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WO2025248500A1 - Antibody drug conjugates that target enpp3 - Google Patents

Antibody drug conjugates that target enpp3

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Publication number
WO2025248500A1
WO2025248500A1 PCT/IB2025/055608 IB2025055608W WO2025248500A1 WO 2025248500 A1 WO2025248500 A1 WO 2025248500A1 IB 2025055608 W IB2025055608 W IB 2025055608W WO 2025248500 A1 WO2025248500 A1 WO 2025248500A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
seq
set forth
acid sequence
sequence set
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/IB2025/055608
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French (fr)
Inventor
Smruthi VIJAYARAGHAVAN
Linxiao CHEN
Eilyn Lacy
Shalom Goldberg
Donna KLEIN
Kristen WILEY
Kristen KELLAR
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.)
Janssen Biotech Inc
Original Assignee
Janssen Biotech Inc
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Publication of WO2025248500A1 publication Critical patent/WO2025248500A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—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
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell

Definitions

  • ENPP3 (CD203c) is a member of the cell surface ENPP family consisting of 7 structurally related molecules with ATP pyrophosphatase and ATPase activities involved in hydrolysis of extracellular nucleotides (Stefan C, Jansen S, Bollen M. NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci.2005;30(10):542-550. doi:10.1016/j.tibs.2005.08.005).
  • ENPP3 is a membrane protein with adenosine triphosphate (ATP) pyrophosphatase and ATPase activities involved in hydrolysis of extracellular nucleotides.
  • ATP adenosine triphosphate
  • ENPP3 ATPase
  • the functional role of ENPP3 in cancer is not well understood.
  • ADCs Antibody Drug Conjugates
  • an antibody drug conjugate having the structure Ab-(L-(L A -D) n ) m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and L A , L A is a divalent moiety connecting L and D, D is a drug; n is 1, 2 or 3; and m is 1, 2 or 3, wherein the antibody comprises: a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31.
  • VH variable heavy chain domain
  • VL variable light chain domain
  • an antibody drug conjugate having the structure, Ab-(L-(L A -D) n ) m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3; L is a linker covalently bound to Ab and L A ; L A is a divalent moiety connecting L and D; D is an auristatin; n is 1, 2 or 3; and m is 1, 2 or 3. In some embodiments, n is 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, n is 3 and m is 2. In some embodiments the drug to antibody ratio is 6.
  • the antibody or antigen binding fragment thereof comprises; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a
  • the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof comprises a VH comprising at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8, or 27-31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31.
  • the antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or antigen binding fragment thereof comprises a heavy chain (HC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or 12-16, and a light chain (LC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10 or 17-21.
  • the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21.
  • the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering.
  • L is attached to the asparagine residue at position 296 according to SEQ ID NO:9.
  • the L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan.
  • the antibody or antigen binding fragment thereof comprises an Fc region.
  • the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for a Fc ⁇ receptor. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3. [0015] In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3.
  • the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232.
  • the drug is an auristatin.
  • the auristatin is selected from the group consisting of auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin.
  • the auristatin is auristatin F hydroxypropylamide (AF HPA) comprising, .
  • L covalently bonds to Ab via a glycan on a Fc constant region of the Ab.
  • L comprises wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to L A .
  • L A is , wherein p is an integer from 1 to 25; q is an integer from 1 to 25; wherein the L D -D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L.
  • p is 4.
  • q is 8.
  • L A - D is
  • the antibody drug conjugate is of Formula (I): wherein d 13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; [0020] In some embodiments, provided herein is an antibody drug conjugate having the
  • the antibody drug conjugate is produced by a method comprising, processing a glycan at position N296 of SEQ ID NO: 9 by incubating an antibody that binds to ENPP3 with an endoglycos
  • compositions comprising the antibody drug conjugate comprise a heterogeneous mixture of different ADC molecules (different drug to antibody ratio (DAR) species).
  • DAR drug to antibody ratio
  • an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of claims SEQ ID NO:7 or 22-26; and CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8, or 27-31.
  • the isolated antibody or antigen binding fragment comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising
  • the isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the VH has at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and the VL has at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9.
  • the antibody or antigen binding fragment thereof comprises an Fc region.
  • the antibody or antigen binding fragment thereof is a full length antibody.
  • the HC comprises the amino acid sequence set forth in any one of SEQ ID NO:9, or 12-16 and the LC comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.
  • the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set
  • the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for an Fc ⁇ receptor.
  • the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. [0025]
  • the antibody or antigen binding fragment thereof is human, chimeric, or humanized.
  • the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3 In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at residues 671-681 (VPPSESQKCSF (SEQ ID NO: 231)) and 762-780 (PDEITKHLANTDVPIPTHY (SEQ ID NO: 232)) [0026] In some embodiments, provided herein is an antibody drug conjugate comprising the antibody or antigen binding fragment of any of the embodiments herein covalently bound to one or more drug molecules.
  • nucleic acid encoding the isolated antibody of any one of the embodiments provided herein.
  • nucleic acid encoding a light chain, a heavy chain, or a light chain and heavy chain encoding the isolated antibody of any one of the embodiments described herein.
  • vector comprising the nucleic acid of any the embodiments provided herein.
  • host cells comprising the vector of any of the embodiments provided herein.
  • kits for producing an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising culturing the host cell of the embodiments provided herein under conditions suitable for expressing the antibody or antigen binding fragment thereof.
  • pharmaceutical compositions comprising the antibody drug conjugate of any one of the embodiments provided herein or the isolated antibody embodiments provided herein and a pharmaceutically acceptable carrier.
  • a solid tumor selected from the group consisting of kidney cancer of clear cell or papillary histologies, a lung adenocarcinoma, an endometrioid uterine cancer, ovarian cancers, or colorectal cancer (CRC) comprising administering the antibody-drug conjugate of any of the embodiments herein or the isolated antibody or antigen binding fragment embodiments provided herein.
  • treating a solid tumor comprises a change in tumor growth inhibition.
  • the tumor volume and/or the rate of tumor volume growth is decreased.
  • provided herein are methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate of any of the embodiments provided herein.
  • the tumor cell expresses ENPP3.
  • the tumor cell is killed through a bystander effect.
  • provided herein are methods of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of any one of the embodiments provided herein to the individual.
  • the tumor cell expresses ENPP3.
  • the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, wherein the antibody drug conjugate is internalized in the tumor cell.
  • FIG.1 is a scheme showing a process for preparing an azido-modified antibody, wherein an intermediate antibody comprising a terminal-GlcNAc moiety is reacted with an azido-modified UDP-GalNAc derivative molecule in the presence of a glycosyltransferase.
  • FIG.2 is a scheme showing an embodiment of the process of preparing an azido- modified antibody.
  • FIG.3A-3B is a scheme showing an embodiment of the process of preparing an antibody-drug conjugate, wherein an azido-modified antibody is conjugated to a Linker- Drug moiety comprising strained cycloalkynyl group.
  • FIG.4 shows tumor growth inhibition in mice bearing xenograft tumors expressing ENPP3 treated with ENPP3 auristatin F hydroxypropyl amide (ENPP3-AF HPA) antibodies.
  • FIG.5 is a bar graph showing the results of an IHC based evaluation of ENPP3 expression on tissue microarrays from multiple solid tumors. Intensity of ENPP3 membrane staining is depicted as none, low, medium, and high.
  • FIGs.6A-E show characterization of ENPP3 receptor density in ccRCC cells.
  • FIG. 6A shows Flow-cytometry-based membrane ENPP3 detection and receptor occupancy measured using a commercial ENPP3 antibody in 13 ccRCC disassociated tumor cells (DTCs).
  • FIG.6B shows Representative histograms of ENPP3 expression in two of the positive ccRCC DTCs.
  • FIG.6C show an IHC image from a ccRCC tissue section at a 5x magnification with no ENPP3 expression.
  • FIG.6D shows an IHC image from a ccRCC tissue section at a 5x magnification with high ENPP3 expression.
  • FIG.6E shows an IHC image from a ccRCC tissue section at a 5x magnification with high ENPP3 expression.
  • FIGs.7A-D provides ENPP3 expression levels in a panel of cancer cell lines (HepG2-liver cancer; H1975 – non-small cell lung cancer (NSCLC); VMRCRCW – renal cell carcinoma; Example cell line 1TUHR10TKB -clear cell renal cell carcinoma (ccRCC); A704 kidney adenocarcinoma)
  • FIG.7A shows Flow-cytometry-based membrane ENPP3 detection and receptor occupancy quantification measured using a commercial ENPP3 antibody on a panel of cancer cell lines with endogenous and overexpressing (OE) ENPP3.
  • FIG 7B-7D shows representative histograms for ENPP3 expression for three cell lines shown in the bar charts in FIG.7A.
  • FIG.8 provides ENPP3 expression in patient derived xenograft (PDX) model systems from ex vivo tumors.
  • PDX patient derived xenograft
  • FIG.9 shows ADC1 binding to ENPP3-expressing tumor cell lines.
  • Example cell line 1 (ENPP3 medium), HepG2 Knock Out (KO) – huENPP3 over expression (OE) (liver cancer), HepG2 KO – cyENPP3 OE (liver cancer), and HepG2 ENPP3 KO (liver cancer, ENPP3 negative) cells were treated with ADC1 and isotype control ADC (HIVB60-Dola) and binding was evaluated by flow cytometry.
  • FIG.10 shows ENPP3 specific binding of ADC1.
  • FIG.11 shows ADC1 internalization in ENPP3-expressing cell lines.
  • a cell line with endogenous medium levels of ENPP3 expression and VMRCRCW – huENPP3 High OE (RCC, ENPP3 high overexpression) cells were treated with ADC1 and an isotype control ADC (B23B251-Dola). The results were evaluated with evaluated by confocal microscopy.
  • FIGs.12A-12B shows ADC1 internalization, phenotypic changes, and cytotoxicity in VMRCRCW–huENPP3 High OE cells (RCC).
  • FIG.12A shows immunofluorescence of ADC1 and an isotype control ADC.
  • FIG.12B shows internalization as measured by immunofluorescence, as mean intensity of the cells, normalized to percent of the medium control.
  • Phenotypic similarity to auristatin payload (auristatin F hydroxypropyl amide (AF-HPA)) represents Pearson correlation to the best matching MMAE concentration at the same time point.
  • the cytotoxic phenotype graph represents Euclidean distance from medium control in phenotypic space; values of ⁇ 10 indicate the radical phenotypic change that occurs for apoptotic cells.
  • the tumor cell loss graph is represented as percent of medium control. [0045] FIG.13 shows the effect of ADC1 on tumor cell viability.
  • Example Cell line 1 Example Cell line 2, HepG2 huENPP3 Over Expression (OE) (liver cancer), VMRCRCW huENPP3 OE (RCC), HepG2 Knock Out (KO) (liver cancer), and H1975 huENPP3 OE (NSCLC) cell lines were treated with ADC1, Isotype-ADC (HIVB60-Dola), auristatin F hydroxypropyl amide (AF-HPA) (ADC1 payload), and auristatin F (AF) (metabolite of AF-HPA).Data plotted at 6 days post treatment. Error bars are standard error of the mean (SEM).
  • FIG.14 shows the effect of ADC1 on tumor cell viability upon 2 hour or 6 day drug exposure.
  • HepG2 huENPP3 Over expression (OE) liver cancer cells were treated with ADC1, Isotype-ADC (HIVB60-Dola), auristatin F hydroxypropyl amide (AF-HPA) (ADC1 payload), and auristatin F (AF) (metabolite of AF-HPA).
  • Error bars are standard error of the mean (SEM).
  • FIGs.15A-C shows ENPP3- induced bystander tumor cell cytotoxicity of ENPP3- expressing tumor cell lines.
  • FIG.15A shows the tumor cell loss and IHC staining after treatment of HepG2 huENPP3 Over Expression (OE) (liver cancer) cells with ADC1, Isotype-ADC (HIVB60-Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF-conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days.
  • OE HepG2 huENPP3 Over Expression
  • FIG.15B shows the tumor cell loss and IHC staining after treatment of HepG2 huENPP3 Knock Out (KO) (liver cancer) cells with ADC1, Isotype- ADC (HIVB60-Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF-conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days.
  • KO HepG2 huENPP3 Knock Out
  • FIG.15C shows the tumor cell loss and IHC staining after treatment of a 1:1 coculture of HepG2 huENPP3 Over Expression (OE) (liver cancer) cells and HepG2 huENPP3 Knock Out (KO) (liver cancer) cells with ADC1, Isotype-ADC (HIVB60- Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF- conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days.
  • FIGs.16A-B shows the effect of ADC1 on tumor volume in a subcutaneous (SC) renal cell carcinoma (RCC) PDX models in NSG mice.
  • SC subcutaneous
  • RRCC renal cell carcinoma
  • FIG.16A tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 21 (dosing indicated by red arrow).
  • Group tumor volumes are graphed as mean ⁇ standard error of the mean (SEM).
  • FIG.16B Tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 22 (dosing indicated by red arrow).
  • Group tumor volumes are graphed as mean ⁇ standard error of the mean (SEM).
  • FIG.17 shows the effect of ADC1 on tumor volume in a subcutaneous (SC) non- small cell lung cancer (NSCLC) PDX in NMRI nude mice.
  • SC subcutaneous
  • NSCLC non- small cell lung cancer
  • Tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 13 (dosing indicated by red arrow).
  • Group tumor volumes are graphed as mean ⁇ standard error of the mean SEM.
  • DETAILED DESCRIPTION [0050] The function of ENPP3 in cancer development and progression is not well understood. ENPP3 was identified as an apically restricted cell surface protein in normal tissues by the inventors.
  • ENPP3 expression is an apically restricted cell surface protein in healthy tissues. In cancer, however, ENPP3 shows non-apical expression.
  • ENPP3 is highly expressed in several solid tumors, including renal cell carcinoma (RCC), endometrial cancer, CRC, hepatocellular carcinoma (HCC), lung adenocarcinoma, and some hematologic tumors like acute basophilic leukemia and neoplastic mast cells (The Human Protein Atlas. ENPP3. https://www.proteinatlas.org/ENSG00000154269-ENPP3. Accessed 17 June 2022.; Hauswirth AW, Escribano L, Prados A, et al. CD203c is overexpressed on neoplastic mast cells in systemic mastocytosis and is upregulated upon IgE receptor cross-linking. Int J Immunopathol Pharmacol.2008;21(4):797-806.
  • ADC antibody drug conjugates
  • ENPP3 is a tumor antigen that is apically restricted in normal cells, that is therefore not typically accessible to the blood stream.
  • therapies, such as ADCs that target ENPP3 may be especially effective for treating tumor cells that express ENPP3 while avoiding normal cells.
  • the ADCs provided herein may provide more targeted cancer therapies while avoiding side effects caused by targeting normal tissues.
  • the ADC advantageously binds specifically to ENPP3 on the surface of tumor tissues and can kill the ENPP3-positive cells at concentrations with low toxicity toward ENPP3 negative cells.
  • the cytotoxicity of the ADC provided herein may be mediated by its internalization, processing, and cytotoxic release in the ENPP3 -expressing tumor cells. Additionally, or alternatively, the cytotoxicity may be mediated by a bystander effect allowing the auristatin to diffuse to neighboring ENPP3 negative tumor cells, resulting in cell killing. In some embodiments, the bystander effect allows the payload to diffuse from antigen- positive tumor cells to adjacent antigen-negative tumor cells, resulting in cell killing.
  • the present ADCs show binding, internalization, and cytotoxicity in ENPP3 positive cancer cells lines (chronic myelogenous leukemia, acute myeloid leukemia, clear cell renal carcinoma, liver cancer, non-small cell lung cancer, kidney adenocarcinoma). In some embodiments, the present ADCs show antitumor efficacy in acute myeloid leukemia, renal cell carcinoma, and non-small cell lung cancer mouse models.
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • an “antibody” may be a natural or conventional antibody in which two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (l) and kappa (k).
  • the light chain includes two domains or regions, a variable domain (VL) and a constant domain (CL).
  • the heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH).
  • the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
  • the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties, such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).
  • the Fv fragment is the N- terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain.
  • the specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant.
  • Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) influence the overall domain structure and hence the combining site.
  • Complementarity Determining Regions or CDRs therefore refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site.
  • the light and heavy chains of an immunoglobulin each have three CDRs, designated CDRL1, CDRL2, CDRL3 and CDRH1, CDRH2, CDRH3, respectively.
  • a conventional antibody antigen-binding site therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain variable region.
  • “Framework Regions” refer to amino acid sequences interposed between CDRs, i.e.
  • a “human framework region” is a framework region that is substantially identical (about 85%, or more, for instance 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the framework region of a naturally occurring human antibody.
  • CDR/FR definition in an immunoglobulin light or heavy chain is to be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org).
  • antibody denotes conventional antibodies and fragments thereof, as well as single domain antibodies and fragments thereof, in particular variable heavy chain of single domain antibodies, and chimeric or humanized.
  • the term “monoclonal antibody” or “mAb” as used herein refers to an antibody molecule of a single amino acid sequence, which is directed against a specific antigen, and is not to be construed as requiring production of the antibody by any particular method.
  • a monoclonal antibody may be produced by a single clone of B cells or hybridoma, but may also be recombinant, i.e produced by protein engineering.
  • the term “chimeric antibody” refers to an engineered antibody which, in its broadest sense, contains one or more regions from one antibody and one or more regions from one or more other antibodies.
  • a chimeric antibody comprises a VH domain and a VL domain of an antibody derived from a non-human animal, in association with a CH domain and a CL domain of another antibody, in an embodiment, a human antibody.
  • a non-human animal any animal such as mouse, rat, hamster, rabbit, or the like can be used.
  • humanized antibody refers to an antibody which is wholly or partially of non-human origin and which has been modified to replace certain amino acids, for instance in the framework regions of the VH and VL domains, in order to avoid or minimize an immune response in humans.
  • the term “human antibody” to an antibody having variable and constant regions derived from human immunoglobulin sequences.
  • Human antibodies may include amino acid residues not encoded by human immunoglobulin sequences (for example mutations introduced by site-specific mutagenesis in vitro), for example in CDRs.
  • a “human antibody” does not include antibodies that contain CDR sequences obtained from other species (such as mice) inserted into human frameworks.
  • Human antibodies may be isolated from a donor, produced by recombinant means and/or produced by a rodent that comprises a modified immune system. This definition of a human antibody includes intact or full-length antibodies, fragments thereof, and/or antibodies comprising at least one human heavy and/or light chain polypeptide.
  • “Fragments” of (conventional) antibodies comprise a portion of an intact antibody, in particular the antigen binding region or variable region of the intact antibody.
  • antibody fragments include Fv, Fab, F(ab’)2, Fab’, dsFv, (dsFv)2, scFv, sc(Fv)2, diabodies, antibodies formed from antibody fragments.
  • a fragment of a conventional antibody may also be a single domain antibody, such as a heavy chain antibody or VHH.
  • Fab denotes an antibody fragment having a molecular weight of about 50,000 and antigen binding activity, in which about a half of the N-terminal side of the heavy chain and the entire light chain are bound together through a disulfide bond.
  • F(ab’)2 refers to an antibody fragment having a molecular weight of about 100,000 and antigen binding activity, which is slightly larger than 2 identical Fab fragments bound via a disulfide bond of the hinge region. It is usually obtained among fragments by treating IgG with a protease, pepsin.
  • a single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide-encoding linker.
  • Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv) 2 .
  • dsFv is a VH::VL heterodimer stabilised by a disulphide bond.
