg per day. In one embodiment, abiraterone acetate is administered at a dose of 1000 mg such as two 500 mg tablets or four 250 mg tablets per day. In some further embodiments, when abiraterone Attorney Docket No. 122622-0241 83 acetate is administered, for example, relevant to any method as disclosed herein, prednisone or an equivalent dose of prednisolone is optionally also administered orally. For example, relevant to any method as disclosed herein, prednisone or an equivalent dose of prednisolone may be administered at a dose of about 5 mg or up to about 10 mg/day such as about 10 mg per day or per approved product label in this case. For example, relevant to any method as disclosed herein, prednisone or an equivalent dose of prednisolone may be administered at a dose of 5 mg or up to 10 mg/day such as 10 mg per day or per approved product label in this case. Prednisolone may only be used when prednisone is unavailable. In one embodiment, the patient may receive only one type of medication (either prednisone or prednisolone) throughout the treatment. In some embodiments, prednisone or prednisolone may be administered with abiraterone acetate according to local/institutional guidelines. Examples [0102] In some embodiments, the present disclosure is specifically described in view of the examples shown below. In some embodiments, those skilled in the art will naturally understand that the embodiments described in the following examples may be extended and generalized Attorney Docket No. 122622-0241 84 to be also implemented in the detailed description of the present disclosure, as long as they are not technically contradictory and consistent with the context. However, the present disclosure is not limited to these. Further, it is by no means to be interpreted in a limited way. [0103] Example 1: Production of anti-B7-H3 antibody-drug conjugate (1) In accordance with a production method described in WO2014/057687 or WO2022/014698 with use of an anti-B7-H3 antibody (namely, an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2), an anti-B7-H3 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A in the formula represents a connecting position to the anti-B7-H3 antibody, is conjugated to the anti-B7- Attorney Docket No. 122622-0241 85 H3 antibody via a thioether bond (hereinafter, referred to as the "anti-B7-H3 antibody-drug conjugate (1)", which is also known as ifinatamab deruxtecan) was produced. The average number of units of the drug-linker conjugated per antibody molecule in anti-B7-H3 antibody-drug conjugate (1) was 4 by a HPLC method. [0104] Example 2: Antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and enzalutamide in a patient derived xenograft (PDX) model PDX tumor (NOp.1567) derived from a patient with castration resistant prostate cancer (CRPC) was provided from National Institutes of Biomedical Innovation, Health and Nutrition. Male NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, The Jackson Laboratory Japan, Inc.) were subcutaneously implanted with a fragment of NOp.1567 PDX tumors, which were maintained in host mice. When the tumor volume reached approximately 200 to 300 mm3, tumor- bearing mice were assigned to four groups as shown in Table 1 (day 0, n = 8 mice/group): [0105] Table 1 Group Dosing Group Compound Dose No schedule Vehicle 1 Soln. A - Q2W x 2 control Attorney Docket No. 122622-0241 86 Soln. B - QD x 3 weeks*1 Anti-B7-H3 Anti-B7-H3 antibody-drug 3 mg/kg Q2W x 2 antibody- 2 conjugate (1) drug conjugate Soln. B - QD x 3 weeks*1 Soln. A - Q2W x 2 3 Enzalutamide Enzalutamide 50 mg/kg QD x 3 weeks*1 Anti-B7-H3 Anti-B7-H3 antibody- antibody-drug 3 mg/kg Q2W x 2 4 drug conjugate (1) conjugate + Enzalutamide 50 mg/kg QD x 3 weeks*1 Enzalutamide *1: Except for Saturday, Sunday, and the final day of the study [0106] The volume to administer each compound was calculated from the individual body weight measured on the day of dosing. Anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln. A (10 mmol/L histidine buffer [pH5.9] containing 9% sucrose and 0.02% polysorbate 20) to prepare a 0.3 mg/mL dosing solution. Enzalutamide which was manufactured by a method known to a person skilled in the art was suspended in Soln. B (0.5% [w/v] methyl cellulose 400) to prepare a 5 mg/mL dosing solution. [0107] Soln. A as a vehicle control of anti-B7-H3 antibody-drug conjugate (1) was administered Attorney Docket No. 122622-0241 87 intravenously to mice in Group 1 (vehicle control) and Group 3 (enzalutamide) at 10 mL/kg on days 0 and 14. Soln. B as a vehicle control of enzalutamide was administered orally to mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) at 10 mL/kg on days 0, 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, and 18. The 0.3 mg/mL dosing solution of anti-B7-H3 antibody-drug conjugate (1) was administered intravenously to mice in Group 2 (anti-B7-H3 antibody- drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + enzalutamide) at 10 mL/kg on days 0 and 14. The 5 mg/mL dosing solution of enzalutamide was administered orally to mice in Group 3 (enzalutamide) and Group 4 (anti-B7-H3 antibody-drug conjugate + enzalutamide) at 10 mL/kg on days 0, 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, and 18. [0108] Tumor length and tumor width were measured with a digital caliper. Tumor volume and tumor growth inhibition (TGI) were calculated by the following formulas: Tumor volume [mm3] = 1/2 × (tumor length [mm]) × (tumor width [mm])2 TGI [%] = (1 – T/C) × 100 C: mean tumor volume of Group 1 (vehicle control) T: mean tumor volume of a treatment group [0109] Attorney Docket No. 122622-0241 88 Welch’s t-test was used to assess the difference in tumor volume at day 21 (the final day of the study) between Group 4 (anti-B7-H3 antibody-drug conjugate + enzalutamide) and Group 2 (anti-B7-H3 antibody-drug conjugate). A P value of less than 0.05 was considered to be statistically significant. [0110] Tumor volumes in the groups are shown in Figure 1. The data represents mean tumor volume ± standard error of the mean (SEM). On day 21 (the final day of the study), TGIs in Group 2 (anti-B7-H3 antibody-drug conjugate), Group 3 (enzalutamide), and Group 4 (anti-B7-H3 antibody- drug conjugate + enzalutamide) were 45%, 36%, and 88%, respectively. The combination of anti-B7-H3 antibody-drug conjugate (1) and enzalutamide showed a statistically significant improvement in antitumor activity compared with anti-B7-H3 antibody-drug conjugate (1) alone (P = 0.0021, Welch’s t-test). All treatment groups were tolerable and there were no obvious differences in the mean of body weight change between Groups 1–4, suggesting the safety of the combined administration of anti-B7-H3 antibody-drug conjugate (1) and an androgen receptor antagonist. [0111] Example 3: Antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and abiraterone acetate in a PDX model Attorney Docket No. 122622-0241 89 Male NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, The Jackson Laboratory Japan, Inc.) are subcutaneously implanted with a fragment of NOp.1567 PDX tumors, which are maintained in host mice. When the tumor volume reaches approximately 200 to 300 mm3, tumor-bearing mice are assigned to four groups as shown in Table 2 (day 0):
Attorney Docket No. 122622-0241 90 Table 2 Group Dosing Group Compound Dose No schedule 1 Vehicle control Soln. A - Q2W x 2 Anti-B7-H3 Anti-B7-H3 2 antibody-drug antibody-drug 3 mg/kg Q2W x 2 conjugate conjugate (1) Soln. A - Q2W x 2 Abiraterone 3 acetate Abiraterone 0.5% in 4 weeks acetate diet Anti-B7-H3 Anti-B7-H3 antibody-drug 3 mg/kg Q2W x 2 antibody-drug conjugate (1) 4 conjugate + Abiraterone Abiraterone 0.5% in acetate 4 weeks acetate diet [0112] The volume to administer each compound is calculated from the individual body weight measured on the day of dosing. Anti-B7-H3 antibody-drug conjugate (1) is diluted with Soln. A (10 mmol/L histidine buffer (pH5.9) containing 9% sucrose and 0.02% polysorbate 20) to prepare a 0.3 mg/mL dosing solution. Abiraterone acetate is manufactured by a method known to a person skilled in the art or commercially available abiraterone acetate can be purchased. Abiraterone acetate is thoroughly mixed with a gamma-ray irradiated powdered FR- 2 diet (Funabashi Farm Co., Ltd) at a concentration of 0.5% (w/w). [0113] Attorney Docket No. 122622-0241 91 Soln. A as a vehicle control of anti-B7-H3 antibody-drug conjugate (1) is administered intravenously to mice in Group 1 (vehicle control) and Group 3 (abiraterone acetate) at 10 mL/kg on days 0 and 14. The 0.3 mg/mL dosing solution of anti-B7-H3 antibody-drug conjugate (1) is administered intravenously to mice in Group 2 (anti-B7-H3 antibody-drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) at 10 mL/kg on days 0 and 14. Mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) are fed a gamma-ray irradiated powdered FR-2 diet without abiraterone acetate for 4 weeks. Mice in Group 3 (abiraterone acetate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) are fed a gamma-ray irradiated powdered FR-2 diet containing 0.5% (w/w) abiraterone acetate for 4 weeks. [0114] Tumor length and tumor width are measured with a digital caliper. Tumor volume and TGI are calculated by the following formulas: Tumor volume [mm3] = 1/2 × (tumor length [mm]) × (tumor width [mm])2 TGI [%] = (1 – T/C) × 100 C: mean tumor volume of Group 1 (vehicle control) T: mean tumor volume of a treatment group [0115] Attorney Docket No. 122622-0241 92 The antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and abiraterone acetate can be evaluated by comparing tumor volumes and TGIs in the groups. It is expected that the combination of anti- B7-H3 antibody-drug conjugate (1) and abiraterone acetate shows a significant improvement in antitumor activity and/or acceptable safety. [0116] Example 4: Antitumor activity of the combination of anti- B7-H3 antibody-drug conjugate (1) and abiraterone acetate in a PDX model Male NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, The Jackson Laboratory Japan, Inc.) were subcutaneously implanted with a fragment of NOp.1567 PDX tumors, which were maintained in host mice. When the tumor volume reached approximately 220 to 370 mm3, tumor-bearing mice were assigned to four groups as shown in Table 3 (day 0, n = 8 mice/group):
Attorney Docket No. 122622-0241 93 Table 3 Group Dosing Group Compound Dose No schedule Vehicle 1 Soln. A - Days 0 and 14 control Anti-B7-H3 Anti-B7-H3 2 antibody-drug antibody-drug 3 mg/kg Days 0 and 14 conjugate conjugate (1) Soln. A - Days 0 and 14 Abiraterone 3 acetate Abiraterone From Day 0 to 0.5% in diet acetate Day 28 Anti-B7-H3 Anti-B7-H3 antibody-drug 3 mg/kg Days 0 and 14 antibody-drug conjugate (1) 4 conjugate + Abiraterone Abiraterone From Day 0 to acetate 0.5% in diet acetate Day 28 [0117] The dosing volumes of Soln. A (10 mmol/L histidine buffer (pH5.9) containing 9% sucrose and 0.02% polysorbate 20) or anti-B7-H3 antibody-drug conjugate (1) given to each mouse were calculated based on the respective body weights measured on each day of dosing. Anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln. A to prepare a 0.3 mg/mL dosing solution. Abiraterone acetate (ZYTIGA®) was purchased from Janssen Pharmaceutical K.K. which is commercially available. Abiraterone acetate was ground and thoroughly mixed with a gamma-ray-irradiated