  • (dsFv)2 denotes two dsFv coupled by a peptide linker.
  • the term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL).
  • hybrida denotes a cell, which is obtained by subjecting a B cell prepared by immunizing a non-human mammal with an antigen to cell fusion with a myeloma cell derived from a mouse or the like which produces a desired monoclonal antibody having an antigen specificity.
  • purified and “isolated” it is meant, when referring to a polypeptide (i.e.
  • nucleic acid molecule which encodes a particular polypeptide refers to a nucleic acid molecule which is substantially free of other nucleic acid molecules that do not encode the subject polypeptide; however, the molecule may include some additional bases or moieties which do not deleteriously affect the basic characteristics of the composition.
  • isolated can refer to a molecule that has been separated from at least some of the components with which it is typically found in nature or produced.
  • a polypeptide is referred to as “isolated” when it is separated from at least some of the components of the cell in which it was produced.
  • a polypeptide is secreted by a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produced it is considered to be “isolating” the polypeptide.
  • a polynucleotide is referred to as “isolated” when it is not part of the larger polynucleotide (such as, for example, genomic DNA or mitochondrial DNA, in the case of a DNA polynucleotide) in which it is typically found in nature or is separated from at least some of the components of the cell in which it was produced, e.g., in the case of an RNA polynucleotide.
  • a DNA polynucleotide that is contained in a vector inside a host cell may be referred to as “isolated”.
  • the terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length.
  • polymers of amino acid residues can contain natural or non-natural amino acid residues, and include, but are not limited to, dimers, trimers, peptides, oligopeptides, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition.
  • the terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like.
  • polypeptide also refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, so long as the protein maintains the desired activity.
  • polypeptide and “protein” encompass ENPP3 antigen binding proteins, including antibodies, antibody fragments, or sequences that have deletions from, additions to, and/or substitutions of one or more amino acids of the antigen binding protein.
  • a “native sequence” or a “naturally-occurring” polypeptide comprises a polypeptide having the same amino acid sequence as a polypeptide found in nature.
  • a native sequence polypeptide can have the amino acid sequence of naturally-occurring polypeptide from any mammal.
  • Such native sequence polypeptide can be isolated from nature or can be produced by recombinant or synthetic means.
  • polypeptide “native sequence” polypeptide specifically encompasses naturally-occurring truncated or secreted forms of the polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide.
  • a polypeptide “variant” means a biologically active polypeptide (e.g., an antigen binding protein or antibody) having at least about 70%, 80%, or 90% amino acid sequence identity with the native or a reference sequence polypeptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.
  • variants include, for instance, polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the polypeptide.
  • a variant will have at least about 80% amino acid sequence identity.
  • a variant will have at least about 90% amino acid sequence identity.
  • a variant will have at least about 95% amino acid sequence identity with the native sequence polypeptide.
  • Percent (%) amino acid sequence identity and “homology” with respect to a peptide, polypeptide or antigen binding protein (e.g., antibody) sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN TM (DNASTAR) software.
  • the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B.
  • leader sequence refers to a sequence of amino acid residues located at the N-terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein.
  • immunoglobulin refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds.
  • L light
  • H heavy
  • the structure of immunoglobulins has been well characterized. See, for instance, Fundamental Immunology (Paul, W., ed., 7 th ed. Raven Press, N .Y. (2013)).
  • each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as V H or VH) and a heavy chain constant regio n (C H or CH).
  • the heavy chain constant region typically is comprised of three domains, C H 1, C H 2, and C H 3.
  • the heavy chains are generally inter- connected via disulfide bonds in the so-called “hinge region.”
  • Each light chain typically is comprised of a light chain variable region (abbreviated herein as V L or VL) and a light chain constant region (C L or CL).
  • the light chain constant region typically is comprised of one domain, C L .
  • the CL can be of ⁇ (kappa) or ⁇ (lambda) isotype.
  • an immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3 and IgG4.
  • Isotype refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • the terms “hypervariable region,” “HVR,” “Complementarity Determining Region,” and “CDR” are used interchangeably.
  • CDR refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH ⁇ -sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL ⁇ -sheet framework.
  • CDR1, CDR2 and CDR3 in VH domain are also referred to as HCDR1, HCDR2 and HCDR3, respectively.
  • CDR1, CDR2 and CDR3 in VL domain are also referred to as LCDR1, LCDR2 and LCDR3, respectively. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences.
  • CDR regions are well known to those skilled in the art and have been defined by well- known numbering systems.
  • the Kabat Complementarity Determining Regions are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed.1991); Nick Deschacht et al., J Immunol 2010; 184:5696-5704).
  • Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol.196:901-17 (1987)).
  • the end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol.2 (Kontermann and Dübel eds., 2d ed.2010)).
  • IMGT ImMunoGeneTics
  • IG immunoglobulins
  • TCR T-cell receptors
  • MHC major histocompatibility complex
  • CDR complementary determining region
  • the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, Chothia, or Contact method.
  • the particular amino acid sequence of a CDR is given.
  • CDR regions may also be defined by a combination of various numbering systems, e.g., a combination of Kabat and Chothia numbering systems, or a combination of Kabat and IMGT numbering systems. Therefore, the term such as “a CDR1 as set forth in a specific VH” includes any CDR1 as defined by the exemplary CDR numbering systems described above, but is not limited thereby.
  • variable region e.g., a VH or VL
  • CDRs within the region can be defined by different numbering systems or combinations thereof.
  • the terms “CDR” and “complementary determining region” of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., “CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above.
  • the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, AbM, Chothia, or Contact method.
  • the antigen binding protein comprises CDRs and/or HVRs as defined by the IMGT system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the Kabat system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the AbM system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the Chothia system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the IMGT system.
  • variable region refers to the domain of an antigen binding protein (e.g., an antibody) heavy or light chain that is involved in binding the antigen binding protein (e.g., antibody) to antigen.
  • the variable regions or domains of the heavy chain and light chain (VH and VL, respectively) of an antigen binding protein such as an antibody can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and/or form of structurally defined loops), such as complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).
  • CDRs complementarity-determining regions
  • heavy chain constant region refers to a region comprising at least three heavy chain constant domains, C H 1, C H 2, and C H 3.
  • Nonlimiting exemplary heavy chain constant regions include ⁇ , ⁇ , and ⁇ .
  • Nonlimiting exemplary heavy chain constant regions also include ⁇ and ⁇ .
  • Each heavy constant region corresponds to an antibody isotype.
  • an antibody comprising a ⁇ constant region is an IgG antibody
  • an antibody comprising a ⁇ constant region is an IgD antibody
  • an antibody comprising an ⁇ constant region is an IgA antibody.
  • an antibody comprising a ⁇ constant region is an IgM antibody
  • an antibody comprising an ⁇ constant region is an IgE antibody.
  • IgG antibodies include, but are not limited to, IgG1 (comprising a ⁇ 1 constant region), IgG2 (comprising a ⁇ 2 constant region), IgG3 (comprising a ⁇ 3 constant region), and IgG4 (comprising a ⁇ 4 constant region) antibodies;
  • IgA antibodies include, but are not limited to, IgA1 (comprising an ⁇ 1 constant region) and IgA2 (comprising an ⁇ 2 constant region) antibodies;
  • IgM antibodies include, but are not limited to, IgM1 and IgM2.
  • HC heavy chain
  • full-length heavy chain refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.
  • light chain constant region refers to a region comprising a light chain constant domain, C L .
  • Nonlimiting exemplary light chain constant regions include ⁇ and ⁇ .
  • the term “light chain” (LC) as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region.
  • the term “full- length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.
  • the “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5 th Ed.
  • epitope refers to a site on an antigen (e.g., ENPP3), to which an antigen-binding protein (e.g., an antibody or fragments thereof) that targets that antigen.
  • an antigen e.g., ENPP3
  • an antigen-binding protein e.g., an antibody or fragments thereof
  • the epitope can comprise amino acids residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues that are not directly involved in the binding, including amino acid residues that are effectively blocked or covered by the antigen binding molecule (i.e., the amino acids are within the footprint of the antigen binding molecule).
  • Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography, two-dimensional nuclear magnetic resonance, and HDX-MS (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol.66, G.E. Morris, Ed. (1996)).
  • antigen binding proteins e.g., antibodies or fragments thereof
  • a “nonlinear epitope,” “discontinuous,” or “conformational epitope” comprises noncontiguous polypeptides, amino acids, and/or sugars within the antigenic protein to which an antibody specific to the epitope binds.
  • a “linear epitope” or a “continuous epitope” comprises contiguous polypeptides, amino acids, and/or sugars within the antigenic protein to which an antigen binding protein (e.g., an antibody or fragment thereof) specific to the epitope binds.
  • a “paratope” or “antigen binding site” is the site on the antigen binding protein (e.g., antibody or fragment thereof) that binds the epitope and typically includes the amino acids that are in close proximity to the epitope once the antibody is bound (see, e.g., Sela- Culang et al., 2013, Front Immunol.4:302).
  • affinity refers to the strength of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (K d ). Affinity can be measured by common methods known in the art, including those described herein.
  • K d dissociation constant
  • Affinity can be measured by common methods known in the art, including those described herein.
  • the term “specifically binds”, “binding” or simply “binds” or other related terms in the context of the binding of an antigen binding protein to its target antigen means that the antigen binding protein exhibits essentially background binding to non-target molecules.
  • an antigen binding protein that specifically binds the target antigen may, however, cross-react with ENPP3 proteins from different species.
  • a ENPP3 antigen binding protein specifically binds human ENPP3 when the dissociation constant (K D ) is 10 -7 M or less, such as about 10 -8 M or less, such as about 10 -9 M or less, about 10 -10 M or less, or about 10 -11 M or even less as measured via a surface plasma resonance (SPR) technique (e.g., BIACore, GE-Healthcare Uppsala, Sweden) using the antibody as the ligand and the antigen as the analyte.
  • SPR surface plasma resonance
  • K D refers to the dissociation equilibrium constant of a particular antigen binding protein-antigen interaction (e.g., antibody-antigen interaction). Affinity, as used herein, and K D are inversely related, such that higher affinity is intended to refer to lower K D , and lower affinity is intended to refer to higher K D.
  • An “antibody-drug-conjugate” or simply “ADC” refers to an antibody conjugated to a drug such as an auristatin. An antibody-drug-conjugate typically binds to the target antigen (e.g., ENPP3) on a cell surface followed by internalization of the antibody-drug- conjugate into the cell where the drug is released.
  • target antigen e.g., ENPP3
  • An antibody-drug-conjugate as used herein include antibody drug conjugates in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any form i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or
  • ADC antibody-drug conjugate
  • ADC refers to an antibody as defined hereinabove, to which one or more therapeutic moieties are conjugated via a linker (linker drugs).
  • a “drug-to-antibody ratio” refers to the number of linker drugs conjugated to the antibody. Conjugation processes typically yield a heterogeneous mixture of different ADC molecules, i.e. different DAR species having different drug-to-antibody ratios. Therefore, the term “ADC” also refers to such mixtures of DAR species.
  • the term “average DAR” refers to the average DAR of the population of such DAR species.
  • a “cytotoxic effect” refers to the depletion, elimination and/or killing of a target cell.
  • a “cytostatic effect” refers to the inhibition of cell proliferation.
  • Fc receptor or “FcR” describes a receptor that binds to the Fc region of an antibody.
  • an Fc ⁇ R is a native human FcR.
  • an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of those receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain
  • Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • FcR Fc receptor
  • FcRn neonatal receptor
  • antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.
  • CDC complement dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • B cell receptor e.g. B cell receptor
  • B cell activation e.g. B cell activation
  • Such functions can be affected by, for example, binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system.
  • the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of the CD33 targeted cell.
  • Fc regions of antibodies can recruit Fc receptor (FcR)-expressing cells and juxtapose them with antibody-coated target cells.
  • FcR Fc receptor
  • Cells expressing surface FcR for IgGs including Fc ⁇ RIII (CD16), Fc ⁇ RII (CD32) and Fc ⁇ RIII (CD64) can act as effector cells for the destruction of IgG-coated cells.
  • effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils and eosinophils.
  • Engagement of Fc ⁇ R by IgG activates antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP).
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • ADCC is mediated by CD16 + effector cells through the secretion of membrane pore- forming proteins and proteases, while phagocytosis is mediated by CD32 + and CD64 + effector cells (see, e.g., Fundamental Immunology, 4 th ed., Paul ed., Lippincott-Raven, N.Y., 1997, Chapters 3, 17 and 30; Uchida et al., 2004, J. Exp. Med.199:1659-69; Akewanlop et al., 2001, Cancer Res.61:4061-65; Watanabe et al., 1999, Breast Cancer Res. Treat.53:199-207.
  • Human effector cells are leukocytes which express one or more FcRs and perform effector functions. In certain embodiments, the cells express at least Fc ⁇ RIII and perform ADCC effector function(s). Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils.
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • monocytes cytotoxic T cells
  • neutrophils neutrophils.
  • the effector cells may be isolated from a native source, e.g., from blood.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • cytotoxic effector cells e.g. NK cells, neutrophils, and macrophages.
  • NK cells express Fc ⁇ RIII only, whereas monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu.
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to the Fc region of antibodies (of the appropriate subclass), which are bound to their cognate antigen on a target cell. This binding activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane and subsequent cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.
  • complement receptors e.g., CR3
  • a CDC assay e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.
  • Polypeptide variants with altered Fc region amino acid sequences polypeptides such as an antibody with a variant Fc region
  • increased or decreased C1q binding capability are described, e.g., in U.S. Pat. No.6,194,551 B1, U.S. Pat. No.7,923,538, U.S. Pat. No.7,994,290 and WO 1999/51642. See also, e.g., Idusogie et al., J. Immunol.164: 4178-4184 (2000).
  • ADCP antibody-dependent cellular phagocytosis
  • phagocytic immune cells e.g., macrophages, neutrophils and dendritic cells
  • Fc region of Ig Fc region of Ig.
  • nucleic acid molecule nucleic acid
  • polynucleotide are used interchangeably herein and refer to a polymer of nucleotides of any length. Such polymers of nucleotides can contain natural and/or non-natural nucleotides, and include, but are not limited to, DNA, RNA, and PNA.
  • Nucleic acid sequence refers to the linear sequence of nucleotides that comprise the nucleic acid molecule or polynucleotide.
  • vector means any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage or virus) used to transfer a nucleic acid molecule into a host cell.
  • a vector typically includes a nucleic acid molecule engineered to contain a cloned polynucleotide or polynucleotides encoding a polypeptide or polypeptides of interest that can be propagated in a host cell.
  • a vector may include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and/or enhancers) that regulate the expression of the polypeptide of interest, and/or one or more selectable marker genes.
  • the term includes vectors which are self- replicating nucleic acid molecules as well as vectors incorporated into the genome of a host cell into which it has been introduced.
  • expression vector refers to a vector that is suitable for transformation of a host cell and that can be used to express a polypeptide of interest in a host cell.
  • host cell or “host cell line” are used interchangeably herein and refer to a cell or population of cells that may be or has been a recipient of a vector or isolated polynucleotide.
  • Host cells can be prokaryotic cells or eukaryotic cells.
  • “operably linked” means that the components to which the term is applied are in a relationship that allows them to carry out their inherent functions under suitable conditions. For example, a control sequence in a vector that is “operably linked” to a protein coding sequence is ligated thereto such that expression of the protein coding sequence is achieved under conditions compatible with the transcriptional activity of the control sequences.
  • transfection means the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein.
  • transformation refers to a change in a cell’s genetic characteristics, and a cell has been transformed when it has been modified to contain new DNA or RNA. For example, a cell is transformed where it is genetically modified from its native state by introducing new genetic material via transfection, transduction, or other techniques.
  • the transforming DNA can recombine with that of the cell by physically integrating into a chromosome of the cell or can be maintained transiently as an episomal element without being replicated or can replicate independently as a plasmid.
  • a cell is considered to have been "stably transformed” when the transforming DNA is replicated with the division of the cell.
  • a “disease” or “disorder” as used herein refers to a condition where treatment is needed, such as cancer.
  • “Cancer” and “tumor,” as used herein, are interchangeable terms that refer to any abnormal cell or tissue growth or proliferation in an animal including solid tumors and leukemias.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas.
  • the term “treating” includes, but is not limited to, any or all of: inhibiting growth of cancer cells, inhibiting replication of cancer cells, reducing the number of cancer cells, and lessening of overall tumor burden.
  • a “reference” as used herein, refers to any sample, standard, or level that is used for comparison purposes.
  • a reference can be obtained from a healthy and/or non-diseased sample. In some examples, a reference can be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased on non-treated sample of a subject individual.
  • a reference is obtained from one or more healthy individuals who are not the subject or patient.
  • to “suppress” a function or activity is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another condition.
  • an antibody which suppresses tumor growth reduces the rate of growth of the tumor compared to the rate of growth of the tumor in the absence of the antibody.
  • An “effective amount” or “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug or agent that, when used alone or in combination provides a treatment effect.
  • administering refers to the physical introduction of a therapeutic agent (such as an ADC) to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • a therapeutic agent such as an ADC
  • pharmaceutical formulation and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.
  • a “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent (such as an ADC) that together comprise a “pharmaceutical composition” for administration to a subject.
  • a pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is appropriate for the formulation employed.
  • sugar refers to a monosaccharide, for example glucose (Glc), galactose (Gal), mannose (Man) and fucose (Fuc).
  • sugar derivative refers to a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and/or functional groups.
  • examples of a sugar derivative include, but are not limited to, amino sugars and sugar acids.
  • examples of a sugar derivative also include compounds denoted as S’(F’) X1 , wherein S’ is a sugar or a sugar derivative, F’ is a functional group and x 1 indicates the number of functional groups.
  • core-GlcNAc moiety refers to a monosaccharide, polysaccharide, or oligosaccharide moiety comprising a GlcNAc (e.g., a core-GlcNAc) which is attached to an antibody (e.g., via the C1 position of the GlcNAc).
  • the GlcNAc is attached to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody.
  • the core-GlcNAc moiety is present at a native glycosylation site of an antibody or is introduced on a different site on the antibody.
  • the core-GlcNAc moiety is a monosaccharide (e.g., the core-GlcNAc moiety is also a terminal-GlcNAc moiety).
  • the core-GlcNAc moiety further comprises a fucose, e.g., the core-GlcNAc moiety is a disaccharide core-GlcNAc-( ⁇ 1-6- Fuc) moiety (which may be referred to as GlcNAc(Fuc)).
  • the antibody when antibody comprises a core-GlcNAc moiety, the antibody may comprise a monosaccharide or a disaccharide core-GlcNAc moiety, and the core-GlcNAc moiety may further comprise a fucose (e.g., a disaccharide core-GlcNAc(Fuc) moiety). If the core-GlcNAc moiety further comprises a fucose, the fucose may be linked ⁇ -1,6 to O-6 of the core-GlcNAc moiety.
  • a core- GlcNAc moiety further comprising a fucose may be referred to as core-GlcNAc(Fuc).
  • the term “core-GlcNAc” refers to the inner GlcNAc that is a portion of a polysaccharide or oligosaccharide, wherein the polysaccharide or oligosaccharide is attached to an antibody via the inner GlcNAc.
  • the term “terminal-GlcNAc moiety”, as used herein, refers to a moiety comprising a GlcNAc which is attached to an antibody and has a terminal functional group being available for further modification (e.g., with a compound of P”-S”-A”). In some embodiments, the terminal-GlcNAc moiety further comprises a fucose.