powdered FR-2 diet (Funabashi Farm Co., Ltd) at a concentration of 0.5% (w/w). [0118] Attorney Docket No. 122622-0241 94 Soln. A as a vehicle control of anti-B7-H3 antibody-drug conjugate (1) was administered intravenously to mice in Group 1 (vehicle control) and Group 3 (abiraterone acetate) at 10 mL/kg on days 0 and 14. The 0.3 mg/mL dosing solution of anti-B7-H3 antibody- drug conjugate (1) was administered intravenously to mice in Group 2 (anti-B7-H3 antibody-drug conjugate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) at 10 mL/kg on days 0 and 14. Mice in Group 1 (vehicle control) and Group 2 (anti-B7-H3 antibody-drug conjugate) were fed a gamma-ray-irradiated powdered FR-2 diet without abiraterone acetate from day 0 to day 28 as a control for abiraterone acetate treatment. Mice in Group 3 (abiraterone acetate) and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) were fed the gamma-ray irradiated powdered FR-2 diet containing 0.5% (w/w) abiraterone acetate from day 0 to day 28. [0119] Tumor length and tumor width were measured with a digital caliper. Tumor volume and TGI were calculated by the following formulas: Tumor volume [mm3] = 1/2 × (tumor length [mm]) × (tumor width [mm])2 TGI [%] = (1 – T/C) × 100 C: mean tumor volume of Group 1 (vehicle control) T: mean tumor volume of a treatment group [0120] Attorney Docket No. 122622-0241 95 Student’s t-test was used to assess the difference in tumor volume on day 28 (the final day of the study) between Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) and Group 2 (anti-B7-H3 antibody- drug conjugate). A P value of less than 0.05 was considered to be statistically significant. [0121] Tumor volumes in the tested groups are shown in Figure 2. The data represents mean tumor volume ± standard error of the mean. On day 28 (the final day of the study), Group 2 (anti-B7-H3 antibody-drug conjugate), Group 3 (abiraterone acetate), and Group 4 (anti-B7-H3 antibody-drug conjugate + abiraterone acetate) showed TGIs of 56%, 19%, and 75%, respectively. The combination of anti-B7-H3 antibody-drug conjugate (1) and abiraterone acetate showed a statistically significant improvement in antitumor activity compared with anti-B7-H3 antibody-drug conjugate (1) alone on day 28(P = 0.0212, Student’s t- test). Furthermore, there were no obvious differences in mean body weight change among the tested groups, suggesting the safety of the combined administration of anti-B7-H3 antibody-drug conjugate (1) and an androgen receptor signaling inhibitor. [0122] Example 5: Clinical trial protocol to evaluate the safety and efficacy of Ifinatamab Deruxtecan (I-DXd)-based Attorney Docket No. 122622-0241 96 treatment combinations or Ifinatamab Deruxtecan alone in participants with Metastatic Castration-resistant Prostate Cancer (mCRPC) This is a Phase 1/2 open-label umbrella study of of ifinatamab deruxtecan (referred to throughout this Example as I-DXd) -based treatment combinations or as monotherapy in participants with metastatic castration- resistant prostate cancer (mCRPC). The study consists of multiple treatment arms. There will be two monotherapy treatment arms (Arms 1 (docetaxel) and 2 (I-DXd)) that will enroll participants into the Efficacy Phase of the study at the majority of sites. There will be one combination treatment arm of I-DXd plus abiraterone acetate or enzalutamide(referred to throughout this Example as androgen receptor pathway inhibitors (ARPI); Arm 4) that will initiate and enroll participants into the Safety Lead-in Phase at separate selected sites, followed by the Efficacy Phase. [0123] Primary Objectives: (1) To evaluate the safety and tolerability for each treatment arm. (2) To estimate the prostate-specific antigen (PSA) response rate for each treatment arm. (3) To evaluate the safety and tolerability and to establish a recommended Phase 2 dose (RP2D) of combination treatment arm. [0124] Attorney Docket No. 122622-0241 97 Secondary Objectives for efficacy phase: (1) To estimate the objective response rate (ORR) per prostate cancer working group (PCWG)-Modified RECIST 1.1 (Response Evaluation Criteria In Solid Tumors), as assessed by blinded independent central review (BICR), for each treatment arm. (2) To evaluate radiographic progression- free survival (rPFS) per PCWG-Modified RECIST 1.1, as assessed by BICR, for each treatment arm. (3) To evaluate overall survival (OS) for each treatment arm. (4) To evaluate the duration of response (DOR) per PCWG-Modified RECIST 1.1, as assessed by BICR for each treatment arm. (5) To evaluate the time from allocation/randomization to initiation of the first subsequent anticancer therapy (TFST) for each treatment arm. (6) To evaluate the time to PSA progression for each treatment arm. (7) To evaluate the time to pain progression (TTPP) for each treatment arm. [0125] Tertiary/Exploratory Objectives: (1) To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of I-DXd alone and/or other treatments. (2) To evaluate the change from baseline in disease-related symptoms and health-related quality of life (HRQoL) using brief pain inventory-short form (BPI-SF) and Functional Assessment of Cancer Attorney Docket No. 122622-0241 98 Therapy-Prostate (FACT-P) questionnaires. (3) To characterize the pharmacokinetic (PK) parameters following administration of I-DXd in each treatment arm. (4) To evaluate the immunogenicity of I-DXd following administration in each treatment arm. 5.1 Number of Participants [0126] The study uses a design in which new treatment arms will be opened for enrollment to evaluate new I-DXd- based investigational treatment combinations. Therefore, the total number of participants will depend on the number of treatment arms open for enrollment. [0127] At least 80 participants will be enrolled in each of the monotherapy treatment arms. Monotherapy treatment arms will continue enrolling participants when combination treatment arm is open and enrolling, so enrollment is expected to be approximately 120 participants per monotherapy treatment arm. Approximately 60 participants will be enrolled in the combination treatment arm. [0128] In the Safety Lead-in Phase, approximately 10 participants will be enrolled in the combination treatment arm. If the combination treatment arm moves from the Safety Lead-in Phase into the Efficacy Phase, the number of enrolled participants in the combination Attorney Docket No. 122622-0241 99 treatment arm will be approximately 60 participants including the participants enrolled in the Safety Lead-in and the Efficacy Phases together (i.e., ~10 participants at the RP2D in Safety Lead-in plus ~50 participants in Efficacy Phase). [0129] Participants with bone-only disease will be eligible to enter the study, but the number of participants with bone-only disease will be capped at 50% of the enrollment per treatment arm. 5.2 Study Groups, Design and Dosages [0130] Participants are assigned to one of three arms (Arm 1, Arm 2 and Arm 4) and treated according to Table 4 below:
Attorney Docket No. 122622-0241 100 Table 4: Study Interventions Arm Intervention Unit Dose Dosage Route of Regimen/ Use Name Name Strength(s) Level(s) Administration Treatment Period/ Vaccination Regimen Arm Docetaxel 10 or 20 75 mg/m2 IV Infusion q3w Comparator 1 mg/mL Arm Prednisone 5 mg or 5 mg Oral 10 mg/day Comparator 1 or per 10 mg or per equivalent approved approved dose of product product prednisolone label label Arm I-DXd 100 mg 8 mg/kg, IV Infusion q3w Test 2 10 mg/kg, Product and 12 mg/kg Arm 4 Arm Abiraterone 500 mg; 1000 mg Oral qd Test 4 acetate 250 mg Product Arm Prednisone 5 mg or 10 mg/day Oral bid Test 4 (or per or Product equivalent approved per dose of product approved Prednisolone label product ) label Arm Enzalutamide 40 mg 160 mg Oral qd Test 4 Product IV = intravenous; q3w = every 3 weeks; qd = once daily; bid = twice daily; I-DXd = ifinatamab deruxtecan (other current or former names or aliases include MK-2400, and DS-7300a) [0131] Docetaxel is included in the study as an active comparator. Concomitant treatment with prednisone concurrently docetaxel treatments is required per docetaxel labeling. Prednisone is the preferred steroid to be used in the study. Prednisolone should Attorney Docket No. 122622-0241 101 only be used when prednisone is unavailable. Participants should receive only one type of medication (either prednisone or prednisolone) throughout the entire study. Prednisone/prednisolone will be administered with abiraterone acetate according to local/institutional guidelines. [0132] Study treatment will follow a 21-day cycle. In all treatment arms, study intervention can be administered ±3 days of the targeted Day 1 for each cycle, except Cycle 1 when treatment can only be administered +3 days of targeted Day 1. [0133] The study scheme is depicted in Figure 3. 5.2.1 Docetaxel Dose Preparation and Administration [0134] Docetaxel and prednisone/prednisolone will be prepared and administered as per the corresponding approved product label(s). The recommended dose of docetaxel for mCRPC is 75 mg/m2 q3w as a 1-hour IV infusion for a maximum of 10 cycles. The recommended premedication is dexamethasone 8 mg po (orally) at 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion. Steroid pretreatment before docetaxel administration as per local standard of care Attorney Docket No. 122622-0241 102 (SOC) is allowed. Prednisone/prednisolone 5 mg po bid (up to 10 mg/day) is administered throughout docetaxel treatment. After cessation of docetaxel treatment, prednisone/prednisolone should be discontinued. Participants should be titrated off prednisone/prednisolone per local guidance as determined by the investigator. 5.2.2 Ifinatamab Deruxtecan Dose Preparation and Administration [0135] The dose of 12 mg/kg q3w will be used as the starting dose for participants receiving I-DXd monotherapy in Arm2 in individuals with mCRPC. Participants will be administered single-agent I-DXd intravenous (IV), at the dose of 12 mg/kg starting at Cycle 1 Day 1 and at Day 1 of each 21-day cycle (q3w). [0136] There is a Safety Lead-in to demonstrate a tolerable safety profile and confirm a RP2D for the combination of investigational agents in Arm 4. During the Safety Lead-in Phase, a 3-day pause between the first and second participant and a 24-hour pause between subsequent participants enrolled will occur in each dose cohort. Participants will be closely followed for dose limiting toxicities (DLTs) during Cycle 1 (the DLT evaluation period). The BOIN design Attorney Docket No. 122622-0241 103 (See Section 4.2.3) with a target DLT rate of 30% will be used to determine an acceptable dose level for the Efficacy Phase. Up to 6 participants will initially be enrolled at a dose cohort. Once a dose has cleared the DLT evaluation period and an escalation decision based on the BOIN design is made, the dose cohort may be expanded (“backfilled”) to a total of approximately 10 participants to collect additional data. DLT information from these backfilled participants will be included in the evaluation of the preliminary RP2D. During the dose-escalation phase, DLT information from the backfilled participants will be considered for subsequent dose decisions and maximum tolerated dose (MTD) determination. [0137] The initial planned doses for the combination study intervention in Arm 4 is shown in Table 5.