  • the terminal-GlcNAc moiety is formed by reacting the core-GlcNAc moiety of a glycoprotein (e.g., an antibody glycan) with an endoglycosidase.
  • a glycoprotein e.g., an antibody glycan
  • glycoprotein is herein used in its normal scientific meaning and refers to a protein comprising one or more monosaccharide or oligosaccharide chains (“glycans”) covalently bonded to the protein.
  • a glycan may be attached to a hydroxyl group on the protein (O-linked-glycan), to an amide function on the protein (N-glycoprotein), or to a carbon on the protein (C-glycoprotein).
  • a glycoprotein may comprise more than one glycan, may comprise a combination of one or more monosaccharide and one or more oligosaccharide glycans, and may comprise a combination of N-linked, O-linked and C- linked glycans. It is estimated that more than 50% of all proteins have some form of glycosylation and therefore qualify as glycoprotein. [0131]
  • the term "glycan” is herein used in its normal scientific meaning and refers to a monosaccharide or oligosaccharide chain that is linked to a protein. Glycan thus refers to the carbohydrate-part of a glycoprotein.
  • the glycan is attached to a protein via the C-1 carbon of one sugar, which may be without further substitution (monosaccharide) or may be further substituted at one or more of its hydroxyl groups (oligosaccharide).
  • a naturally occurring glycan typically comprises 1 to about 10 saccharide moieties. However, when a longer saccharide chain is linked to a protein, said saccharide chain is also considered a glycan.
  • a glycan of a glycoprotein may be a monosaccharide.
  • a glycan may also be an oligosaccharide.
  • An oligosaccharide chain of a glycoprotein may be linear or branched.
  • oligosaccharide the sugar that is directly attached to the protein is called the core sugar.
  • a sugar that is not directly attached to the protein and is attached to at least two other sugars is called an internal sugar.
  • a sugar that is not directly attached to the protein but to a single other sugar, i.e. carrying no further sugar substituents at one or more of its other hydroxyl groups is called the terminal sugar.
  • a glycan may be an O-linked glycan, an N-linked glycan, or a C-linked glycan.
  • a monosaccharide or oligosaccharide glycan is bonded to a C-atom in an amino acid of the protein.
  • glycosyltransferase refers to a superfamily of enzymes that are involved in the synthesis of complex carbohydrates present on glycoproteins and glycolipids.
  • N-acetylgalactosaminyl transferase (GalNAc-T or GalNAc transferase) is a N-acetyl-D-galactosamine transferase enzyme that catalyzes the addition of N-acetyl-D- galactosamine to proteins.
  • conjugates of the disclosure are useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as solid tumors or leukemias.
  • the ADCs as disclosure herein in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the ADCs of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.
  • Anti-ENPP3 antibody “antibody that binds to ENPP3,” “ENPP3 antibody” and “antibody or antigen binding fragment thereof that binds to ENPP3” are used interchangeably herein to refer to an antibody or antigen binding fragment thereof that specifically binds to ENPP3.
  • ENPP3 Antibodies [0138] In some aspects, provided herein are antibodies or antigen binding fragment thereof that bind to ENPP3. In some embodiments, the isolated antibody of this invention is specific to human and cynomolgus monkey ENPP3 proteins.
  • the isolated antibody of this invention binds to ENPP3 and does not bind to cells expressing other forms of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family members.
  • ENPP ectonucleotide pyrophosphatase/phosphodiesterase
  • provided herein are isolated anti-ENPP3 antibodies that bind to the extracellular region of ENPP3.
  • the isolated antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3.
  • the isolated antibody or antibody fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the isolated anti- ENPP3 antibody or antigen binding fragment thereof is human. In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof is chimeric. In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof is humanized. [0141] In some embodiments, the isolated anti-ENPP3 antibody comprises a Fc region. In some embodiments, the anti-ENPP3 Fc region has been mutated to abolish interactions with Fc ⁇ receptors. In some embodiments, the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering.
  • the isolated antibody comprises an L234A mutation. In some embodiments, the isolated antibody comprises an L235 mutation. In some embodiments, the isolated antibody comprises a D265S mutation. In some embodiments, the isolated antibody comprises L234A, L235A, and D265S mutations.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in any of SEQ ID NO: 1, 32, 38, 44, 50, or 56 a CDRH2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 2, 33, 39, 45, 51, or 57 a CDRH3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 3, 34, 40, 46, 52, or 58, a CDRL1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 4, 35, 41, 47, 53, or 59 a CDRL2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 5, 36, 42, 48, 54, or 60 and a CDRL3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 6, 37, 43, 43, 49, 66 or 61.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49.
  • isolated the anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:7.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:22 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 27.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:22.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:24 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 29.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:24.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 29.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:25 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:25.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 30.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:26 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 31.
  • the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:26.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 31.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26.
  • the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31.
  • the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:3 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:7.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:5; and a C DR3-L comprising the amino acid sequence set forth in SE Q ID NO:6 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:8.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:32; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:33; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:22.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:35; a CDRL2 comprising the amino acid sequence set forth in SEQ ID N O:36; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:37 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:27.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:38; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:39; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:40 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:23.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:41; a CDRL2 comprising the amino acid sequence set forth in SEQ ID N O:42; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:43 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:28.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:44; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:45; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:46 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:24.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:47; a CDRL2 comprising the amino acid sequence set forth in SEQ ID N O:48; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:49 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:29.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:50; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:51; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:52 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:25.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:53; a CDRL2 comprising the amino acid sequence set forth in SEQ ID N O:54; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:55 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:30.
  • the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:56; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:57; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:58 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:26.
  • the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:59; a CDRL2 comprising the amino acid sequence set forth in SEQ ID N O:60; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:61 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:31.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:1, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:2 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:3.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:32, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:33 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:34.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:38, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:39 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:40.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:44, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:45 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:46.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:50, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:51 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:52.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:56, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:57 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:58.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:4, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:5 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:6.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:35, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:36 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:37.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:41, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:42 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:43.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:47, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:48 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:49.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:53, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:54 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:55.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:59, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:60 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:61.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:10 or 17-21.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:12, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:13, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:18.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:14, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:19.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:15, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:20.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16 and the light chain comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:9 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 10. [0189] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:12 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 17. [0190] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:13 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 18.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:14 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 19.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:15 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 20.
  • the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:16 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 121.
  • the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 of SEQ ID NO: 9.
  • a modified glycan is a non-native glycan.
  • the modified glycan is the native glycans on the antibody Fc at position N296 of SEQ ID NO 9. that has been enzymatically processed by an endoglycosidase (e.g. an EndoSH) to the core N- acetylglucosamine followed by attachment of an azido-modified N-acetylgalactosamine utilizing a glycosyl transferase (e.g., a GalNAc transferase).
  • an endoglycosidase e.g. an EndoSH
  • the modified glycan is at a position corresponding to N296 of SEQ ID NO: 9.
  • the antibody in any of the foregoing embodiments can be an antibody in any form.
  • the antibody described in any of the above embodiments can be, for example, a monoclonal antibody, a human, humanized or chimeric antibody, and antigen binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library.
  • the antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
  • immunoglobulin isotype e.g., IgG, IgE, IgM, IgD, IgA and IgY
  • class e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 or subclass.
  • an isolated antibody or antigen binding fragment thereof with the HVR and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain.
  • Antigen-binding fragments, including single-chain antibodies may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, CH3 and CL domains.
  • antigen-binding fragments comprising any combination of variable region(s) with a hinge region, CH1, CH2, CH3 and CL domains.
  • one or several amino acids e.g., 1, 2, 3 or 4
  • amino or carboxy terminus of the light and/or heavy chain such as the C- terminal lysine of the heavy chain
  • the isolated antibody or antigen binding fragment thereof is a human antibody that binds ENPP3.
  • the human antibody that binds to ENPP3 is generated by a rodent with a modified immune system. In some embodiments, the human antibody that binds to ENPP3 is generated by a human immune system.
  • the isolated antibody or antigen binding fragment thereof is a humanized antibody that binds ENPP3.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody is a genetically engineered antibody in which the HVRs (e.g., CDRs) or portions thereof from a non-human “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539; Carter, US 6,407,213; Adair, US 5,859,205; and Foote, US 6,881,557).
  • the acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence.
  • Human acceptor sequences can be selected for a high degree of sequence identity in the variable region frameworks with donor sequences to match canonical forms between acceptor and donor HVRs or CDRs among other criteria.
  • a humanized antibody is an antibody having HVRs or CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences.
  • a humanized heavy chain typically has all three HVRs or CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences.
  • a humanized light chain usually has all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences.
  • the variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 80%, 85%, 90%, 95% or 100% of corresponding residues defined by Kabat are identical.
  • Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on HVR (e.g,.CDR) conformation and/or binding to antigen.
  • the human framework amino acid can be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid: (1) noncovalently binds antigen directly, (2) is adjacent to an HVR or CDR region, (3) otherwise interacts with an HVR or CDR region (e.g. is within about 6 ⁇ of such a region); (4) mediates interaction between the heavy and light chains, or (5) is the result of somatic mutation in the mouse chain. (6) is a site of glycosylation.
  • Framework residues from classes (1)-(3) are sometimes alternately referred to as canonical and vernier residues.
  • Canonical residues refer to framework residues defining the canonical class of the donor CDR loops determining the conformation of a CDR loop (Chothia and Lesk, J. Mol. Biol.196, 901-917 (1987), Thornton & Martin, J. Mol. Biol., 263, 800-815, 1996).
  • Vernier residues refer to a layer of framework residues that support antigen-binding loop conformations and play a role in fine-tuning the fit of an antibody to antigen (Foote & Winter, 1992, J Mol Bio.224, 487-499).
  • Human framework regions that may be used for humanization include, but are not limited to, framework regions selected using the “best-fit” method (see, e.g., Sims et al. (1993) J.
  • Immunol.151 :2296 framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. (1992) Proc. Natl. Acad. Sci. USA, 89:4285; and Presta et al. (1993) J. Immunol, 151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633); and framework regions derived from screening FR libraries (see, e.g., Baca et al., (1997) J. Biol.
  • the heavy and light chain variable regions of isolated antibodies described herein can be linked to at least a portion of a human constant region.
  • the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD.
  • the human light chain constant region is of an isotype selected from ⁇ and ⁇ .
  • an isolated antibody described herein comprises a human IgG constant region.
  • an isolated antibody described herein comprises a human IgG4 heavy chain constant region.
  • an isolated antibody described herein comprises an S241P mutation in the human IgG4 constant region. In some embodiments, an isolated antibody described herein comprises a human IgG4 constant region and a human ⁇ light chain.
  • the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference.
  • the “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody.
  • Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype binds to a non-polymorphic region of a one or more other isotypes. Reference to a human constant region includes a constant region with any natural allotype or any permutation of residues occupying polymorphic positions in natural allotypes. Also, up to 1, 2, 5, or 10 mutations may be present relative to a natural human constant region, such as those indicated above to reduce Fc ⁇ receptor binding.
  • the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering.
  • the antibody comprises an L234A mutation.
  • the antibody comprises an L235 mutation.
  • the antibody comprises a D265S mutation.
  • the antibody comprises L234A, L235A, and D265S mutations.
  • one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain may be missing or derivatized in a proportion or all of the molecules.
  • constant region depends, in part, whether antibody-dependent cell- mediated cytotoxicity, antibody dependent cellular phagocytosis and/or complement dependent cytotoxicity are desired.
  • human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity
  • human isotype IgG2 weak complement- dependent cytotoxicity
  • human IgG4 lacks complement-dependent cytotoxicity.
  • Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4.
  • Light chain constant regions can be lambda or kappa.
  • the isolated antibody comprises one or more (e.g., one) core- GlcNAc moiety on each heavy chain, said core-GlcNAc moiety being optionally fucosylated.
  • the whole antibody comprises two or more (e.g., two) optionally fucosylated, core-GlcNAc moieties.
  • said core-GlcNAc moiety is present at a native N-glycosylation site of the antibody.
  • the antibody comprises, or is engineered to comprise, at least one chemically reactive group or a chemically reactive amino acid moiety or side chains.
  • the anti-ENPP3 antibody is a modified anti-ENPP3 antibody.
  • a “modified antibody” or “modified anti-ENPP3 antibody” as used herein is an antibody which has been post-translationally modified.
  • the modified antibody is an intermediate in a process to produce an antibody drug conjugate.
  • the modified antibody comprises processed or non-native glycans.
  • the modified anti-ENPP3 antibody * denotes a direct or indirect attachment to the rest of the modified anti-ENPP3 antibody.
  • S is a sugar or a derivatized sugar.
  • A is a functional group being capable of forming a covalent bond with a functional group of the Linker-Drug moiety,
  • the modified anti-ENPP3 antibody prior to conjugation, comprises a sugar-derivative moiety of * S A .
  • the modified anti-ENPP3 antibody comprises an asparagine group in the region 290-305 (e.g., at N297; EU numbering).
  • the sugar-derivative moiety is directly or indirectly attached to the asparagine group (e.g., at N297; EU numbering).
  • the “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest (5th ed.1991)).
  • the modified anti-ENPP3 antibody, prior to conjugation * omprises a modified-GlcNAc moiety, Glc S" A" c NAc , wherein GlcNAc is N- acetylglucosamine.
  • the modified-GlcNAc moiety is connected to the rest of the modified anti-ENPP3 antibody via the C1 position of the GlcNAc. In some embodiments, the modified-GlcNAc moiety further comprises a fucose. [0218] In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to the asparagine group (e.g., at N297, EU Numbering). In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to N297. In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached at position N180 of SEQ ID NO: 11, a position corresponding to N297 (as numbered by EU numbering).
  • the modified-GlcNAc moiety is directly or indirectly attached to the antibody at position N296 of SEQ ID NO: 9 a position corresponding to N297 (as numbered by EU numbering).
  • the modified anti-ENPP3 antibody is conjugated to the Linker- Drug moiety via a covalent bond formed between A” and a functional group of the Linker-Drug moiety.
  • the modified antibody that binds to ENPP3 of the present disclosure is obtained by a process comprising: a.
  • GlcNAc N-acetylglucosamine
  • S is a sugar or a derivatized sugar
  • A is azido, keto, or alkynyl
  • P is uridine diphosphate (UDP), guanosine diphosphate (GDP) or cytidine diphosphate (CDP).
  • the antibody is a monoclonal antibody (mAb).
  • the antibody is an IgA, IgD, IgE, IgG, or IgM antibody.
  • the antibody is an IgG antibody, e.g., an IgGl, IgG2, IgG3, or IgG4 antibody. In some embodiments, the antibody is an IgGl antibody.
  • the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety.
  • the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety connected to each heavy chain of the antibody.
  • the core-GlcNAc moiety further comprises a fucose.
  • the antibody is a full-length antibody, and the antibody glycan comprises two or more core-GlcNAc moiety connected to the full-length antibody.
  • the antibody is a full-length antibody, and the antibody glycan comprises two core-GlcNAc moieties connected to the full-length antibody. [0230] In some embodiments, at least one of the two or more core-GlcNAc moieties further comprises a fucose. [0231] In some embodiments, each of the two or more core-GlcNAc moiety further comprises a fucose.
  • the antibody is a single chain antibody or an antibody that binds to ENPP3 fragment (e.g., a Fab or Fc fragment), the antibody glycan comprises one or more core-GlcNAc moiety (which optionally further comprises fucose) connected to the antibody.
  • the core-GlcNAc moiety is connected to a position of the antibody, wherein the core-GlcNAc moiety does not substantially hinder the antigen- binding site of the antibody.
  • the core-GlcNAc moiety is connected to the Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the CH domain.
  • the core-GlcNAc moiety is connected to the Fab or Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody. In some embodiments, the core-GlcNAc moiety is connected to a native N-glycosylation site of the antibody. [0235] In some embodiments, the antibody is an IgG, antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG.
  • the antibody is an IgG
  • antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG (e.g., the N297 N-glycosylation site of IgG; EU numbering).
  • the N297 N-glycosylation site is present in the conserved Fc region of the heavy chain of an IgG antibody at asparagine in the region 290-305 (e.g., at N297; EU numbering).
  • the intermediate antibody is of Formula (XXII): wherein: Ab is an antibody that binds to ENPP3; GlcNAc is N-acetylglucosamine; Fuc is fucose; u 3 is 0 or 1; and u 4 is an integer ranging from is 1 to 16. [0238] In some embodiments, u 4 is an integer ranging from 1 to 10. In some embodiments, u 4 is 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, u 4 is 1, 2, 3, 4, 5 or 6. In some embodiments, u 4 is 1, 2, 3 or 4. In some embodiments, u 4 is 2 or 4. In some embodiments, u 4 is 1 or 2. In some embodiments, u 4 is 1.
  • u 4 is 2.
  • the antibody comprises one core-GlcNAc moiety (e.g., u 4 is 1). In some embodiments, the antibody comprises two core-GlcNAc moieties (e.g., u 4 is 2). [0240] In some embodiments, the modified antibody that binds to ENPP3 is obtained by the process outlined in Scheme 1.
  • contacting an intermediate antibody of Formula (XXIII) comprising one terminal-GlcNAc moiety with a compound having the sulture of P" S" A" , in the presence of a glycosyltransferase provides a modified anti-ENPP3 antibody comprising one modified-GlcNAc moiety (e.g., the modified anti-ENPP3 antibody of Formula (XXIIIa)).
  • the modified antibody that binds to ENPP3 is obtained by contacting an intermediate antibody of Formula (XXIV) comprising two terminal-GlcNAc m oieties with a compound having the structure of P" S" A" , in the presence of a glycosyltransferase, provides a modified anti-ENPP3 antibody comprising two modified- GlcNAc moieties (e.g., the modified anti-ENPP3 antibody of Formula (XXIVa)).
  • Scheme 1 Ab GlcNAc Glycosyl Transferase ( XXIII) ( XXIV) (XXIVa) wherein u 3 , Ab, S”, A”, and P” are as defined herein.
  • the antibody glycan to be modified in the process according to the present disclosure comprises a glycan, said glycan comprising a core-GlcNAc moiety, i.e., a GlcNAc moiety that is present at the non-reducing end of the glycan.
  • the glycan comprises one or more saccharide moieties and may be linear or branched.
  • the intermediate antibody upon reacting with endoglycosidase, the intermediate antibody may be formed, which comprises a terminal GlcNAc moiety (e.g., the intermediate antibody of Formula (XXIII) or (XXIV)).
  • the endoglycosidase is endoglycosidase Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof.
  • the endoglycosidase is Endo S or Endo SH, or a combination thereof.
  • the endoglycosidase is Endo SH.
  • step (b) of the process (the formation of the modified antibody that binds to ENPP3 is as shown in FIG.1, wherein the intermediate antibody comprises a monoclonal antibody (mAb) and a terminal GlcNAc moiety (which optionally comprises a fucose (e.g., u 3 is 0 or 1)) on each heavy chain of the monoclonal antibody (mAb).
  • the terminal-GlcNAc moiety is converted into modified-GlcNAc moiety.
  • said conversion may be executed via r eaction of the terminal GlcNAc moiety with the compound of the presence of a glycosyltransferase.
  • the compound of P" S" A" is GalNAz-UDP (e.g., 4- AzGalNAc-UDP).
  • the terminal-GlcNAc moiety is *-GlcNAc- GalNAz or *-GlcNAc(Fuc)-GalNAz, wherein * denotes the attachment to the rest of the modified antibody that binds to ENPP3.