Attorney Docket No. 122622-0241 104 Table 5: Dose Levels for Study Interventions in Arm 4 Evaluated in the Safety Lead-in. Arm/ Dose Level Next Dose Dose Level Study Start Level Decrease Intervention Arm 4 I-DXd 8 mg/kg 12 mg/kg 10 mg/kga Abiraterone b 1000 mg 1000 mg 1000 mg acetate, or Enzalutamide 160 mg 160 mg 160 mg BOIN=Bayesian Optimal Interval Design; DLT=dose-limiting toxicity; I-DXd=ifinatamab deruxtecan; RP2D=recommended Phase 2 dose a If the 10 mg/kg dose needs to be decreased due to DLTs the 8 mg/kg dose may be determined to be the RP2D after backfilling, if needed, and following the BOIN design. b Additional co-medications are administered with abiraterone acetate. [0001] During the Safety Lead-in Phase of combination treatment Arm 4, the dose of I-DXd will be adjusted. The starting dose of I-DXd will be 8 mg/kg in a q3w regimen. If the dose requires deescalation below 8 mg/kg after DLT evaluation, the arm will be discontinued. If the dose may escalate, the next dose cohort will be 12 mg/kg q3w. Dose deescalation may occur to 10 mg/kg, if needed after DLT evaluation at a 12 mg/kg dose level. Finally, if the 10 mg/kg dose is not tolerable after DLT evaluation, the dose may deescalate to 8 mg/kg q3w and backfill to approximately 10 participants, if needed. The BOIN design will be followed to confirm the RP2D. Attorney Docket No. 122622-0241 105 [0138] At any dose level, the initial dose of I-DXd will be infused for 90 ±10 minutes. If there is no infusion-related reaction (IRR) during or after the initial dose, the subsequent doses of I-DXd may be infused for 30 ±5 minutes. [0139] Before each dose of I-DXd, it is strongly recommended to premedicate participants with antihistamines, acetaminophen, and/or corticosteroids to prevent or ameliorate IRR. In particular, before each dose of I-DXd, for prevention of nausea and vomiting participants will be premedicated with a 2- or 3-drug combination regimen (e.g., corticosteroids with either a 5-HT3 receptor antagonist (e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g., aprepitant, casopitant, netupitant, or rolapitant) as well as other drugs as indicated) according to local or standard practice guidelines. [0140] The drug is prepared based on the participant’s baseline body weight, defined as the last measurement before the first dose. The dose must be recalculated if the participant’s weight changes by ≥10% from baseline. After the recalculation, the updated participant’s weight will be used as the new baseline Attorney Docket No. 122622-0241 106 weight. The site may follow local institutional policy for recalculating dose based on weight changes of less than 10%. 5.2.3 Bayesian Optimal Interval in the Safety Lead-in [0141] Participants will be closely followed for DLTs for the first cycle (i.e., 21 days) after the first dose of study intervention (the DLT evaluation period) using the Bayesian Optimal Interval (BOIN) design (Yuan, Y., et al (2016) Clin Cancer Res. ;22(17):4291- 301) with a target DLT rate of 30%. The dose will be evaluated on an ongoing basis as participants complete the DLT evaluation period. In Table 6, the columns indicate the numbers of participants treated at the current dose level, and the rows indicate the numbers of participants experiencing a DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 2 out of 3 participants at this dose level develop a DLT, the dose will be deescalated to the next lower dose level but may be reescalated at a later time if the lower dose is well tolerated. If 3 out of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be deescalated, if allowed per Attorney Docket No. 122622-0241 107 protocol, and the current dose will not be explored further. [0142] Dose finding will follow the BOIN design with a target DLT rate of 30%, dose escalation DLT-rate boundary of 23.6%, and dose de-escalation DLT-rate boundary of 35.9%. Dose-escalation and de-escalation decisions are based on the BOIN design and depend on the number of participants enrolled and number of participants with at least 1 DLT observed at the current dose level. [0143] If a dose de-escalation decision is made before 10 participants have completed enrollment at the starting dose, the enrollment at this dose level will be halted and a new set of participants will be enrolled and treated at the next lower dose level. This process will continue until 10 participants have been enrolled at any of the tested doses and the BOIN table indicates “S” for staying at current dose. If, at any point, the dosing decision is “E” after evaluation of all enrolled patients at a dose, the dose may be escalated to a higher predetermined dose provided that the higher dose has not previously been discontinued due to a “DU” decision. [0144] Attorney Docket No. 122622-0241 108 A “D” or “DU” decision at the lowest dose level will stop the evaluation of the study intervention under study. An “E” decision at the highest dose level will result in staying at that level. During dose finding, it may be acceptable to deescalate or escalate to an intermediate dose that was not predefined and not previously studied if evaluation of toxicity at such a dose is desired. [0145] The totality of the data will be considered prior to determining the dose level in the Efficacy Evaluation. Table 6: Dose-finding Framework of BOIN Design with Target DLT Rate 30% Number of Number of Participants Evaluable for DLT at Participants With Current Dose At Least 1 DLT 3 4 5 6 7 8 9 10 0 E E E E E E E E 1 S S E E E E E E 2 D D D S S S E E 3 DU DU D D D D S S 4 DU DU DU D D D D 5 DU DU DU DU DU D 6 DU DU DU DU DU 7 DU DU DU DU 8 DU DU DU 9 DU DU 10 DU BOIN= Bayesian Optimal Interval; D=Deescalate to the next lower dose; DLT=dose-limiting toxicity; DU=The current dose is unacceptably toxic; E=Escalate to the next higher dose; S=Stay at the current dose. 5.2.4 ARPI Dose Preparation and Administration [0146] Attorney Docket No. 122622-0241 109 According to local/institutional guidelines, abiraterone acetate will be administered as dose of 1000 mg (two 500 mg tablets or four 250 mg tablets) po qd with prednisone/prednisolone 5 mg orally bid. Participants are advised to swallow the abiraterone acetate tablet as a single dose whole with water at the same time each day on empty stomach. Participants should not eat food 2 hours before and 1 hour after taking abiraterone acetate. Refer to local guidelines and regulations for more details. After discontinuation, participants should complete prednisone/prednisolone taper per investigator’s discretion. [0147] According to local/institutional guidelines, enzalutamide will be administered at a dose of 160 mg (four 40 mg capsules/tablets) po qd with or without food. Participants are advised to swallow the enzalutamide capsule whole and do not chew, dissolve, or open the capsules. Refer to local guidelines and regulations for more details. 5.3 Target Population [0148] Participants must be at least 18 years of age with mCRPC. An individual is eligible for inclusion in the Attorney Docket No. 122622-0241 110 study if the individual meets all of the following criteria: • Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report. • Have prostate cancer progression while on androgen deprivation therapy (ADT; or post bilateral orchiectomy) within 6 months before Screening, as determined by one of the following: a. Clinical disease progression and prostate- specific antigen (PSA) progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at Screening should be ≥1 ng/mL; b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or without PSA progression; c. Radiographic disease progression in bone based on PCWG-Modified RECIST 1.1, defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Attorney Docket No. 122622-0241 111 • Have progression under the following conditions if the participant received first generation antiandrogen therapy before enrollment: a. Evidence of progression >4 weeks since last flutamide treatment; b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment. • Have current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft-tissue lesion per RECIST 1.1 by CT/MRI. • Have received prior treatment with one or two androgen receptor pathway inhibitors (ARPIs; e.g., abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castration-resistant prostate cancer (nmCRPC) or mCRPC and progressed during or after at least 8 weeks of treatment (at least 14 weeks of treatment for participants with bone progression). Note: Participants who have received at most 2 prior ARPIs are not eligible for Arm 4. Attorney Docket No. 122622-0241 112 • Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM). If the participant is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (participants who have not undergone a bilateral orchiectomy) this therapy must have been initiated at least 4 weeks before allocation/randomization and treatment must be continued throughout the study. • Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks before allocation/randomization. • Have had prior treatment with PARP inhibitor (PARPi) if indicated by local approved regimen or were deemed ineligible to receive PARPi. 5.4 Dose‑limiting Toxicity [0149] The DLT window of observation will be during Cycle 1 of Arm 4. [0150] The occurrence of any of the following toxicities will be considered a DLT if clearly not related to the disease or disease-related processes, such as disease progression, environmental factors, unrelated trauma, and so on: Attorney Docket No. 122622-0241 113 • Grade 4 nonhematologic toxicity (not based on laboratory value) • Hematologic toxicity: • Grade 4 thrombocytopenia of any duration • Grade ≥3 thrombocytopenia associated with clinically significant bleeding, regardless of duration • Grade ≥3 thrombocytopenia lasting >7 days • Grade 4 anemia of any duration • Grade 4 lymphocyte count decreased lasting ≥14 days • Any other Grade 4 hematologic toxicity lasting >7 days • Febrile neutropenia Grade 3 or Grade 4: • Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour • Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated Attorney Docket No. 122622-0241 114 • All nonhematologic adverse event (AE) Grade ≥3 in severity should be considered a DLT, with the following exceptions: • Grade 3 fatigue lasting <1 week • Grade 3 diarrhea, nausea, or vomiting for <72 hours with adequate antiemetic and other supportive care • Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care • Any Grade 3 or Grade 4 nonhematologic laboratory value if: • Clinically significant medical intervention is required to treat the participant, or • The abnormality leads to hospitalization, or • The abnormality persists for >1 week • Grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increased • The abnormality results in a drug-induced liver injury (DILI) • In the presence or absence of liver metastases: • AST or ALT >5 × upper limit of normal (ULN) for ≥14 days, or • AST or ALT >8 × ULN • Exceptions: Attorney Docket No. 122622-0241 115 • Clinically nonsignificant, treatable, or reversible laboratory abnormalities including liver function tests, uric acid, etc. • Grade 3 electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions • Grade ≥3 amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis • Other nonhematologic AEs including: • Symptomatic congestive heart failure (CHF) • Left ventricular ejection fraction (LVEF) decline to <40% • Participant has absolute>20% drop from their LVEF baseline • Any LVEF decline from baseline leading to discontinuation of study treatment • Grade ≥2 ILD or pneumonitis • Prolonged delay (>2 weeks) in initiating Cycle 2 due to study intervention-related toxicity • Any study intervention-related toxicity that causes the participant to discontinue intervention during Cycle 1 Attorney Docket No. 122622-0241 116 • Missing >25% of study intervention doses as a result of drug-related AEs during the first cycle • Grade 5 toxicity 5.5 Dose Modification of Docetaxel (Arm 1) [0151] The dose regimen and modification guidelines based on the US FDA drug label will be adopted according to local regulations and guidelines for administration of docetaxel. [0152] If a dose reduction is required, after resolution of the toxicity, the participant can resume treatment with docetaxel at a dose level as outlined in Table 7. Once the dose has been reduced, it may not be escalated up to a previous dose level. [0153] Table 7: Docetaxel Dose Reduction Guidelines (Arm 1) Drug Dose/Potency Regimen Initial 75 mg/m2 Every 3 weeks docetaxel dose Dose reduction 60 mg/m2 Every 3 weeks 5.6 Dose Modification of I-DXd (Arm 2 and Arm 4) [0154] No dose modification of I-DXd is required for Grade 1 or Grade 2 events, unless specified. For Grade 3 or Grade 4 events, monitoring (including local laboratory Attorney Docket No. 122622-0241 117 tests when appropriate) will be performed frequently and at an interval of no greater than 7 days until the adverse event (AE) is determined to be resolving or back to baseline. [0155] If a dose reduction is required, after resolution of the toxicity, the participant can resume treatment with I-DXd at a dose level as outlined in Table 8. Once the dose of I-DXd has been reduced because of toxicity, all subsequent doses should be administered at that lower dose level unless further dose reduction is required. More than 2 dose reductions are not allowed and participants cannot reduce the dose of I-DXd below 8 mg/kg. The participant will be withdrawn from the study treatment if further toxicity meeting the requirement for dose reduction occurs. Once the dose of I-DXd is reduced, no dose reescalation is permitted. Table 8: I-DXd Dose Reduction Guidelines (Arm 2 and Arm 4) Starting Dose Dose Level -1 Dose Level -2 12 mg/kg 10 mg/kg 8 mg/kg 10 mg/kg 8 mg/kg N/A 8 mg/kg N/A N/A N/A=not applicable. [0156] Attorney Docket No. 122622-0241 118 While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto. [0157] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