  • the steps of the deglycosylation/trimming step and the formation of the modified antibody that binds to ENPP3 are conducted sequentially.
  • the steps of the deglycosylation/trimming step and the formation of the modified antibody that binds to ENPP3 are conducted simultaneously.
  • the process for the preparation of a modified antibody that binds to ENPP3 is performed in a suitable buffer solution, e.g., buffered saline (e.g. phosphate-buffered saline, Tris-buffered saline), citrate, HEPES, Tris and glycine.
  • the buffer solution is phosphate-buffered saline (PBS) or Tris buffered saline.
  • the buffer solution is phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • the process is performed at a temperature ranging from about 4 to about 50 °C. In some embodiments, the process is performed at a temperature ranging from about 10 to about 45 °C. In some embodiments, the process is performed at a temperature ranging from about 20 to about 40 °C. In some embodiments, the process is performed at a temperature ranging from about 30 to about 37 °C. In some embodiments, the process is performed at a temperature of about 30 °C. In some embodiments, the process is performed at a temperature of 30 °C.
  • the process is performed at a pH value ranging from about 5 to about 9 (e.g., from about 5.5 to about 8.5, from about 6 to about 8, or from about 7 to about 8). In some embodiments, the process is performed at a pH value of about 7.4.
  • the process for the preparation of a modified antibody that binds to ENPP3 is as shown in FIG.2.
  • the process for the preparation of a modified antibody that binds to ENPP3 comprises: (a) contacting a glycoprotein (e.g., an anti-ENPP3 antibody glycan) comprising an antibody that binds to ENPP3 and core-GlcNAc moiety connected to site N297; EU numbering, of the antibody, with endoglycosidase Endo SH, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and (b) contacting the intermediate antibody with 4-AzGalNAc-UDP in the presence of a ⁇ -(l,4)-GalNAcT enzyme, thereby forming the modified anti-ENPP3 antibody comprising the modified-GlcNAc moiety; wherein steps (a) and (b) are conducted concurrently.
  • a glycoprotein e.g., an anti-ENPP3 antibody glycan
  • the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa.
  • the ⁇ -(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa.
  • the ⁇ -(l,4)-GalNAcT enzyme containing an N-terminal 6xHis tag is derived from Trichopulsia ni.
  • the process is conducted in PBS buffer at pH value of about 7.4 and at a temperature of about 30 o C.
  • Endoglycosidases are enzymes that are capable of cleaving internal glycosidic linkages in glycan structures, thereby remodeling or trimming the glycan structure.
  • endoglycosidases can be used for the facile homogenization of heterogeneous glycan populations, when they cleave at predictable sites within conserved glycan regions.
  • One class of endoglycosidases comprises the endo- ⁇ -N-acetylglucosaminidases (EC 3.2.1.96, commonly known as Endo S or ENGases), a class of hydrolytic enzymes that removes N-glycans from glycoproteins by hydrolyzing the ⁇ -l,4-glycosidic bond in the ⁇ , ⁇ '-diacetylchitobiose core (as described in Wong et al. Chem.
  • Endo- ⁇ -N-acetylglucosaminidases are widely found in nature with common chemoenzymatic variants including Endo D, which is specific for paucimannose; Endo A and Endo H, which are specific for high mannose; Endo F subtypes, which range from high mannose to biantennary complex; and Endo M, which can cleave most N-glycan structures (high mannose/complex-type/hybrid-type), except fucosylated glycans, and the hydrolytic activity for the high-mannose type oligosaccharides is significantly higher than that for the complex-and hybrid-type oligosaccharides.
  • these ENGases show specificity toward the distal N-glycan structure and not the protein displaying it, making them useful for cleaving most N-linked glycans from glycoproteins under native conditions.
  • endoglycosidases Fl, F2, and F3 are suitable for deglycosylation of native proteins.
  • the linkage specificities of Endo Fl, F2, and F3 suggest a general strategy for deglycosylation of proteins that may remove all classes of N-linked oligosaccharides without denaturing the protein.
  • biantennary and triantennary structures can be immediately removed by endoglycosidases F2 and F3, respectively.
  • Endo S is a secreted endoglycosidase from Streptococcus pyogenes, and also belongs to the glycoside hydrolase family 18, as disclosed by Collin et al. (EMBO J., 2001, 20, 3046), which is incorporated by reference herein in its entirety.
  • Endo S has a more defined specificity and is specific for cleaving only the conserved N-glycan in the Fc domain of human IgGs (no other substrate has been identified to date), suggesting that a protein-protein interaction between the enzyme and IgG provides this specificity.
  • Endo S49 also known as Endo S2 is described in WO 2013/037824, incorporated by reference herein in its entirety, is isolated from Streptococcus pyogenes NZ131 and is a homologue of Endo S. Endo S49 has a specific endoglycosidase activity on native IgG and cleaves a larger variety of Fc glycans than Endo S.
  • Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer.
  • Endo SH specifically cleaves the N-linked glycans between two N- acetylglucosame (GluNAc) moieties in the core region of the glycan chain.
  • the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, Endo M, Endo A, or a combination thereof.
  • the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, or a combination thereof.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, or Endo S49.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof.
  • endoglycosidases Fl, F2, and F3 are suitable for deglycosylation of native proteins.
  • Endo Fl, F2, and F3 suggest a general strategy for deglycosylation of proteins that may remove all classes of N-linked oligosaccharides without denaturing the protein.
  • biantennary and triantennary structures can be immediately removed by endoglycosidases F2 and F3, respectively.
  • oligo-mannose and hybrid structures can be removed by Endo Fl.
  • Endo S is a secreted endoglycosidase from Streptococcus pyogenes, and also belongs to the glycoside hydrolase family 18, as disclosed by Collin et al.
  • Endo S has a more defined specificity and is specific for cleaving only the conserved N-glycan in the Fc domain of human IgGs (no other substrate has been identified to date), suggesting that a protein-protein interaction between the enzyme and IgG provides this specificity.
  • Endo S49 also known as Endo S2
  • Endo S49 has a specific endoglycosidase activity on native IgG and cleaves a larger variety of Fc glycans than Endo S.
  • Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer. Endo SH specifically cleaves the N-linked glycans between two N- acetylglucosame (GluNAc) moieties in the core region of the glycan chain.
  • GluNAc N- acetylglucosame
  • the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, Endo M, Endo A, or a combination thereof.
  • the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, or a combination thereof.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, or Endo S49.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof.
  • the glycoprotein is an anti-ENPP3 antibody and the oligosaccharide to be trimmed is a diantennary structure of the complex type and is present at the IgG conserved N-glycosylation site at N297, EU numbering
  • the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof.
  • the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof.
  • the glycoprotein is an anti-ENPP3 antibody and the glycan to be trimmed is a diantennary structure of the complex type, and is not present at the IgG conserved N-glycosylation site at N297, EU numbering
  • the endoglycosidase is Endo Fl, Endo F2, Endo F3, or a combination thereof.
  • the endoglycosidase is Endo H, Endo M, Endo A, Endo F1, or a combination thereof.
  • the endoglycosidase when the glycoprotein is an anti-ENPP3 antibody and the oligosaccharide to be trimmed is a high mannose in addition to having a diantennary structure of the complex type is present at the IgG conserved N-glycosylation site at N297, EU numbering, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof. In some embodiments, the endoglycosidase is Endo S or Endo SH. In some embodiments, the endoglycosidase is Endo SH.
  • the endoglycosidase enzyme as defined herein comprises a sequence encoding a tag for ease of purification.
  • said tag includes, but is not limited to, a FLAG-tag, poly(His)-tag, HA-tag, Myc-tag, SUMO-tag, GST-tag, MBP-tag, or a CBP-tag.
  • said tag is a 6xHis tag (SEQ ID NO: 233).
  • said tag is covalently linked to the endoglycoside enzyme at the C- terminus of the enzyme or at an internal residue.
  • said tag is covalently linked to the endoglycoside enzyme at the N-terminus of the enzyme.
  • the Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa.
  • the process to form a modified antibody that binds to ENPP3 comprises treating the deglycosylated/trimmed antibody having an optionally fucosylated terminal N- acetylglucosamine (Gal-NAc) moiety with a compound of Formula S’’(A’’)-P’’ in the presence of a glycosyltransferase to form the modified antibody that binds to ENPP3 having a GlcNAc-S’’(A’’) substituent bonded to the antibody at C1 of the GalNAc moiety via a ⁇ -1,4-O-glycosidic bond.
  • Gal-NAc N- acetylglucosamine
  • the glycosyltransferases is a ⁇ -l,4-galactosyltransferases (4Gal-T), a ⁇ -(1,4)-Acetylgalactosaminyltransferase ( ⁇ -(l,4)-GalNAcT or GalNAcT) or a mutant thereof.
  • ⁇ -(1,4)-Acetylgalactosaminyltransferases ( ⁇ -(l,4)-GalNAcTs or GalNAcTs) have been identified in a number of organisms, including humans, Caenorhabditis elegans (Kawar et al, J. Biol.
  • a ⁇ -(l,4)-GalNAcT is an enzyme that catalyzes the transfer of N- acetylgalactosamine (GalNAc) from uridine diphosphate-GalNAc (UDP-GalNAc, also referred to as GalNAc-UDP) to a terminal GlcNAc moiety of a glycoprotein glycan, wherein C1 of the GalNAc moiety is attached to the antibody via a ⁇ -1,4-O-glycosidic bond.
  • the terminal GlcNAc moiety is fucosylated.
  • the ⁇ -(l,4)-GalNAcT enzyme used in the process of the invention is or is derived from an invertebrate ⁇ -(l,4)-GalNAcT enzyme, such as, for example, is or is derived from a ⁇ -(l,4)-GalNAcT that originates from invertebrate animal species.
  • the ⁇ -(1,4)-GalNAcT enzyme can be or can be derived from any invertebrate ⁇ - (l,4)-GalNAcT enzyme known by one skilled in the art.
  • the ⁇ - (l,4)-GalNAcT enzyme is or is derived from a ⁇ -(l,4)-GalNAcT enzyme that originates from the phylum of Nematoda, such as, for example, of the class of Chromadorea or Secernentea, or of the phylum of Arthropoda, such as, for example, of the class of Insecta.
  • the ⁇ -(l,4)-GalNAcT enzyme is or is derived from a ⁇ - (l,4)-GalNAcT enzyme that originates from Caenorhabditis elegans, Caenorhabditis remanei, Caenorhabditis briggsae, Ascaris suum, Trichoplusia ni, Drosophila melanogaster, Wuchereria bancrofti, Loa loa, Cerapachys biroi, Zootermopsis nevadensis, Camponotus floridanus, Crassostrea gigas or Danaus plexippus, (e.g., from Caenorhabditis elegans, Ascaris suum, Trichoplusia ni or Drosophila melanogaster).
  • the ⁇ -(l,4)-GalNAcT enzyme is, or is derived from, a ⁇ -(l,4)- GalNAcT enzyme that originates from Caenorhabditis elegans, Ascaris suum or Trichoplusia ni.
  • the ⁇ -(l,4)-GalNAcT enzyme is, or is derived from, a ⁇ -(l,4)-GalNAcT enzyme that originates from Trichoplusia ni.
  • the term "derived from” comprises e.g. truncated enzymes, mutant enzymes, enzymes comprising a tag for ease of purification or a combination of these modifications.
  • a ⁇ -(l,4)-GalNAcT enzyme that is derived from a ⁇ - (l,4)-GalNAcT enzyme is herein also referred to as a derived ⁇ -(1,4)-GalNAcT enzyme or a modified ⁇ -(l,4)-GalNAcT enzyme or a ⁇ -(l,4)-GalNAcT mutant enzyme.
  • the derived ⁇ -(l,4)-GalNAcT enzyme is modified by adding additional N- or C- terminal amino acids or chemical moieties or by deleting N- or C- terminal amino acids to increase stability, solubility, activity and/or ease of purification.
  • the ⁇ -(l,4)-GalNAcT enzyme is modified by deleting the N- terminal cytoplasmic domain and transmembrane domain, referred to as a truncated enzyme.
  • a ⁇ -(l,4)-GalNAcT enzyme wherein one or more amino acid has been substituted, added or deleted is herein also referred to as a mutant ⁇ -(l,4)-GalNAcT enzyme or a derived ⁇ -(l,4)-GalNAcT enzyme.
  • the ⁇ -(l,4)-GalNAcT enzyme is modified by deleting the N-terminal cytoplasmic domain and transmembrane domain and mutated by substituting one or more amino acids.
  • a substitution of one or more amino acids is herein also referred to as a mutation.
  • An enzyme comprising one or more substituted amino acids is also referred to as a mutant enzyme.
  • the enzyme when the glycosyltransferase is a ⁇ -(l,4)-GalNAcT enzyme or truncated ⁇ -(l,4)-GalNAcT enzyme, the enzyme further comprises one or more mutations.
  • these mutations include, but are not limited to, substitution of the isoleucine (He, also referred to as I) at position 257 by leucine (Leu, also referred to as L), methionine (Met, also referred to as M), or alanine (Ala, also referred to as A).
  • substitution of the methionine (Met, also referred to as M) at position 312 by histidine (His, also referred to as H) is also included.
  • the numbering of amino acid position is herein based on the numbering of amino acid position in the wild-type ⁇ -(l,4)-GalNAcT enzyme.
  • a ⁇ -(l,4)-GalNAcT enzyme is, for example, a truncated enzyme
  • the number used herein to indicate the position of an amino acid substitution corresponds to the numbering of amino acid position in the corresponding wild-type ⁇ -(l,4)-GalNAcT enzyme.
  • the glycosyltransferase is a ⁇ (l,4)-GalT enzyme comprising a mutant catalytic domain.
  • a catalytic domain may have an amino acid sequence as found in a wild-type enzyme or have an amino acid sequence that is different from that of a wild-type sequence.
  • a catalytic domain having an amino acid sequence that is different from a wild-type sequence is herein referred to as a mutant catalytic domain.
  • the mutation may comprise a single amino acid change (for example, a point mutation), or multiple amino acids changes (for example, 1 to 10, or 1 to 6, or 1, 2, 3 or 4, or 1 or 2 amino acids), or a deletion or insertion of one or more amino acids (for example, 1 to 10, or 1 to 6, or 1, 2, 3 or 4,or 1 or 2) amino acids.
  • said mutant catalytic domain may be present in a full-length enzyme, for example, ⁇ (l,4)- galactosyltransferase or ⁇ (l,3)-N-galactosyltransferase, but also in a polypeptide fragment or a recombinant polypeptide comprising said mutant catalytic domain, optionally linked to additional amino acids.
  • GalT ⁇ (l,4)-galactosyltransferase I is herein referred to as GalT.
  • Such mutant GalT catalytic domains are disclosed in, for example, WO 2004/063344, which is incorporated by reference herein in its entirety. WO 2004/063344 also discloses Tyr- 289 mutants of GalT and their methods of preparation. These mutants are referred to as Y289L, Y289N or Y289I.
  • the GalT mutant catalytic domain is Y289L, Y289N, Y289I, Y284L, or R228K.
  • the GalT mutant catalytic domain is Y289L.
  • the GalT Y289F, GalT Y289M, GalT Y289V, GalT Y289G, GalT Y289I, GalT Y289A, GalT Y289N, and GalT Y289L mutants may be produced via site-directed mutagenesis processes, described in, for example, WO2004063344, Qasba et al, Prot. Expr. Pur.2003, 30, 219 and Qasba et al, J. Biol. Chem.2002, 277, 20833 (all incorporated by reference herein in their entirety).
  • the tyrosine amino acid (Y) at position 289 is replaced by a phenyl alanine (F) amino acid
  • said tyrosine is replaced by a methionine (M) amino acid
  • M methionine
  • V valine
  • G glycine
  • I isoleucine
  • I isoleucine
  • Y289A by an analine (A) amino acid.
  • the ⁇ -(l,4)-GalNAcT enzyme comprises a sequence encoding a tag for ease of purification.
  • said tag includes, but is not limited to, a FLAG-tag, poly(His)-tag, HA-tag, Myc-tag, SUMO-tag, GST-tag, MBP-tag, or a CBP- tag.
  • said tag is a 6xHis tag (SEQ ID NO: 233).
  • said tag is covalently linked to the ⁇ -(l,4)-GalNAcT enzyme at the C- terminus of the enzyme.
  • said tag is covalently linked to the ⁇ -(l,4)- GalNAcT enzyme at the N-terminus of the enzyme.
  • ⁇ -(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa.
  • the ⁇ -(l,4)-GalNAcT enzyme containing an N-terminal 6xHis tag (SEQ ID NO: 233) is derived from Trichopulsia ni.
  • the molecule of P”-S”-A for use in the process of preparing a modified antibody that binds to ENPP3 of the present disclosure, may be any sugar derivative nucleotide that is a substrate for a suitable galactosyltransferase catalyst.
  • S”-A is a sugar derivative moiety, wherein: [0296] S” is a sugar or a derivatized sugar; and A” is a functional group being capable of forming a covalent bond with a functional group of the Linker-Drug moiety.
  • A” is an azido, keto, or alkynyl moiety. In some embodiments, A” is an azido or keto moiety. In some embodiments, A” is an azido moiety. In some embodiments, A” is -N 3 . In some embodiments, A” is a keto moiety. [0298] In some embodiments, A” is -[C(R 8k ) 2 ] x2 C(O)R 9k , wherein: R 9k is methyl or optionally substituted C 2-24 alkyl; each R 8k independently is a hydrogen, halogen, or R 9k ; and x 2 is an integer ranging from 0 to 24.
  • x 2 is an integer ranging from 0 to 10. In some embodiments, x 2 is 0, 1, 2, 3, 4, 5, or 6. [0300] In some embodiments, each R 8k is hydrogen. [0301] In some embodiments, A” is an alkynyl moiety. In some embodiments, A” is terminal alkynyl, cycloalkynyl, or heterocycloalkynyl moiety. In some embodiments, A” is terminal alkynyl moiety. In some embodiments, A” is cycloalkynyl moiety. In some embodiments, A” is heterocycloalkynyl moiety.
  • A” is -[C(R 8k ) 2 ] x2 -C ⁇ C-R 8k group, wherein R 8k and x 2 are as defined herein.
  • A” is -[CH 2 ] x2 -C ⁇ CH.
  • S”-A is derived from a sugar or a derivatized sugar, e.g., an amino sugar or an otherwise derivatized sugar.
  • examples of sugars and derivatized sugars include, but are not limited to, galactose (Gal), mannose (Man), glucose (Glc), glucuronic acid (Gcu), and fucose (Fuc).
  • amino sugar is a sugar wherein a hydroxyl (OH) group is replaced by an amine group.
  • amino sugars include, but are not limited to, N-acetylglucosamine (GlcNAc), and N- acetylgalactosamine (GalNAc).
  • examples of otherwise derivatized sugars include, but are not limited to, glucuronic acid (Gcu), and N-acetylneuraminic acid (sialic acid).
  • S”-A is derived from galactose (Gal), mannose (Man), N- acetylglucosamine (GlcNAc), glucose (Glc), N-acetylgalactosamine (GalNAc), glucuronic acid (Gcu), fucose (Fuc), or N-acetylneuraminic acid (sialic acid).
  • S”-A is derived from GlcNAc, Glc, Gal, or GalNAc.
  • S”-A is derived from GlcNAc.
  • S”-A is derived from Glc.
  • S”-A is derived from Gal or GalNAc. In some embodiments, S”-A” is derived from Gal. In some embodiments, S”-A” is derived from GalNAc.