Attorney Docket No. 122622-0241 119 WHAT IS CLAIMED: 1. A pharmaceutical product comprising an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor for administration in combination, wherein the anti-B7-H3 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula is conjugated to an anti-B7-H3 antibody or a functional fragment thereof via a thioether bond: wherein A in the formula represents a connecting position to the anti-B7-H3 antibody or functional fragment thereof. 2. The pharmaceutical product according to claim 1, wherein the androgen receptor signaling inhibitor is an androgen synthesis inhibitor or an androgen receptor antagonist. Attorney Docket No. 122622-0241 120 3. The pharmaceutical product according to claim 2, wherein the androgen synthesis inhibitor is a CYP17 inhibitor. 4. The pharmaceutical product according to claim 3, wherein the CYP17 inhibitor is abiraterone or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical product according to claim 3 or 4, wherein the CYP17 inhibitor is abiraterone acetate or abiraterone decanoate. 6. The pharmaceutical product according to claim 5, wherein the CYP17 inhibitor is abiraterone acetate and wherein the pharmaceutical product further optionally comprises prednisone or prednisolone in combination. 7. The pharmaceutical product according to claim 2, wherein the androgen receptor antagonist is selected from the group consisting of enzalutamide, apalutamide, darolutamide, and pharmaceutically acceptable salts thereof. 8. The pharmaceutical product according to claim 7, wherein the androgen receptor antagonist is enzalutamide. Attorney Docket No. 122622-0241 121 9. The pharmaceutical product according to any one of claims 1 to 8, wherein the anti-B7-H3 antibody or functional fragment thereof comprises a CDRH1 comprising an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 comprising an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 comprising an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 comprising an amino acid sequence consisting of amino acid residues 69 to 75 of SEQ ID NO: 2, and a CDRL3 comprising an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2. 10. The pharmaceutical product according to any one of claims 1 to 9, wherein the anti-B7-H3 antibody or functional fragment thereof comprises a CDRH1 consisting of an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1, a CDRH2 consisting of an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1, a CDRH3 consisting of an amino acid sequence consisting of amino acid residues 118 to 130 of SEQ ID NO: 1, a CDRL1 consisting of an amino acid sequence consisting of amino acid residues 44 to 53 of SEQ ID NO: 2, a CDRL2 consisting of an amino acid sequence consisting of amino acid residues 69 to 75 of Attorney Docket No. 122622-0241 122 SEQ ID NO: 2, and a CDRL3 consisting of an amino acid sequence consisting of amino acid residues 108 to 116 of SEQ ID NO: 2. 11. The pharmaceutical product according to any one of claims 1 to 10, wherein the anti-B7-H3 antibody or functional fragment thereof comprises a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 2. 12. The pharmaceutical product according to any one of claims 1 to 11, wherein the anti-B7-H3 antibody or functional fragment thereof comprises a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 141 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 128 of SEQ ID NO: 2. 13. The pharmaceutical product according to any one of claims 1 to 12, wherein the anti-B7-H3 antibody is an IgG1. Attorney Docket No. 122622-0241 123 14. The pharmaceutical product according to any one of claims 1 to 13, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2. 15. The pharmaceutical product according to any one of claims 1 to 14, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2. 16. The pharmaceutical product according to any one of claims 1 to 15, wherein a lysine residue is deleted from each of the carboxyl termini of both of the heavy chains of the anti-B7-H3 antibody. 17. The pharmaceutical product according to any one of claims 1 to 16, wherein the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate is in the range from 3 to 5. Attorney Docket No. 122622-0241 124 18. The pharmaceutical product according to any one of claims 1 to 17, wherein the anti-B7-H3 antibody-drug conjugate is represented by the following formula: wherein ‘Antibody’ in the formula represents the anti-B7- H3 antibody or functional fragment thereof conjugated to the drug-linker via a thioether bond, and n represents drug-to-antibody ratio. 19. The pharmaceutical product according to any one of claims 1 to 17, wherein the anti-B7-H3 antibody-drug conjugate is represented by the following formula: wherein ‘Antibody’ in the formula represents the anti-B7- H3 antibody conjugated to the drug-linker via a thioether Attorney Docket No. 122622-0241 125 bond and n represents the average number of units of the drug-linker conjugated per antibody molecule in the anti- B7-H3 antibody-drug conjugate, wherein n is in the range from 3 to 5, and wherein the anti-B7-H3 antibody comprises a heavy chain comprising an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 21 to 233 of SEQ ID NO: 2. 20. The pharmaceutical product according to any one of claims 1 to 19, wherein the anti-B7-H3 antibody-drug conjugate is ifinatamab deruxtecan. 21. The pharmaceutical product according to any one of claims 1 to 20, wherein the anti-B7-H3 antibody or functional fragment thereof is an anti-B7-H3 antibody. 22. The pharmaceutical product according to any one of claims 1 to 21, wherein the anti-B7-H3 antibody or functional fragment thereof is an antibody comprising two heavy chains and two light chains. 23. The pharmaceutical product according to any one of claims 1 to 22, wherein the product is a combined preparation comprising the anti-B7-H3 antibody-drug Attorney Docket No. 122622-0241 126 conjugate and the androgen receptor signaling inhibitor, for separate simultaneous or sequential administration. 24. The pharmaceutical product according to any one of claims 1 to 23, wherein the product is for treating or preventing cancer. 25. The pharmaceutical product according to claim 24, wherein the cancer is cancer expressing androgen receptor and/or B7-H3. 26. The pharmaceutical product according to claim 24 or 25, wherein the cancer is prostate cancer or breast cancer. 