  • the functional group A” may be attached to S” in various ways. [0306] In some embodiments, A” is directly attached to the carbon atom at C2, C3, C4, or C6 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position). [0307] In some embodiments, S” is a fucose or a derivatized fucose, which lacks any hydroxyl C6 position.
  • A” when A” is attached to C6 position of the fucose or derivatized fucose, A” is directly attached to the carbon atom at the C6 position.
  • A” is an azido moiety, and A” is attached to C2, C4, or C6 position of the sugar or derivatized sugar of S”.
  • A” is an azido moiety, and A” is directly attached to the carbon atom at C2, C3, C4 or C6 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position).
  • S”-A” is 6- azidofucose (6-AzFuc).
  • A” is an azido moiety
  • A” is attached to the N-acetyl moiety of an amino sugar or a derivatized amino sugar (e.g., by replacing the acetyl moiety with an azidoacetyl moiety).
  • S”-A is 2- azidoacetamidogalactose (GalNAz), 6-azido-6-deoxygalactose (6-AzGal), 6-azido-6- deoxy-2-acetamidogalactose (6-AzGalNAc), 4-azido-4-deoxy-2- acetamidogalactose (4- AzGalNAc), 6-azido-6-deoxy-2-azidoacetamidogalactose (6- AzGalNAz), 2- azidoacetamidoglucose (GlcNAz), 6-azido-6-deoxyglucose (6-AzGlc), 6-azido-6-deoxy- 2-acetamidoglucose (6-AzGlcNAc), 4-azido-4-deoxy-2- acetamidoglucose (4- AzGlcNAc), or 6-azido-6-deoxy-2-azido
  • S”-A is GalNAz, 4-AzGalNAc, GlcNAz, or 6-AzGlcNAc.
  • P”-S”-A is a compound of Formula (XXIVb), (XXXIVc), or (XXIVd), or a salt thereof.
  • A” keto, and A’’ is directly attached to the carbon atom at C2 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position).
  • A” is attached to the nitrogen atom of an amino sugar or derivatized amino sugar, e.g., a C2-derivatized amino sugar.
  • the derivatized amino sugar comprises a moiety of -NC(O)-R 9k , wherein R 9k is methyl or optionally substituted C 2-24 alkyl (e.g., ethyl).
  • R 9k is ethyl.
  • S”-A is 2-deoxy-(2-oxopropyl)-galactose (2-keto-Gal), 2-N- propionyl-galactosamine (2-N-propionylGal-NAc), 2-N-(4-oxopentanoyl)-galactosamine (2-N-Lev-Gal), or 2-N-butyryl-galactosamine (2-N-butyryl-GalNAc).
  • S”-A is 2- ketoGalNAc or 2-N-propionyl-GalNAc.
  • P”-S”-A is a compound of Formula (XXIVe) or (XXIVf), or a salt thereof.
  • A” is terminal alkynyl, cycloalkynyl, or heterocycloalkynyl. In some embodiments, A” is attached to a C2-derivatized amino sugar of S”.
  • S”-A is 2-(but-3-ynoic acid amido)-2-deoxy-galactose.
  • P”-S”-A is a compound of Formula (XXIVg) or a salt thereof.
  • P”-S”-A is a compound of Formula (XXIVd) or a salt thereof.
  • compounds of P”-S”-A” may be synthesized according to various methods known in the art.
  • the compound is synthesized by linking a nucleoside monophosphate or a nucleoside diphosphate P” to a sugar derivative , e.g., as disclosed in Wang et al. (Chem. Eur. J. 16:13343-13345 (2010)), Piller et al. (ACS Chem. Biol.7:753 (2012)), Piller et al. (Bioorg. Med. Chem. Lett.
  • P is a nucleoside mono- or diphosphate.
  • P” is uridine diphosphate (UDP), guanosine diphosphate (GDP), thymidine diphosphate (TDP), cytidine diphosphate (CDP), or cytidine monophosphate (CMP).
  • P” is uridine diphosphate (UDP).
  • P”-S”-A is a compound of Formula (XXIVb), (XXIVc), (XXIVd), (XXIVe), (XXIVf), or (XXIVg): (XXIVe) (XXIVf) (XXIVg) or a salt thereof, wherein: R 9k is a C 2-24 alkyl group.
  • P”-S”-A” is GalNAz-UDP (e.g., Formula (XXIVb)), 6- AzGal-UDP (e.g., Formula (XXIVc)), 6-AzGalNAc-UDP (e.g., Formula (XXIVd)), 4- AzGalNAz-UDP, 6-AzGalNAz-UDP, 6- AzGlc-UDP, 6-AzGlcNAz-UDP, 2-ketoGal- UDP (e.g., Formula (XXIVe)), 2-N-propionylGalNAc-UDP (e.g., Formula (XXIVf), wherein R 9k is ethyl), or 2-(but-3-ynoic acid amido)-2-deoxy-galactose-UDP (e.g., Formula (XXIVg)).
  • GalNAz-UDP e.g., Formula (XXIVb)
  • 6- AzGal-UDP e.g., Formula
  • P”-S”-A is GalNAz-UDP or 4-AzGalNAc-UDP.
  • P”-S”-A is a compound of Formula (XXIVb) or (XXIVd).
  • the syntheses of GalNAz-UDP (e.g., Formula (XXIVb)) and 6-AzGalNAc-UDP (e.g., Formula (XXIVd)) are disclosed in Piller et al. (Bioorg. Med. Chem. Lett.15:5459-5462 (2005)) and Wang et al. (Chem. Eur. J.16:13343-13345 (2010)), each of which is incorporated by reference herein in its entirety.
  • P”-S”-A is 4-AzGalNAc-UDP.
  • P”- S”-A is a compound of Formula (XXIVd) or a salt thereof.
  • the synthesis of 2-ketoGal- UDP (XXIVe) is disclosed in Qasba et al. (J. Am. Chem. Soc.125:16162 (2003)), and in the supporting information thereof, both of which are incorporated by reference herein in their entireties.
  • the synthesis of 2-(but-3-ynoic acid amido)-2-deoxy-galactose-UDP is disclosed in PCT Appl’n Pub. No.
  • ADC antibody-drug conjugate
  • ADC comprising one or more Linker-Drug moieties covalently bonded to an antibody or antigen binding fragment thereof that binds to ENPP3 (Ab), wherein each Linker-Drug moiety comprises a multifunctional linker that connect Ab to one or more drugs (e.g., an auristatin).
  • an ADC has the structure: Ab-(L-(L A -D) n ) m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and L A , L A is a divalent moiety connecting L to D, D is a drug.
  • n is an integer 1, 2, or 3 and m is an integer 1, 2, or 3.
  • the antibody comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31.
  • the drug (D) is an auristatin.
  • the ADC provided herein has certain advantages over other ADCs including increased anti-tumor activity and decreased toxicity.
  • the drug is an auristatin (i.e., D is an auristatin).
  • DAR drug-to-antibody ratio
  • the present disclosure provides an ADC composition comprising a mixture of ADCs, wherein each antibody in the mixture is identical, except that the number of drugs or drug-linkers that are conjugated to each antibody can vary.
  • the antibody drug conjugate (ADC) comprises an antibody that binds to human and cynomolgus monkey ENPP3 proteins.
  • the ADC comprises an antibody that binds to ENPP3 and does not bind to cells expressing other forms of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family members.
  • ADCs comprising anti-ENPP3 antibodies that bind to the extracellular region of ENPP3.
  • the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3.
  • the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof is human, chimeric or humanized.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is human.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is chimeric. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is humanized. [0332] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising a Fc region. In some embodiments, the anti-ENPP3 Fc region has been mutated to abolish interactions with Fc ⁇ receptors. In some embodiments, the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody comprises an L234A mutation. In some embodiments, the antibody comprises an L235 mutation. In some embodiments, the antibody comprises a D265S mutation.
  • the antibody comprises L234A, L235A, and D265S mutations.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 1, 32, 38, 44, 50, or 56, a CDRH2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 2, 33, 39, 45, 51, or 57, a CDRH3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 3, 34, 40, 46, 52, or 58, a CDRL1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 4, 35, 41, 47, 53, or 59, a CDRL2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 5, 36, 42, 48, 54, or 60, and a CDRL3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 6, 37,
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. [0342] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:22 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 27.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27. [0343] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:23 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 28.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28. [0344] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:24 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 29.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 29. [0345] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:25 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. [0346] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:26 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 31.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 31. [0347] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7.
  • VH variable heavy chain domain
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31.
  • the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31.
  • VH variable heavy chain domain
  • VL variable light chain domain
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:3 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:7.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:5; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:6 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:8.
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:32; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:33; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:22.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:35; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:36; and a CDR3-L comprising the amino acid s equence set forth in S EQ ID NO:37 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:27.
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:38; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:39; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:40 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:23.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:41; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:42; and a CDR3-L comprising the amino acid s equence set forth in S EQ ID NO:43 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:28.
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:44; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:45; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:46 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:24.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:47; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:48; and a CDR3-L comprising the amino acid s equence set forth in S EQ ID NO:49 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:29.
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:50; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:51; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:52 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:25.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:53; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:54; and a CDR3-L comprising the amino acid s equence set forth in S EQ ID NO:55 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:30.
  • the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:56; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:57; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:58 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:26.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:59; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:60; and a CDR3-L comprising the amino acid s equence set forth in S EQ ID NO:61 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:31.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:1, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:2 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:3.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:32, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:33 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:34.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:38, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:39 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:40.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:44, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:45 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:46.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:50, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:51 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:52.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:56, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:57 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:58.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:4, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:5 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:6.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:35, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:36 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:37.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:41, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:42 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:43.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:47, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:48 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:49.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:53, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:54 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:55.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:59, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:60 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:61.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:10 or 17-21.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:12, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:23, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:18.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:14, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:19.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:15, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:20.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16 and the light chain comprising the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:9 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:12 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 17.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:13 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 18.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:14 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 19.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:15 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 20.
  • the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:16 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 21.
  • the ADC comprises an antibody or antigen binding fragment thereof comprising a modified glycan at position N296 according to SEQ ID NO:9 (position N297 according to EU numbering).
  • a modified glycan is a non-native glycan.
  • the modified glycan is the native glycans on the antibody Fc at site N296 according to SEQ ID NO:9 (position N297 according to EU numbering).
  • the ADC comprises an antigen binding protein in any of the foregoing embodiments in any form.
  • the ADC may comprise an antigen binding protein described in any of the above embodiments can be, for example, a monoclonal antibody, , a human, humanized or chimeric antibody, and antigen binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library.
  • the antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
  • the ADC comprises an antibody with one or several amino acids (e.g., 1, 2, 3 or 4) at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivitized in some or all of the molecules in a composition.
  • one specific example of such a modification is an antibody or antigen binding fragment thereof in which the carboxy terminal lysine of the heavy chain is missing (e.g., as part of a post-translational modification).
  • any of the sequences described herein include post-translational modifications to the specified sequence during expression of the antibody or antigen binding fragment thereof in cell culture (e.g., a CHO cell culture).
  • A. Drugs and Linkers [0388]
  • the anti-ENPP3 antibody or modified anti-ENPP3 antibody is conjugated to one or more Linker-Drug moieties.
  • the anti-ENPP3 antibody or modified anti-ENPP3 antibody is conjugated to a m number of Linker-Drug moieties, wherein m is 1, 2 or 3.
  • m is 1 or 2.
  • m is 1.
  • m is 2.
  • m is 3.
  • each Linker-Drug moiety is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. In some embodiments, Linker-Drug moiety is attached at position 296 according to SEQ ID NO:9 (position N297 according to EU numbering). In some embodiments, Linker-Drug moiety is attached at position 296 of SEQ ID NO:9 (position N297 according to EU numbering). [0389] In some embodiments, each Linker-Drug moiety comprises a multifunctional linker that connect Ab to one or more drugs (D).
  • each Linker-Drug moiety has the structure -L-(L A -D) n , in which the multifunctional linker comprises L A connecting each D directly to the rest (L) of the multifunctional linker.
  • each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering.
  • L is attached at position 296 at SEQ ID NO:9.
  • L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan.
  • L covalently bonds to Ab via a glycan on a Fc constant region of the Ab.
  • L comprises , wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to L A .
  • L comprises , wherein the wavy line denotes attachment to the glycan and * denotes attachment to L A .
  • Cleavable Bonds [0391]
  • the L A -D moiety can comprise a cleavable bond. Exemplary cleavable bonds are described in WO2018098269 and WO2021/142199, which are incorporated herein in their entireties by reference.
  • the L A -D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect.
  • Functional groups for forming moieties comprising a cleavable bond can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone moieties, hydroxyl amine groups to form oxime moieties, carboxylic or amino groups to form amide moieties, carboxylic or hydroxy groups to form ester moieites, aminocarbonyl groups or oxycarbonyl to form carbamate groups, and sugars to form glycosidic bonds.
  • L A comprises a disulfide bond that is cleavable through disulfide exchange, an acid-labile bond that is cleavable at acidic pH, and/or bonds that are cleavable by hydrolases (e.g., peptidases, esterases, and glucuronidases).
  • L A comprises a carbamate group (i.e., -O-C(O)- NR-, in which R is H or alkyl or the like).
  • the cleavable bond(s) can be cleavable by other mechanisms.
  • the cleavable bond(s) can be enzymatically cleaved by one or more enzymes, including a tumor- associated protease, to liberate the drug(s), which in one embodiment is protonated in vivo upon release to provide a drug.
  • L A can comprise one or more amino acids.
  • each amino acid in L A can be natural or unnatural and/or a D- or L- isomer provided that there is a cleavable bond.
  • L A comprising an alpha, beta, or gamma amino acid that can be natural or non-natural.
  • L A comprises 1 to 12 (e.g., 1 to 6, or 1 to 4, or 1 to 3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) amino acids in contiguous sequence.
  • L A can comprise only natural amino acids.
  • L A can comprise only non-natural amino acids.
  • L D can comprise a natural amino acid linked to a non-natural amino acid.
  • L D can comprise a natural amino acid linked to a D-isomer of a natural amino acid.
  • L A comprises a dipeptide such as -Val-Cit-, -Phe-Lys- or -Val- Ala-.
  • L A comprises a monopeptide, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, a decapeptide, an undecapeptide or a dodecapeptide unit.
  • L A comprises a peptide (e.g., of 1 to 12 amino acids), which is conjugated directly to one or more drugs.
  • the peptide is a single amino acid or a dipeptide.
  • each amino acid in L A is independently selected from alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino-heterocyclo- alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof.
  • each amino acid is independently selected from alanine, ⁇ - alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, citrulline and selenocysteine.
  • each amino acid is independently selected from the group consisting of alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, citrulline and derivatives thereof.
  • each amino acid is selected from the proteinogenic or the non- proteinogenic amino acids.
  • each amino acid in L A can be independently selected from L- or D-isomers of the following amino acids: alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aniinoalkanedioic acid, heterocyclo- carboxylic acid, citrulline, statine, diaminoalkanoic acid, valine, citrulline or derivatives thereof.
  • L A can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, e.g., a tumor-associated protease.
  • L A is , wherein p is an integer from 1 to 25, q is an integer from 1 to 25, wherein the L D -D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L.
  • p is 4.
  • q is 8.
  • the L D -D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect.
  • Functional groups for forming moieties comprising a cleavable bond can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone moieties, hydroxyl amine groups to form oxime moieties, carboxylic or amino groups to form amide moieties, carboxylic or hydroxy groups to form ester moieties, aminocarbonyl groups or oxycarbonyl to form carbamate groups, and sugars to form glycosidic bonds.
  • L D comprises a disulfide bond that is cleavable through disulfide exchange, an acid-labile bond that is cleavable at acidic pH, and/or bonds that are cleavable by hydrolases (e.g., peptidases, esterases, and glucuronidases).
  • L D comprises an aminocarbonyl group (i.e., - C(O)-NR-, in which R is H or alkyl or the like).
  • the cleavable bond(s) can be cleavable by other mechanisms.
  • the cleavable bond(s) can be enzymatically cleaved by one or more enzymes, including a tumor- associated protease, to liberate the drug(s), which in one embodiment is protonated in vivo upon release to provide a drug.
  • L D can comprise one or more amino acids.
  • each amino acid in L D can be natural or unnatural and/or a D- or L- isomer provided that there is a cleavable bond.
  • L D comprising an alpha, beta, or gamma amino acid that can be natural or non-natural.
  • L D comprises 1 to 12 (e.g., 1 to 6, or 1 to 4, or 1 to 3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) amino acids in contiguous sequence.
  • L D can comprise only natural amino acids.
  • L D can comprise only non-natural amino acids.
  • L D can comprise a natural amino acid linked to a non-natural amino acid.
  • L D can comprise a natural amino acid linked to a D-isomer of a natural amino acid.
  • L D comprises a peptide (e.g., of 1 to 12 amino acids), which is conjugated directly to one or more drugs.
  • the peptide is a single amino acid or a dipeptide.
  • each amino acid in L D can be independently selected from L- or D-isomers of the following amino acids: alanine, ⁇ -alanine, arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aminoalkanoic acid, heterocyclo- carboxylic acid, citrulline, statine, diaminoalkanoic acid, valine, citrulline or derivatives thereof.
  • each amino acid in L D is independently cysteine, homocysteine, penicillamine, ornithine, lysine, serine, threonine, glycine, glutamine, alanine, aspartic acid, glutamic acid, selenocysteine, proline, glycine, isoleucine, leucine, methionine, valine, citrulline or alanine.
  • L D can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, e.g., a tumor-associated protease.
  • conjugates of the disclosure comprise one or more occurrences of D, wherein D is a drug (e.g., an auristatin drug moiety), wherein the one or more occurrences of D may be the same or different.
  • D is an auristatin.
  • auristatins include auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin.
  • the auristatin is auristatin F hydroxypropylamide (AF HPA).
  • AF HPA auristatin F hydroxypropylamide
  • suitable auristatins are also described in U.S. Publication Nos.2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/117,531, WO 2005/081711, WO 04/010957; WO 02/088172 and WO01/24763, and U.S. Pat. Nos.
  • the auristatin drug moiety is or comprises a compound of Formula (XIIa), (XIIc), or (XIIe):
  • the auristatin drug moiety (D) is or comprises: [0423] In some embodiments, L A -D is
  • one or more occurrences of the antibody that binds to ENPP3 or modified antibody that binds to ENPP3 is attached to the Linker-Drug moiety, wherein the one or more occurrences of antibody that binds to ENPP3 or modified antibody that binds to ENPP3 may be the same or different.
  • one or more Linker-Drug moieties that comprises one or more occurrences of D are connected to one antibody that binds to ENPP3 or modified antibody that binds to ENPP3.
  • each Linker-Drug moiety has the structure -L-(L A -D) n as described herein and an ADC has the structure Ab-(L-(L A -D) n ) m , wherein m is an integer ranging from about 1 to about 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. [0426] In some embodiments, the targeting ligands, the linkers and the drug or prodrug fragments described herein can be assembled into the conjugate or scaffold of the disclosure, for example according to the disclosed techniques and methods. Therapeutic and targeting conjugates of the disclosure, and methods for producing them, are described below by way of non-limiting example.
  • the disclosure also relates to a Linker-Drug moiety comprising or the cysteine engineered antibody that binds to ENPP3 at least two moieties, wherein each moiety is capable of conjugation to a thiol group in an antibody that binds to ENPP3 so as to form a protein-Linker-Drug conjugate.
  • a Linker-Drug moiety comprising or the cysteine engineered antibody that binds to ENPP3 at least two moieties, wherein each moiety is capable of conjugation to a thiol group in an antibody that binds to ENPP3 so as to form a protein-Linker-Drug conjugate.
  • one or more thiol groups of the antibody that binds to ENPP3 or the cysteine engineered antibody that binds to ENPP3 are produced by reducing a protein.
  • the one or more thiol groups of the antibody that binds to ENPP3or the cysteine engineered antibody that binds to ENPP3 may then react with one or more Linker-Drug moieties that are capable of conjugation to a thiol group from the antibody that binds to ENPP3, or the cysteine engineered antibody that binds to ENPP3 with the Linker-Drug moiety.
  • the at least two moieties connected to the antibody that binds to ENPP3 or the cysteine engineered antibody that binds to ENPP3 are maleimide groups.
  • the antibodies may be activated for conjugation with Linker- Drug moiety by treatment with a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride).
  • a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride).
  • full length, monoclonal antibodies can be reduced with an excess of TCEP to reduce disulfide bonds (e.g., between the cysteine present in the corresponding parent antibodies or the cysteine engineered antibody) to yield a reduced form of the antibody.
  • the newly introduced and unpaired cysteine may remain available for reaction with Linker-Drug moiety to form the antibody conjugates of the present disclosure.
  • an excess of Linker-drug moiety is added to effect conjugation and form the ADC, and the conjugation mixture is purified to remove excess Linker-drug intermediate and other impurities.
  • Conjugates disclosed herein can be purified (i.e., removal of any starting materials) by extensive diafiltration. If necessary, additional purification by size exclusion chromatography can be conducted to remove any aggregated conjugates.
  • the conjugates as purified typically contain less than 5% (e.g., ⁇ 2% w/w) aggregated conjugates as determined by SEC; less than 0.5% (e.g., ⁇ 0.1% w/w) free (unconjugated) drug as determined by RP-HPLC; less than 1% drug carrying-peptide-containing scaffolds as determined by SEC and less than 2% (e.g., ⁇ 1% w/w) unconjugated antibody that binds to ENPP3 as determined by HIC-HPLC.
  • 5% e.g., ⁇ 2% w/w
  • aggregated conjugates as determined by SEC
  • 0.5% e.g., ⁇ 0.1% w/w
  • free (unconjugated) drug as determined by RP-HPLC
  • less than 1% drug carrying-peptide-containing scaffolds as determined by SEC and less than 2% (e.g., ⁇ 1% w/w) unconjugated antibody that binds to ENPP3 as determined by
  • modified ENPP3 ADCs of the present disclosure may be obtained by reacting the modified antibody that binds to ENPP3 of the present disclosure with a Linker-Drug moiety comprising a functional group (e.g., W P ), which is capable of forming one or more covalent bond(s) with the functional group A” of the modified- * G lcNAc moiety, GlcNAc S" A" , in the modified antibody that binds to ENPP3.
  • W P comprises alkynyl e.g., cycloalkynyl, heterocycloalkynyl, or terminal alkynyl.
  • the functional group A” of the modified antibody that binds to ENPP3 is azido, keto, or alkynyl. In some embodiments, the functional group A” of the modified antibody that binds to ENPP3 is azido. In some embodiments, the azido functional group A” of the modified anti-ENPP3 antibody reacts with the alkynyl of W P (e.g., the cycloalkynyl, heterocycloalkynyl, or terminal alkynyl) of the Linker-Drug moiety to form a triazole moiety (e.g., via a cycloaddition reaction).
  • W P e.g., the cycloalkynyl, heterocycloalkynyl, or terminal alkynyl
  • W P of the Linker-Drug moiety comprises a terminal alkynyl, and the cycloaddition reaction may be performed in the presence of a catalyst (e.g., a Cu(I) catalyst).
  • W P of the Linker-Drug moiety comprises cycloalkynyl or heterocycloalkynyl (e.g., strained cycloalkynyl or heterocycloalkynyl).
  • W P of the Linker-Drug moiety comprises a strained cycloalkynyl or heterocycloalkynyl
  • the cycloaddition reaction may be performed in the presence or absence of a catalyst.
  • the cycloaddition reaction may occur spontaneously by a reaction called strain-promoted azide-alkyne cycloaddition (SPAAC), which is known in the art as “metal-free click chemistry”.
  • SPAAC strain-promoted azide-alkyne cycloaddition
  • the strained cycloalkynyl or heterocycloalkynyl is as described herein.
  • the functional group A” of the modified antibody that binds to ENPP3 and W P of the Linker-Drug moiety forms a triazole moiety.
  • the functional group A” of the modified antibody that binds to ENPP3 and W P of the Linker-Drug moiety forms a triazole moiety of Formula wherein * denotes a direct or indirect attachment to the rest of the modified anti-ENPP3 antibody; and ** indicates attachment to the rest of the Linker-Drug moiety.
  • the formed triazole moiety in ADC may be resistant to hydrolysis and/or other degradation pathways.
  • an aldehyde or ketone-modified antibody that binds to ENPP3 of the present disclosure is reacted with a Linker-Drug moiety comprising a hydroxylamine or a hydrazine, the resulting oxime or hydrazone moiety in the modified ENPP3 ADC may be relatively inert at neutral conditions.
  • the modified antibody that binds to ENPP3 and modified ENPP3 ADC of the present disclosure may be synthesized by practical synthetic routes, as the process for introducing the functional group A” (e.g., azido, keto, or alkynyl) into the antibody is straightforward and generally applicable.
  • the functional group A e.g., azido, keto, or alkynyl
  • a site-specific ENPP3 ADC of the present disclosure is obtained by a process comprising reacting a modified antibody that binds to ENPP3with a Linker-Drug moiety, wherein: [0443] the Linker-Drug moiety comprises cycloalkynyl or heterocycloalkynyl, [0444] the modified antibody that binds to ENPP3, prior to conjugation, comprises an * antibody that binds to ENPP3 and a modified GlcNAc moiety of GlcNAc S" A" attached to an antibody that binds to ENPP3 via the C1 position of the GlcNAc; GlcNAc is N-acetylglucosamine; S” is a sugar or a derivatized sugar; and A” is azido.
  • A” is cycloalkynyl or heterocycloalkynyl. In some embodiments, A” is cycloalkynyl. In some embodiments, A” is heterocycloalkynyl. [0446] In some embodiments, A” is strained cycloalkynyl or heterocycloalkynyl. In some embodiments, A” is strained cycloalkynyl. In some embodiments, A” is strained heterocycloalkynyl.
  • a site-specific an ENPP3 ADC of the present disclosure is obtained by a process comprising the steps of: (a) contacting an intermediate antibody of Formula (XXII); wherein: Ab is an antibody that binds to ENPP3; GlcNAc is N-acetylglucosamine; Fuc is fucose; u3 is 0 or 1; and d13 is an integer ranging from 1 to 12; w ith a compound , wherein: S” is a sugar or a derivatized sugar; A” is azido; and P is uridine diphosphate (UDP), guanosine diphosphate (GDP), or cytidine diphosphate (CDP); in the presence of an galactosyltransferase, thereby forming a modified antibody that * b inds to ENPP3 comprising the modified-GlcNAc moiety, GlcNAc S" A" , (optionally, the modified-
  • the process for preparing a site-specific ENPP3 ADC is as depicted in FIGs.3A-3B.
  • the modified antibody that binds to ENPP3 comprising an azido at each amino acid N297, EU numbering, of the antibody is conjugated with a Linker-drug moiety comprising strained cycloalkynyl or heterocycloalkynyl by metal-free click chemistry to form the site-specific antibody-drug conjugate of the present disclosure.
  • the modified antibody that binds to ENPP3 comprises at least one azido moiety and the Linker-drug moiety comprises a strained cycloalkynyl
  • the presence of a copper catalyst is not necessary for the cycloaddition reaction between the azido in the modified antibody and the strained cycloalkynyl or heterocycloalkynyl of the Linker-Drug moiety.
  • the cycloaddition reaction proceeds in the absence of a copper catalyst, which may alleviate several possible disadvantages of using a copper catalyst in the process.
  • a Cu(I) catalyst is generally required in the cycloaddition of an azido moiety of an antibody and a terminal alkyne moiety.
  • extensive optimization and fine-tuning of conditions may be required to find the optimal parameters for efficient conversion. Nevertheless, even under such conditions, the concomitant formation of reactive oxygen species cannot always be fully avoided, which in turn may induce oxidative damage to the antibody/protein (e.g., oxidation of methionine, histidine, cysteine or disulfide bonds).
  • Other protocols have employed Cu(I) sources such as CuBr for labeling fixed cells and synthesizing glycoproteins.
  • the modified antibody that binds to ENPP3 comprising an azido is conjugated with a Linker-Drug moiety comprising strained cycloalkynyl or heterocycloalkynyl (e.g., by metal-free click chemistry).
  • the azido moiety of the modified antibody that binds to ENPP3 and the strained cycloalkynyl or heterocycloalkynyl of the Linker- Drug moiety forms a triazole moiety of Formula XXXV), wherein * denotes a direct or indirect attachment to the rest of the modified antibody; and ** indicates attachment to the rest of the Linker-Drug moiety.
  • the ENPP3 ADC of the present disclosure comprises one or more occurrences of D, wherein each D independently is a drug (e.g., an auristatin drug moiety), wherein the one or more occurrences of D may be the same or different.
  • one or more specific sites of the antibody that binds to ENPP3 is attached to the Linker-Drug moiety, wherein the Linker-Drug moieties attached to the one or more specific sites may be the same or different.
  • one or more Linker-Drug moieties that comprises one or more occurrences of D are attached to one anti-ENPP3 antibody.
  • D is or comprises an auristatin drug moiety, for example an auristatin, for example auristatin F (AF), for example auristatin F hydroxypropylamide (AF-HPA).
  • the modified antibody that binds to ENPP3 is modified at the amino acid N297, EU numbering.
  • the total number of specific bonds formed between the Linker- Drug moiety and the modified anti-ENPP3 antibody (or total number of attachment points) is 12 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 10 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 8 or less.
  • the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 is 6 or less. In some embodiments, the total number of specific bonds formed between the Linker- Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 4 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 2 or less. [0459] In some embodiments, the total number of specific bonds formed between the Linker- Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 2.
  • the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 is 1.
  • the modified antibody that binds to ENPP3, linker, or drug described herein may be assembled into the conjugate or scaffold of the present disclosure according to various techniques and methods known in the art. The conjugate of the present disclosure, and method for producing the conjugate, are described herein (e.g., by way of non-limiting embodiments and examples).
  • the total number of bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 12 or less.
  • the ratio between the Linker-Drug moiety and the modified antibody that binds to ENPP3 is greater than 1:1 and less than or equal to 12:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 12:1, about 11:1, about 10;1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is between 2:1 and 10:1.
  • the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is between about 2:1 and about 4:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 4:1, about 3:1, or about 2:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 2:1, or 1:1.
  • the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 2:1.
  • each half antibody is conjugated to a Linker-Drug moiety.
  • the antibody comprises an asparagine group in the region 290- 305 (e.g., at N297, EU numbering) attached to the sugar-derivative moiety, which comprises a functional group A”; and the modified antibody that binds to ENPP3 is conjugated to the Linker-Drug moiety by a covalent bond formed between A” and a functional group of the Linker-Drug moiety.
  • the Linker-Drug moiety comprises at least two functional groups, each of which is capable of forming a covalent bond with a functional group A” of the sugar-derivative moiety of the modified antibody that binds to ENPP3 (e.g., at amino acid N297, EU numbering, of the antibody) to form an antibody-drug conjugate.
  • the ratio between the modified antibody that binds to ENPP3 and the Linker-Drug moiety is between about 1:1 and about 1:2.
  • the modified antibody that binds to ENPP3 drug conjugate and scaffold of the present disclosure can be purified (e.g., to remove any starting materials) by extensive diafiltration.
  • the purified conjugate or scaffold comprises less than 5% w/w (e.g., ⁇ 2% w/w) aggregated conjugates as determined by SEC; less than 0.5% w/w (e.g., ⁇ 0.1% w/w) free (unconjugated) drug as determined by RP-HPLC; less than 1% w/w drug carrying-peptide-containing scaffolds as determined by SEC; and/or less than 2% w/w (e.g., ⁇ 1% w/w) unconjugated antibodies as determined by HIC-HPLC.
  • the conjugate described herein is an ENPP3 ADC comprising a modified antibody that binds to ENPP3 and two molecules of a fully synthetic macromolecular linker- payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA).
  • the fully synthetic macromolecular linker-payload is conjugated to the modified anti-ENPP3 antibody in a site-specific manner enabled by glycan remodeling of the antibody at the asparagine group at position 297 of the antibody according to EU numbering.
  • the average drug-to-antibody ratio (DAR) of the ENPP3 antibody-drug conjugate is about 6.
  • the ENPP3 antibody-drug conjugate is a conjugate of Formula (I): Formula (I): a. d 13 is about 2 b.
  • the ANTIBODY binds ENPP3 and comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and CDRL3 of a variable light chain domain (VL0 comprising the amino acid sequence set forth in SEQ ID NO:8.
  • VH variable heavy chain domain
  • VL0 variable light chain domain
  • the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; and d.
  • GlcNAc is GlcNAc; is Fuc; and is GalNAc.
  • GlcNAc refers to N-acetylglucosamine (i.e., ⁇ -D-(Acetylamino)-2-deoxy- glucopyranose or N-Acetyl-D-glucosamine).
  • Fuc refers to fucose (i.e., (2S,3R,4R,5S)-6-Methyltetrahydro-2H-pyran-2,3,4,5-tetraol or 6-Deoxy-l-galactose).
  • GalNAc refers to N-acetylgalactosamine (i.e., 2-(Acetylamino)-2-deoxy-D-galactose, 2-Acetamido-2-deoxy-D-galactose, N-Acetylchondrosamine, 2-Acetamido-2-deoxy-D- galactopyranose, or N-Acetyl-D-galactosamine).
  • the GlcNAc is bonded to the conjugate through a reactive moiety of GlcNAc.
  • the Fuc is bonded to the conjugate through a reactive moiety of Fuc.
  • the GalNAc is bonded to the conjugate through a reactive moiety of GalNAc.
  • the Linker-Drug moiety is attached to the antibody at position N180 of SEQ ID NO: 11, a position corresponding to N297 (as numbered by EU numbering).
  • the Linker-Drug moiety is attached to the antibody at a position corresponding to N180 of SEQ ID NO: 11.
  • Corresponding positions are determined, for example, using a sequence alignment tool.
  • the Linker-Drug moiety is attached to the antibody at position N296 of SEQ ID NO: 9 a position corresponding to N297 (as numbered by EU numbering).
  • the Linker-Drug moiety is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 9.
  • the Linker- Drug moiety is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 9.
  • Corresponding positions are determined, for example, using a sequence alignment tool.
  • the antibody binds to ENPP3.
  • the antibody comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8.
  • VH variable heavy chain domain
  • VL variable light chain domain
  • the process for the preparation of an antibody that binds to ENPP3 comprises: (a) contacting a glycoprotein (e.g., an antibody that binds to ENPP3 glycan) comprising an antibody that binds to ENPP3 and core-GlcNAc moiety connected to site N297 (according to EU numbering) of the antibody, with endoglycosidase Endo SH, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and (b) contacting the intermediate antibody with 4-AzGalNAc-UDP in the presence of a ⁇ -(l,4)-GalNAcT enzyme, thereby forming the modified antibody that binds to ENPP3 comprising the modified-GlcNAc moiety; wherein steps (a) and (b) are conducted concurrently.
  • a glycoprotein e.g., an antibody that binds to ENPP3 glycan
  • site N297 accordinging to EU numbering
  • the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa.
  • the ⁇ -(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa.
  • the ⁇ -(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) is derived from Trichopulsia ni.
  • the process is conducted in PBS buffer at pH value of about 7.4 and at a temperature of about 30 o C.
  • the ENPP3 antibody-drug conjugate can be generated and purified by well-known techniques e.g., WO 2018098269 and US 17/568,378, each of which is incorporated herein in its entirety by reference.
  • the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-a): wherein is GalNAc; and d 13 is about 2. [0488] In some embodiments, the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-b):
  • the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-c):
  • the ENPP3 antibody-drug conjugate is a conjugate of Formula (IA):
  • the conjugate described herein is a ENPP3 antibody-drug conjugate comprising a modified antibody that binds to ENPP3 and two molecules of a fully synthetic macromolecular linker-payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA).
  • AF-HPA auristatin F-hydroxypropyl amide
  • the free auristatin payload, auristatin F hydroxypropyl amide (AF-HPA) comprises:
  • the primary AF-HPA metabolite, Auristatin F (AF) comprises: . V. Antigen Binding Protein Expression and Production A.
  • Nucleic Acid Molecules Encoding Antigen Binding Proteins [0493] Nucleic acid molecules that encode for the antigen binding proteins described herein, or portions thereof, are also provided. [0494] The nucleic acid molecules can be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid is "isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids (e.g., other chromosomal DNA, e.g., the chromosomal DNA that is linked to the isolated DNA in nature) or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, restriction enzymes, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York.
  • a nucleic acid described herein can be, for example, DNA or RNA and may or may not contain intronic sequences.
  • nucleic acid molecules comprising polynucleotides that encode one or more chains of an anti-ENPP3 antibodies, provided herein.
  • a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of an anti-ENPP3 antibody.
  • a nucleic acid molecule comprises both a polynucleotide sequence that encodes a heavy chain and a polynucleotide sequence that encodes a light chain, of an anti-ENPP3 antibody.
  • a first nucleic acid molecule comprises a first polynucleotide sequence that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide sequence that encodes a light chain.
  • the polynucleotides are codon optimized.
  • the nucleic acid molecule comprises a polynucleotide encoding the VH of one of the antibodies provided herein.
  • the nucleic acid comprises a polynucleotide encoding the VL of one of the antibodies provided herein.
  • the nucleic acid encodes both the VH and the VL of one of the antibodies provided herein.
  • the nucleic acid encodes an antibody VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8.
  • the nucleic acid encodes a variant of one or more of the above amino acid sequences (e.g., the heavy chain and/or light chain amino acid sequences, or the VH and/or VL amino acid sequences disclosed herein), wherein the variants has at most 25 amino acid modifications, such as at most 20, such as at most 15, 14, 13, 12 or 11 amino acid modifications, such as 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino-acid modifications, such as deletions or insertions, preferably substitutions, such as conservative substitutions.
  • nucleic acids encoding VH and VL segments are obtained, these nucleic acids can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL- or VH-encoding nucleic acid is operatively linked to another nucleic acid encoding another polypeptide, such as an antibody constant region or a flexible linker.
  • the isolated nucleic acid encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding nucleic acid to another nucleic acid molecule encoding heavy chain constant regions (hinge, CH1, CH2 and/or CH3).
  • heavy chain constant regions hinge, CH1, CH2 and/or CH3.
  • sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242) and nucleic acid fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, for example, an IgG1 region.
  • the VH-encoding nucleic can be operatively linked to another nucleic acid molecule encoding only the heavy chain CH1 constant region.
  • the isolated nucleic acid molecule encoding the VL region can be converted to a full- length light chain gene (as well as a Fab light chain gene) by operatively linking the VL- encoding nucleic acid molecule to another nucleic acid molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242) and nucleic acid fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region.
  • the VH- and VL-encoding nucleic acid fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 (SEQ ID NO: 234), such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci.