27. The pharmaceutical product according to claim 26, wherein the cancer is prostate cancer. 28. The pharmaceutical product according to claim 27, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC). 29. The pharmaceutical product according to any one of claims 24 to 28, wherein the androgen receptor signaling inhibitor is abiraterone acetate or enzalutamide. Attorney Docket No. 122622-0241 127 30. The pharmaceutical product according to any one of claims 1 to 29, wherein the antibody-drug conjugate is to be administered at a dose of about 4.8 mg/kg to 12 mg/kg. 31. The pharmaceutical product according to any one of claims 1 to 30, wherein the antibody-drug conjugate is to be administered at a dose of about 4.8 mg/kg, about 6.4 mg/kg, about 8 mg/kg, about 10 mg/kg, or about 12 mg/kg. 32. The pharmaceutical product according to claim 31, wherein the antibody-drug conjugate is to be administered at a dose of about 8 mg/kg. 33. The pharmaceutical product according to claim 31, wherein antibody-drug conjugate is to be administered at a dose of about 10 mg/kg. 34. The pharmaceutical product according to claim 31, wherein the antibody-drug conjugate is to be administered at a dose of about 12 mg/kg. 35. The pharmaceutical product according to any one of claims 1 to 34, wherein the antibody-drug conjugate is to be administered once every three weeks. Attorney Docket No. 122622-0241 128 36. The pharmaceutical product according to any one of claims 1 to 35, wherein the antibody-drug conjugate is to be administered intravenously. 37. The pharmaceutical product according to any one of claims 1 to 36, wherein the antibody-drug conjugate is to be administered via a 90 ± 10 minutes IV fusion. 38. The pharmaceutical product according to claim 37, wherein the antibody-drug conjugate is to be administered via a 30 ± 5 minutes IV fusion if there is no substantial infusion-related reaction (IRR) during or after the initial dose of the antibody-drug conjugate administration. 39. The pharmaceutical product according to any one of claims 1 to 38, wherein before each dose of the anti-B7- H3 antibody-drug conjugate administration, an effective amount of any one or more of drugs selected from the group consisting of antihistamines, acetaminophen, and corticosteroids is to be administered to prevent or ameliorate infusion-related reaction (IRR). 40. The pharmaceutical product according to any one of claims 1 to 31 and 33 to 39, wherein if a dose reduction is required due to the toxicity of the antibody-drug conjugate administration, a dose of the antibody-drug Attorney Docket No. 122622-0241 129 conjugate administered is reduced from about 12 mg/kg to about 10 mg/kg, or from about 10 mg/kg to about 8 mg/kg. 41. The pharmaceutical product according to any one of claims 7 to 40, wherein enzalutamide is to be administered orally once per day. 42. The pharmaceutical product according to any one of claims 7 to 41, wherein enzalutamide is to be administered at a dose of 160 mg, optionally wherein enzalutamide is to be administered as four 40 mg capsules or tablets. 43. The pharmaceutical product according to any one of claims 4 to 6 and 9 to 40, wherein abiraterone acetate is to be administered orally once per day. 44. The pharmaceutical product according to any one of claims 4 to 6, 9 to 40 and 43, wherein abiraterone acetate is to be administered at a dose of 1000 mg, optionally wherein abiraterone acetate is to be administered as two 500 mg tablets or four 250 mg tablets. 45. The pharmaceutical product according to claim 6 or 44, wherein prednisone or an equivalent dose of prednisolone is to be further administered orally. Attorney Docket No. 122622-0241 130 46. The pharmaceutical product according to claim 6, 44 or 45, wherein prednisone or an equivalent dose of prednisolone is to be further administered at a dose of up to 10 mg, optionally wherein prednisone or an equivalent dose of prednisolone is to be administered as 5 mg or 10 mg per day or per approved product label. 47. An anti-B7-H3 antibody-drug conjugate, for use in treating or preventing cancer in combination with an androgen receptor signaling inhibitor, wherein the anti- B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of claims 1 to 46. 48. The anti-B7-H3 antibody-drug conjugate for the use according to claim 47, by separate simultaneous or sequential administration in combination with the androgen receptor signaling inhibitor. 49. The anti-B7-H3 antibody-drug conjugate for the use according to claim 47 or 48, wherein the cancer is as defined in any one of claims 24 to 28. 50. An androgen receptor signaling inhibitor, for use in treating or preventing cancer in combination with an anti-B7-H3 antibody-drug conjugate, wherein the anti-B7- Attorney Docket No. 122622-0241 131 H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of claims 1 to 46. 51. The androgen receptor signaling inhibitor for the use according to claim 50, by separate simultaneous or sequential administration in combination with the anti- B7-H3 antibody-drug conjugate. 52. The androgen receptor signaling inhibitor for the use according to claim 50 or 51, wherein the cancer is as defined in any one of claims 24 to 28. 53. Use of an anti-B7-H3 antibody-drug conjugate for the preparation of a medicament for treating or preventing cancer, by administration in combination with an androgen receptor signaling inhibitor, wherein the anti-B7-H3 antibody-drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of claims 1 to 46. 54. Use of an androgen receptor signaling inhibitor for the preparation of a medicament for treating or preventing cancer, by administration in combination with an anti-B7-H3 antibody-drug conjugate, wherein the anti- B7-H3 antibody-drug conjugate and the androgen receptor Attorney Docket No. 122622-0241 132 signaling inhibitor are as defined in any one of claims 1 to 46. 55. The use according to claim 53 or 54, wherein the cancer is as defined in any one of claims 24 to 28. 56. A pharmaceutical combination of an anti-B7-H3 antibody-drug conjugate and an androgen receptor signaling inhibitor, for use in the treatment or prevention of cancer, wherein the anti-B7-H3 antibody- drug conjugate and the androgen receptor signaling inhibitor are as defined in any one of claims 1 to 46, and wherein the cancer is as defined in any one of claims 24 to 28. 57. A method of treating or preventing cancer comprising administering an anti-B7-H3 antibody-drug conjugate as defined in any one of claims 1, 9 to 23, and 30 to 40 to a subject in need thereof; and administering an androgen receptor signaling inhibitor as defined in any one of claims 1 to 8, 29, and 41 to 46 to the subject. 58. The method according to claim 57, wherein the cancer is as defined in any one of claims 24 to 28.
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