  • a flexible linker e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 (SEQ ID NO: 234)
  • nucleic acid molecules that are suitable for use as primers or hybridization probes for the detection of nucleic acid sequences are also provided.
  • a nucleic acid molecule can comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion (e.g., ENPP3 binding portion) of a polypeptide.
  • An expression vector can include, but is not limited to, sequences that affect or control transcription, translation, and, if introns are present, affect RNA splicing of a coding region operably linked thereto.
  • Nucleic acid sequences necessary for expression in prokaryotes include a promoter, optionally an operator sequence, a ribosome binding site and possibly other sequences. Eukaryotic cells are known to utilize promoters, enhancers, and termination and polyadenylation signals.
  • the expression vector can also include a secretory signal peptide sequence that is operably linked to the coding sequence of interest, such that the expressed polypeptide can be secreted by the recombinant host cell, for more facile isolation of the polypeptide of interest from the cell, if desired.
  • Other signal or secretory peptides are known to those of skill in the art and may be fused to any of the variable region polypeptide chains, for example, to facilitate or optimize expression in particular host cells.
  • Expression and cloning vectors of the invention will typically contain a promoter that is recognized by the host organism and operably linked to the molecule encoding the polypeptide. A large number of promoters, recognized by a variety of potential host cells, are well known.
  • a suitable promoter is operably linked to the DNA encoding e.g., heavy chain, light chain, or other component of the antibodies and antigen-binding fragments of the invention, by removing the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into the vector.
  • Suitable promoters for use with yeast hosts are also well known in the art.
  • Yeast enhancers are advantageously used with yeast promoters.
  • Suitable promoters for use with mammalian host cells are well known.
  • nucleic acids encoding the different components of the antibody or antigen binding fragment thereof can be inserted into the same expression vector.
  • the nucleic acid encoding an anti-ENPP3 antibody light chain or variable region, as provided herein can be cloned into the same vector as the nucleic acid encoding an anti-ENPP3 antibody heavy chain or variable region as provided herein.
  • B. Host Cells After the vector has been constructed and the one or more nucleic acid molecules encoding the components of the antibody or antigen binding fragment thereof described herein has been inserted into the proper site(s) of the vector or vectors, the completed vector(s) may be inserted into a suitable host cell for amplification and/or polypeptide expression. [0507] Thus, in another aspect, host cells comprising nucleic acid molecules or vectors such as described herein are also provided.
  • antibody heavy chains and/or antilight chains can be expressed in prokaryotic cells, such as bacterial cells, or in eukaryotic cells.
  • the selection of an appropriate host cell depends upon various factors, such as desired expression levels, polypeptide modifications that are desirable or necessary for activity (such as glycosylation or phosphorylation) and ease of folding into a biologically active molecule.
  • a suitable host cell Once a suitable host cell has been prepared, it can be used to express the desired antibody or antigen binding fragment thereof.
  • methods for producing an antibody or antigen binding fragment thereof as described herein are also provided.
  • such methods comprise culturing a host cell comprising one or more expression vectors as described herein in a culture medium under conditions permitting expression of the antibody or antigen binding fragment thereof as encoded by the one or more expression vectors; and recovering the antibody or antigen binding fragment thereof from the culture medium.
  • the antibody or antigen binding fragment thereof is produced in a cell-free system.
  • the solid tumor is selected from the group consisting of kidney cancer, lung adenocarcinoma, endometrioid uterine cancer, ovarian cancer, and colorectal cancer (CRC).
  • the kidney cancer is of clear cell or papillary histology.
  • methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate to the individual.
  • the tumor cells expresses ENPP3. In some embodiments the tumor cells does not express ENPP3.
  • the tumor cell does not express ENPP3 and is killed through a bystander effect.
  • the administration of the antibody-drug conjugate results in a strong bystander effect.
  • the bystander effect allows the payload to diffuse from antigen-positive tumor cells to adjacent antigen-negative tumor cells, resulting in cell killing.
  • the administration of the antibody-drug conjugate results in a low off-target effect.
  • disclosed herein is a method of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of the present invention.
  • the tumor cell expresses ENPP3.
  • the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, the antibody binds the extracellular region of ENPP3. In some embodiments, the ADC is internalized in the tumor cells. In some embodiments, following internalization, the drug is released from the antibody. In some embodiments, the drug is auristatin F. VII.
  • Pharmaceutical compositions and formulations [0516] In some embodiments, the invention provides ADC or antibody mixtures and pharmaceutical compositions comprising any of the ADCs or antibodies as provided herein. [0517] In some embodiments, the compositions are pharmaceutical compositions comprising the ADCs or antibodies provided herein and a pharmaceutically acceptable carrier. In some of those embodiments, the pharmaceutical composition is in liquid form.
  • the pharmaceutical composition is a lyophilized powder.
  • an antibody drug conjugate having the structure Ab-(L-(L A -D) n ) m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and L A , L A is a divalent moiety connecting L and D, D is a drug; n is 1, 2 or 3; and m is 1, 2 or 3, wherein the antibody comprises: a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31.
  • VH variable heavy chain domain
  • an antibody drug conjugate having the structure, Ab-(L-(L A -D) n ) m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3; L is a linker covalently bound to Ab and L A ; L A is a divalent moiety connecting L and D; D is an auristatin; n is 1, 2 or 3; and m is 1, 2 or 3. In some embodiment, n is 2 or 3. In some embodiments, m is 1 or 2.. In some embodiments, n is 3 and m is 2. In some embodiments the drug to antibody ratio is 6. In some embodiments, n is 3 and m is 1. In some embodiments the drug to antibody ratio is 3.
  • the antibody or antigen binding fragment thereof comprises; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a
  • the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof comprises a VH comprising at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8, or 27-31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31.
  • the antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and the VL comprising the amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or antigen binding fragment thereof comprises a heavy chain (HC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or 12-16, and a light chain (LC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10 or 17-21.
  • the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21.
  • the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering.
  • L is attached to the asparagine residue at position 296 according to SEQ ID NO:9.
  • L is attached to the asparagine residue at position 296 of SEQ ID NO:9.
  • the L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan.
  • the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for a Fc ⁇ receptor. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3.
  • the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232.
  • the drug is an auristatin. In some embodiments, the auristatin is selected from the group consisting of auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin.
  • the auristatin is auristatin F hydroxypropylamide (AF HPA) comprising, .
  • L covalently bonds to Ab via a glycan on a Fc constant region of the Ab.
  • L comprises wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to L A .
  • L A is , wherein p is an integer from 1 to 25; q is an integer from 1 to 25; wherein the L D -D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L.
  • p is 4.
  • q is 8.
  • L A - D is
  • the antibody drug conjugate is of Formula (I): wherein d 13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety;
  • the antibody comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a
  • composition comprising the antibody drug conjugate.
  • the composition comprises a heterogeneous mixture of different ADC molecules (i.e., different DAR species having different drug-to-antibody ratios). Therefore, in some embodiments, the term ADC also refers to such mixtures of DAR species.
  • an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of claims SEQ ID NO:7 or 22-26; and CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8, or 27-31.
  • VH variable heavy chain domain
  • VL variable light chain domain
  • the isolated antibody or antigen binding fragment comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising
  • the isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the VH has at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and the VL has at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence identity the amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 of SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody.
  • the HC comprises the amino acid sequence set forth in any one of SEQ ID NO:9, or 12-16 and the LC comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.
  • the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set
  • the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for an Fc ⁇ receptor.
  • the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. [0537]
  • the antibody or antigen binding fragment thereof is human, chimeric, or humanized.
  • the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3 In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at residues 671-681 (VPPSESQKCSF (SEQ ID NO: 231)) and 762-780 (PDEITKHLANTDVPIPTHY (SEQ ID NO: 232)) [0538] In some embodiments, provided herein is an antibody drug conjugate comprising the antibody or antigen binding fragment of any of the embodiments herein covalently bound to one or more drug molecules.
  • nucleic acid encoding the isolated antibody of any one of the embodiments provided herein.
  • nucleic acid encoding a light chain, a heavy chain, or a light chain and heavy chain encoding the isolated antibody of any one of the embodiments described herein.
  • vector comprising the nucleic acid of any the embodiments provided herein.
  • host cells comprising the vector of any of the embodiments provided herein.
  • kits for producing an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising culturing the host cell of the embodiments provided herein under conditions suitable for expressing the antibody or antigen binding fragment thereof.
  • pharmaceutical compositions comprising the antibody drug conjugate of any one of the embodiments provided herein or the isolated antibody embodiments provided herein and a pharmaceutically acceptable carrier.
  • a solid tumor selected from the group consisting of kidney cancer of clear cell or papillary histologies, a lung adenocarcinoma, an endometrioid uterine cancer, ovarian cancers, or colorectal cancer (CRC) comprising administering the antibody-drug conjugate of any of the embodiments herein or the isolated antibody or antigen binding fragment embodiments provided herein.
  • treating a solid tumor comprises a change in tumor growth inhibition.
  • the tumor volume and/or the rate of tumor volume growth is decreased.
  • provided herein are methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate of any of the embodiments provided herein.
  • the tumor cell expresses ENPP3.
  • the tumor cell is killed through a bystander effect.
  • provided herein are methods of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of any one of the embodiments provided herein to the individual.
  • the tumor cell expresses ENPP3.
  • the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, wherein the antibody drug conjugate is internalized in the tumor cell.
  • Example 1 Antibody Screen Generation of antibodies specific to ENPP3 [0545]
  • Transgenic Ablexis AJ mice expressing human variable regions were immunized using either full length ENPP3 amino acid sequence (SEQ ID NO: 62) (Table 1) or full length nucleic acid sequence.
  • SEQ ID NO: 62 full length ENPP3 amino acid sequence
  • a total of 213 antibody clones were recovered and screened for binding to recombinant human ENPP3 and cells expressing ENPP3.90 antibody clones were selected based on binding affinity.
  • the 90 antibody clones were evaluated based on biophysical properties, CDR sequence diversity, and potential post-translational modification (PTM) liabilities, yielding 53 antibodies.
  • PTM post-translational modification
  • VH and VL Variable regions (VH and VL) of each of the select 53 antibodies were engineered as human IgG1_G1m(17).
  • Select panel of anti-ENPP3 antibody-drug conjugates exhibited potent cytotoxicity [0546]
  • Each of the 53 antibodies was conjugated via a linker with antimitotic drug monomethylauristatin F (vcMMAF) to form antibody drug conjugates (ENPP3- vcMMAF).
  • vcMMAF antimitotic drug monomethylauristatin F
  • Cell lines expressing ENPP3 were treated with ENPP3-vcMMAF antibody drug conjugates or Isotype-vcMMAF as a control. Tumor cell cytotoxicity was measured using Cell-Titer-Glow Cell Viability Assay (Promega).
  • suspension cells were counted and plated in 96 well plates in 75uL of complete media. Cells were incubated overnight to allow for recovery. ADCs and compounds were prepared and 1:5 serial dilutions were performed in complete media.75uL of media + compound was added to each well and incubated for 3 or 6 days. Plates were read on either day 3 or day 6 via Cell Titer Glo 2.0 by adding 75uL of CTG reagent to each well. Plates were placed on a shaker for 2 minutes and then incubated at RT for 15 minutes before being read on an Envision plate reader. Raw data was exported from the plate reader to Excel and then analyzed in Prism Graph Pad.
  • ENPP3-vcMMAF antibodies All 53 ENPP3-vcMMAF antibodies tested exhibited dose- dependent cytotoxicity in with varying sensitives.23 ENPP3-vcMMAF antibodies were selected for further analysis based on exhibiting the most potent cytotoxicity. [0547] Next, the selected 23 ENPP3 antibodies were evaluated for binding to Cynomolgus monkey ENPP3.
  • Endo SH was prepared as described in PCT application WO 2017137459, the entire contents of which are incorporated herein by reference.
  • UDP-azido sugar and GalNAcT were prepared as described in US 9,988,662, the entire contents of which is incorporated herein by reference.
  • the drug content of the conjugates was determined spectrophotometrically, otherwise RP-HPLC or LC/MS as performed for quantitative determination of the drug content.
  • the protein content of the antibody-drug conjugates was determined spectrophotometrically or by ELISA.
  • Antibody-drug conjugates, drug carrying scaffolds, or antibody scaffolds were purified (i.e., removal of residual unreacted drug, unconjugated antibody, enzymes or starting materials) by extensive diafiltration, CHT chromatography or HIC, as required. If necessary, additional purification by SEC or HIC were conducted to remove aggregated antibody-drug conjugates.
  • the antibody-drug conjugates contained ⁇ 5% (w/w) (e.g., ⁇ 2% (w/w)) aggregated antibody-drug conjugates as determined by SEC; ⁇ 0.5% (w/w) (e.g., ⁇ 0.1% (w/w)) free (unconjugated) drug as determined by RP- HPLC and/or LC-MS/MS; ⁇ 1% (w/w) of free drug conjugate as determined by SEC and/or RP-HPLC; and ⁇ 10% (w/w) (e.g., ⁇ 1% (w/w)) unconjugated antibody or antibody fragments as determined by HIC-HPLC and/or RP-HPLC.
  • w/w e.g., ⁇ 2% (w/w) aggregated antibody-drug conjugates as determined by SEC
  • ⁇ 0.5% (w/w) e.g., ⁇ 0.1% (w/w)
  • free drug as determined by RP- HPLC and/or LC-MS
  • Azido-modified ENPP3 antibody [0554] To the antibody that binds to ENPP3 (12.71 mg, 0.088 ⁇ mole) in 50 mM Tris-HCl, pH 7.6, was added in the following order: Endo SH (0.127 mg, 1 w-%), GalNAcT (0.64 mg, 5 w-%), UDP-azido sugar (1.34 mg, 2.12 ⁇ mole), and MnCl2 (1.18 mg, 9.4 ⁇ mole), to achieve a final antibody concentration of 13.5 g/L. The reaction was stirred at 30 rpm for 17 hours at 30 °C.
  • ADC 1 Azido-modified antibody that binds to ENPP3 (10.03 mg, 0.070 ⁇ mole) in PBS, pH 7.2 and Scaffold 1A (4.25 mg, 0.67 ⁇ mole, prepared as described in US 17/144,378, US2021/0220477, WO2021142199A1) in water, were gently mixed, then left for 20 hours at 30 °C without shaking or rocking.
  • the crude azido- modified AB1 was purified by protein A column chromatography and dialysis to give the azido-modified AB1 (12.9 mg, 88% yield).
  • Azido-modified AB1 (12.88 mg, 0.09 ⁇ mole) in PBS, pH 7.2 and scaffold 1A (5.62 mg, 0.88 ⁇ mole, prepared as described in US 17/144,378) in water were gently mixed and, left for 20h at 30 °C.
  • the crude product was purified by UF/DF and HIC to give conjugate ADC2 (8.74 mg, 66 % yield) that had a DAR of 5.95 as determined by RP- HPLC.
  • Example 4 Testing of ENPP3 ADCs
  • the select 23 ENPP3 antibodies from Example 1 were conjugated via a linker with antimitotic drug auristatin F hydroxypropyl amide (AF-HPA) (ENPP3-AF-HPA antibodies).
  • AF-HPA antimitotic drug auristatin F hydroxypropyl amide
  • ENPP3-AF-HPA antibodies The cytotoxicity of the ENPP3-AF-HPA antibodies was evaluated using the Cell Titer Glo 2.0 (Promega). Briefly, suspension cells were counted and plated in 96 well plates in 75uL of complete media. Cells were incubated overnight to allow for recovery.
  • ENPP3-AF-HPA antibodies and compounds were prepared and 1:5 serial dilutions were performed in complete media.75uL of media + compound was added to each well and incubated for 3 or 6 days. Plates were read on either day 3 or day 6 via Cell Titer Glo 2.0 (Promega) by adding 75uL of CTG reagent to each well. Plates were placed on a shaker for 2 minutes and then incubated at RT for 15 minutes before being read on an Envision plate reader. Raw data was exported from the plate reader to Excel and then analyzed in Prism Graph Pad.
  • ENPP3 expression was measured by IHC and flow cytometry (dissociated tumors) at a tumor volume equivalent to that at randomization [Signals E168634, E102381].
  • IHC showed ENPP3 positivity in xenograft tumors and flow cytometry showed medium ENPP3 expression (110,000 receptors per cell).
  • the results demonstrated tumor regression activity of the six ENPP3-AF-HPA antibodies (see FIG.4).
  • ENPP3 Antibody 1 demonstrated the strongest tumor inhibition.
  • mice bearing established SC xenografts expressing ENPP3 in female immune-compromised SCID-beige (ie, severe combined immunodeficiency – beige or CB17.Cg PrkdcscidLystbg J/Crl) mice were dosed once IV with 3 ENPP3 ADCs, at Dose A, B, and D or Isotype-ADC (B23B251- AF-HPA) at Dose D.
  • Tumor fragments were implanted on Day 0, followed by treatment on Day 13 (dosing indicated by red arrow).
  • Group tumor volumes are graphed as mean ⁇ SEM.
  • ENPP3 was highly expressed in several solid tumors including clear cell renal cell carcinoma (ccRCC) (93%), papillary renal cancer (78%), uterus endometrioid cancer (53%), colorectal cancer (CRC) (51%), lung adenocarcinoma (50%), the endometrioid subtype of ovarian and cancer (47%) (FIG.5).
  • ccRCC clear cell renal cell carcinoma
  • papillary renal cancer (78%
  • uterus endometrioid cancer (53%
  • colorectal cancer CRC
  • lung adenocarcinoma 50%
  • the endometrioid subtype of ovarian and cancer 47%) (FIG.5).
  • FIG.5 To quantify the expression level of ENPP3 in ccRCC tumors, flow-cytometry-based receptor density studies were performed using commercial ENPP3 antibody clone NP4D6.
  • ENPP3 was identified as a unique tumor-targeting antigen with high expression in several solid tumors and apically restricted normal tissue expression.
  • Example 6 ENPP3 expression in cancer cell lines
  • RRC renal cell carcinoma
  • HCC liver/hepatocellular carcinoma
  • ENPP3 surface expression and receptor density was evaluated on a panel of in vitro established renal cell carcinoma (RCC) and liver/hepatocellular carcinoma (HCC), cell lines with flow cytometry using a commercial ENPP3 antibody (clone NP4D6) binding to an epitope similar to ENPP3 binder arm within ADC1.
  • ENPP3 was overexpressed in several of these tumor cells to generate the overexpression cell lines, A704 huENPP3-OE, H1975 huENPP3-MedOE, H1975 huENPP3-HighOE, VMRCRCW huENPP3-MedOE and VMRC RCW huENPP3-HighOE. Endogenous ENPP3 was knocked out in the HepG2 cell line, generating the negative cell line HepG2 ENPP3 KO.
  • ENPP3 endogenous expression ranged from negative expression (determined as ⁇ lower limit of detection [LLOD], 7,646 receptors/cell) in the H1975 cell line, to low expression ( ⁇ 50,000 receptors/cell) in HepG2 and VMRC-RCW, medium expression (50,000-150,000 receptors/cell) in TUHR10TKB and Example Cell line 1, and high expression (>150,000 receptors/cell) in A704 cell lines (FIG.7A-D). Knock out and overexpression lines showed expected expression level changes (FIG.7A-D).
  • Example 7 ENPP3 expression in tumor PDX models [0568] Ex vivo ENPP3 expression was also measured by IHC and flow cytometry in a NSCLC patient derived xenograft (PDX) model, and 2 RCC PDX models RCC1 and RCC2. All 3 PDX models exhibited high ENPP3 expression by IHC and receptor density measurements of 200,000 (NSCLSC), 310,000 (RCC1), and 410,000 (RCC2) receptors/cell (FIG.8).
  • ADC1 Antibody-drug conjugate 1
  • ADC1 was constructed with a monoclonal antibody (mAb) that binds to ENPP3, ENPP3 Antibody 1, comprising the sequences set forth in Tables 2-14, conjugated to an auristatin and a branched linker.
  • the mAb was generated by co-expression of the anti-ENPP3 heavy chain (HC) and light chain (LC) and binds to the extracellular region of ENPP3 at residues 671-681 (SEQ ID NO 231: VPPSESQKCSF) and 762-780 (SEQ ID NO 232: PDEITKHLANTDVPIPTHY).
  • the auristatin and a branched linker platform consisted of a microtubule inhibitor payload and a branched hydrophilic linker enabling a drug-to-antibody (DAR) 6.
  • the linker consists of branched scaffold to support 3 AF-HPA payloads per linker, and polyethylene glycol (PEG) 8 groups for enhanced hydrophilicity.
  • the payload was auristatin F hydroxypropyl amide (AF-HPA).
  • AF-HPA auristatin F hydroxypropyl amide
  • Auristatin F hydroxypropyl amide has the formula .
  • the drug-linker prior conjugation has the formula .
  • the mAb was conjugated to an auristatin and a branched linker platform using the Synaffix GlycoConnect process.
  • the native glycans on the antibody Fc at site N296 of SEQ ID NO: 9 was enzymatically processed by an endoglycosidase to the core N-acetylglucosamine followed by attachment of an azido-modified N-acetylgalactosamine utilizing a glycosyl transferase.
  • the azido-modified antibody was then coupled to the Dolasythen payload-linker via copper-free click chemistry.
  • Example 9 Biophysical assessment of ADC1 [0575] Binding and intrinsic properties of ADC1 were tested.
  • ADC1 exhibited a favorable biophysical profile with high affinity (0.307 ⁇ 0.005 nM) to human ENPP3, high purity, good conformational stability, low hydrophobicity, and low to no nonspecific binding. Furthermore, it also exhibited favorable stability profiles in human serum, under ex vivo physiological conditions, under degradation studies, and under thermal stress at high concentrations.
  • Example 10 ADC1 binding in tumor cell lines [0576] In vitro cell binding of ADC1 was assessed on several cell lines with endogenous expression and overexpression of human or cynomolgus monkey ENPP3.
  • ADC1 exhibited a dose-dependent binding to all ENPP3-positive cell lines tested, with endogenous expression (Example cell line 1, VMRCRCW, HepG2) and engineered overexpression (HepG2 KO – huENPP3 OE, VMRCRCW huENPP3 High OE, H1975 huENPP3 High OE) Results can be found in FIG.9 and Table 42.
  • ADC1 binding 50% effective concentration (EC 50 ) values for ENPP3 in the endogenously expressed ENPP3 cell lines were 0.27 to 0.52 nM and EC50 values for the engineered ENPP3 overexpression cell lines were 1.4 to 2.6 nM.
  • ADC1 also exhibited a dose-dependent binding to the cynomolgus monkey ENPP3-expressing cell lines HepG2 KO – cyENPP3 OE and H1975 cyENPP3 OE with an EC 50 value of 2.3 and 2.5 nM, respectively.
  • ADC1 did not exhibit binding to ENPP3-negative cell lines HepG2 ENPP3 KO and H1975 and no binding was observed to any of the cell lines with the isotype control ADC HIVB60- Dola.
  • Table 42 Binding of the ADC1 to ENPP3-expressing tumor cell lines (EC 50 ).
  • ADC1 EC 50 values were ND if the dose-response curve did not satisfy one or both of the following criteria: R 2 >0.9 and log (95% confidence interval) difference ⁇ 1.2.
  • ADC1 exhibited a dose-dependent binding only to the ENPP3-expressing CHO-K1 cell line, with an EC 50 value of 0.7 nM, and no binding was observed to CHO-K1 parental cells or CHO-K1 cell lines expressing ENPP1 or ENPP2 (FIG.10).
  • ADC HIVB60-Dola Dolasynthen
  • Example 11 Internalization of ADC1 [0578] Internalization of ADC1 (or the parental unconjugated mAb) was evaluated using confocal-microscopy-based high-content imaging in an ENPP3 medium expressing cell line (Example Cell line 1) and VMRCRCW huENPP3 High OE (ENPP3 high overexpression). ADC1 exhibited a dose-dependent internalization over time, with the maximal antibody internalization seen as early as 30 minutes post binding at 4°C.
  • cellular phenotypic changes associated with microtubule inhibition (monomethyl auristatin E [MMAE]-driven phenotype) and tumor cell cytotoxicity (cytotoxic phenotype) were evaluated using high-content imaging in the presence of ADC1 over time (FIG.12A).
  • ADC1 exhibited a dose- and time-dependent induction of internalization, auristatin (MMAE) and cytotoxic phenotype, with no phenotypic changes were seen with the isotype control ADC B23B251-Dola (FIG.12B).
  • ADC1 induced cytotoxicity in ENPP3 cell lines [0580] ADC1-induced tumor cell cytotoxicity was evaluated on a panel of ENPP3-positive cell lines as well as ENPP3-negative cell line controls.
  • ADC1 exhibited potent dose- dependent cytotoxicity in example cell lines endogenously expressing ENPP3 at a medium level), with an EC 50 value of ⁇ 0.3 nM (FIG.13, Table 43).
  • Table 43 EC 50 values for tumor cell cytotoxicity in a panel of ENPP3-expressing tumor cell lines.
  • ADC1 did not elicit potent cytotoxicity in some solid tumor cell lines with the endogenous ENPP3 levels (HepG2, VMRCRCW and A704). Further these cell lines also exhibited low sensitivity to the payload auristatin F hydroxypropyl amide (AF-HPA) (EC50 >1 nM).
  • ADC1-mediated cytotoxicity was a function of ENPP3 expression level
  • human or cynomolgus monkey ENPP3 was overexpressed in HepG2 and VMRCRCW cell lines at different expression levels and evaluated for ADC1 -mediated cytotoxicity.
  • ADC1 exhibited potent dose-dependent cytotoxicity in these ENPP3-overexpression cell lines, i.e., HepG2 KO – huENPP3 OE and VMRCRCW huENPP3 High OE, with EC 50 values of 0.2 and 0.065 nM, respectively.
  • ENPP3 was overexpressed at moderate levels (91,000 receptors/cell) in the ENPP3-negative H1975 lung cell line, with known higher sensitivity to the auristatin class payload.
  • ADC1 exhibited potent dose- dependent cytotoxicity in the H1975 huENPP3 Med OE cell line with an EC 50 value of 0.95 nM upon 3 days of treatment.
  • Minimal cytotoxicity was observed with ADC1 in ENPP3-negative cell lines HepG2 ENPP3 KO and H1975.
  • ADC1-induced tumor cell cytotoxicity was also evaluated upon shorter drug exposure (i.e., 2 hours), because ADC1 internalization occurs within the first 30 minutes of ADC exposure.
  • results showed that similar to long-term drug exposure (i.e., 6 days), ADC1 exhibited potent dose-dependent cytotoxicity with the 2-hour ADC exposure in the ENPP3 high HepG2 KO-huENPP3 OE cell line, with a modest decrease in EC 50 values compared to longer (ie, 6-day) ADC exposure (FIG.14). While minimal tumor cell cytotoxicity (at the higher ADC1 concentrations) was observed with the isotype control ADC (HIVB60-Dola) upon 6-day drug exposure, no cytotoxicity was observed with the short-term exposure, confirming the specificity of ADC1-induced cytotoxicity and the incubation-time-dependent non-specific isotype control cytotoxicity.
  • ADC1 exhibited potent and dose-dependent cytotoxicity in vitro in tumor cell lines expressing ENPP3, and the potency was dependent on the cell line sensitivity to payload and ENPP3 expression levels.
  • Example 13 ADC1 -mediated bystander effect
  • ADC1-induced bystander effect was evaluated using a coculture of ENPP3-positive and ENPP3-negative cell lines, wherein the cytotoxicity to the ENPP3-negative cell line would be derived from payload bystander activity.
  • This assay was performed using a pair of cell lines fluorescently labeled with different fluorochromes: (i) HepG2 ENPP3 KO (ENPP3 negative, green) and HepG2 KO – huENPP3 OE (ENPP3 positive, red).
  • ADC1 exhibited potent dose-dependent cytotoxicity against the ENPP3-positive cell line HepG2 KO – huENPP3 OE (red), while no tumor cytotoxicity was seen in the ENPP3-negative cell line HepG2 ENPP3 KO (green), when cultured alone.
  • FIG.15A-B When cocultured, ENPP3-negative cell lines were efficiently killed by ADC1 in a dose-dependent manner, demonstrating payload bystander effect. No significant tumor cell cytotoxicity was observed with isotype control ADC HIVB60-Dola against all cell lines and conditions tested, nor with vcMMAF-conjugated ENPP3 antibody (vcMMAF is non-cell permeable and hence absence of bystander effect can be expected) against ENPP3-negative cell line under coculture condition (FIG.15C). This data suggested that ADC1 exhibited ENPP3-specific bystander cytotoxicity of ENPP3-negative cells in the presence of ENPP3-positive tumor cells.
  • Example 14 ADC1 efficacy in mouse xenograft models Renal Cell Carcinoma (RCC) PDX
  • RCC Renal Cell Carcinoma
  • ADC1 treatment at increasing amounts of A, B, C and D resulting in ⁇ TGI of 103%, 106%, 110%, and 111%, respectively (p ⁇ 0.001; FIG.16A) as compared to Isotype-ADC on Day 38 post tumor implantation.
  • ADC1 treatment at B resulted in 8 of 12 partial tumor regressions (PRs) and 2 of 12 CRs
  • C treatment resulted in 11 of 12 PRs and 1 of 12 CRs
  • the D dose resulted in 11 of 12 PRs and 1 of 12 CRs.
  • mice bearing a second (SC) RCC PDX (410,000 receptors/cell), were dosed once IV with ADC1 at increasing amounts of A, B, and C or Isotype-ADC at an amount D (i.e., the highest amount given for ADC1).
  • D i.e., the highest amount given for ADC1.
  • Significant antitumor efficacy was observed with the ADC1 increasing amounts of A, B, C, and D resulting in ⁇ TGI of 71%, 85%, and 100%, respectively (p ⁇ 0.001; FIG.16B) as compared to Isotype-ADC on Day 45 post tumor implantation.
  • ADC1 at amount C dose resulted in 3 of 11 PRs, while the D dose resulted in 7 of 11 PRs on Day 45.
  • Non-small cell lung cancer (NSLC) PDX Female NMRI nude mice bearing SC NSLC PDX (200,000 receptors/cell), were dosed once IV with ADC1 at increasing amounts of A, B, C, and D or Isotype-ADC at an amount D (i.e., the highest amount given for ADC1). Significant antitumor efficacy was observed with ADC1 treatment at C and D resulting in ⁇ TGI of 74% and 100%, respectively (p ⁇ 0.001; FIG.17) as compared to Isotype-ADC-treated control on Day 31 post tumor implantation. ADC1 at C resulted in 2 of 12 PRs and D dose resulted in 9 of 12 PRs on Day 31.
  • ADC1 treatment induced in vivo antitumor efficacy in CDX and PDX tumors, in an ENPP3 expression level dependent manner.

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Abstract

The present invention relates to antibodies that bind to ENPP3 and antibody-drug conjugates comprising an antibody that binds to ENPP3 conjugated to a drug, such as an auristatin. Also provided herein are methods for treating a solid tumor or leukemia comprising administering such ADCs.

Description

ANTIBODY DRUG CONJUGATES THAT TARGET ENPP3 CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/654,908, filed on 31 May 2024 which is incorporated herein by reference in its entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 22, 2025, is named JBI6909WOPCT1_SL.xml, and is 222,907 bytes in size. TECHNICAL FIELD [0003] This application relates to antibody-drug conjugates (ADC) comprising an antibody that binds to ENPP3 conjugated to an auristatin. BACKGROUND [0004] ENPP3 (CD203c) is a member of the cell surface ENPP family consisting of 7 structurally related molecules with ATP pyrophosphatase and ATPase activities involved in hydrolysis of extracellular nucleotides (Stefan C, Jansen S, Bollen M. NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci.2005;30(10):542-550. doi:10.1016/j.tibs.2005.08.005). ENPP3 is a membrane protein with adenosine triphosphate (ATP) pyrophosphatase and ATPase activities involved in hydrolysis of extracellular nucleotides. The functional role of ENPP3 in cancer is not well understood. [0005] The design of Antibody Drug Conjugates (ADCs) with high therapeutic index remains challenging. To our knowledge, no ADC against ENPP3 is under clinical development. SUMMARY [0006] In some embodiments, provided herein is an antibody drug conjugate having the structure Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and LA, LA is a divalent moiety connecting L and D, D is a drug; n is 1, 2 or 3; and m is 1, 2 or 3, wherein the antibody comprises: a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31. [0007] In some embodiments, provided herein is an antibody drug conjugate having the structure, Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3; L is a linker covalently bound to Ab and LA; LA is a divalent moiety connecting L and D; D is an auristatin; n is 1, 2 or 3; and m is 1, 2 or 3. In some embodiments, n is 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, n is 3 and m is 2. In some embodiments the drug to antibody ratio is 6. [0008] In some embodiments, the antibody or antigen binding fragment thereof comprises; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. [0009] In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. [0010] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8, or 27-31. [0011] In some embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. [0012] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain (HC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or 12-16, and a light chain (LC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10 or 17-21. In some embodiments, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. In some embodiments, the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. [0013] In some embodiments, each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. In some embodiments, L is attached to the asparagine residue at position 296 according to SEQ ID NO:9. In some embodiments, the L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan. [0014] In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for a Fcγ receptor. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3. [0015] In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232. [0016] In some embodiments, the drug is an auristatin.In some embodiments, the auristatin is selected from the group consisting of auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin. In some embodiments, the auristatin is auristatin F hydroxypropylamide (AF HPA) comprising, . [0017] In some embodiments, L covalently bonds to Ab via a glycan on a Fc constant region of the Ab. In some embodiments, L comprises wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to LA. In some embodiments, LA is , wherein p is an integer from 1 to 25; q is an integer from 1 to 25; wherein the LD-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L. [0018] In some embodiments, p is 4. In some embodiments, q is 8. In some embodiments, LA- D is
[0019] In some embodiments, provided herein the antibody drug conjugate is of Formula (I): wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; [0020] In some embodiments, provided herein is an antibody drug conjugate having the
Formula (I): wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; is GlcNAc; is Fuc; and is GalNAc, wherein the antibody comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; [0021] In some embodiments, the antibody drug conjugate is produced by a method comprising, processing a glycan at position N296 of SEQ ID NO: 9 by incubating an antibody that binds to ENPP3 with an endoglycosidase, attaching an azido modified N- acetylglucosamine to position N296 according to SEQ ID NO:9 by providing glucosyl transferase, and attaching the linker and drug to the azido-modified N-acetyl glucosamine using a coper-free click chemistry. [0022] In some embodiments, provided herein is a composition comprising the antibody drug conjugate. Compositions comprising the antibody drug conjugate comprise a heterogeneous mixture of different ADC molecules (different drug to antibody ratio (DAR) species). [0023] In some embodiments, provided herein is an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of claims SEQ ID NO:7 or 22-26; and CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8, or 27-31. In some embodiments, the isolated antibody or antigen binding fragment comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the VH has at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and the VL has at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. In some embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8. [0024] In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the HC comprises the amino acid sequence set forth in any one of SEQ ID NO:9, or 12-16 and the LC comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.In some embodiments, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. In some embodiments, the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for an Fcγ receptor. In some embodiments the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. [0025] In some embodiments the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3 In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at residues 671-681 (VPPSESQKCSF (SEQ ID NO: 231)) and 762-780 (PDEITKHLANTDVPIPTHY (SEQ ID NO: 232)) [0026] In some embodiments, provided herein is an antibody drug conjugate comprising the antibody or antigen binding fragment of any of the embodiments herein covalently bound to one or more drug molecules. [0027] In some embodiments, provided herein are nucleic acid encoding the isolated antibody of any one of the embodiments provided herein. In some embodiments, provided herein are nucleic acid encoding a light chain, a heavy chain, or a light chain and heavy chain encoding the isolated antibody of any one of the embodiments described herein. In some embodiments, provided herein are vector comprising the nucleic acid of any the embodiments provided herein. In some embodiments, provided herein are host cells comprising the vector of any of the embodiments provided herein. [0028] Provided herein are methods of producing an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising culturing the host cell of the embodiments provided herein under conditions suitable for expressing the antibody or antigen binding fragment thereof. [0029] In some embodiments, provided herein are pharmaceutical compositions comprising the antibody drug conjugate of any one of the embodiments provided herein or the isolated antibody embodiments provided herein and a pharmaceutically acceptable carrier. [0030] In some embodiments, provided herein are methods of treating a solid tumor selected from the group consisting of kidney cancer of clear cell or papillary histologies, a lung adenocarcinoma, an endometrioid uterine cancer, ovarian cancers, or colorectal cancer (CRC) comprising administering the antibody-drug conjugate of any of the embodiments herein or the isolated antibody or antigen binding fragment embodiments provided herein. In some embodiments, treating a solid tumor comprises a change in tumor growth inhibition. In some embodiments, the tumor volume and/or the rate of tumor volume growth is decreased. [0031] In some embodiments, provided herein are methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate of any of the embodiments provided herein. In some embodiments, the tumor cell expresses ENPP3. In some embodiments, the tumor cell is killed through a bystander effect. [0032] In some embodiments, provided herein are methods of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of any one of the embodiments provided herein to the individual. In some embodiments, the tumor cell expresses ENPP3. In some embodiments, the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, wherein the antibody drug conjugate is internalized in the tumor cell. In some embodiments, following internalization, the drug is released from the antibody. BRIEF DESCRIPTION OF THE DRAWINGS [0033] FIG.1 is a scheme showing a process for preparing an azido-modified antibody, wherein an intermediate antibody comprising a terminal-GlcNAc moiety is reacted with an azido-modified UDP-GalNAc derivative molecule in the presence of a glycosyltransferase. [0034] FIG.2 is a scheme showing an embodiment of the process of preparing an azido- modified antibody. [0035] FIG.3A-3B is a scheme showing an embodiment of the process of preparing an antibody-drug conjugate, wherein an azido-modified antibody is conjugated to a Linker- Drug moiety comprising strained cycloalkynyl group. [0036] FIG.4 shows tumor growth inhibition in mice bearing xenograft tumors expressing ENPP3 treated with ENPP3 auristatin F hydroxypropyl amide (ENPP3-AF HPA) antibodies. [0037] FIG.5 is a bar graph showing the results of an IHC based evaluation of ENPP3 expression on tissue microarrays from multiple solid tumors. Intensity of ENPP3 membrane staining is depicted as none, low, medium, and high. Percentage of samples scoring membrane-positive (low, medium, or high) is listed, along with the number of positive tumor tissues. [0038] FIGs.6A-E show characterization of ENPP3 receptor density in ccRCC cells. FIG. 6A shows Flow-cytometry-based membrane ENPP3 detection and receptor occupancy measured using a commercial ENPP3 antibody in 13 ccRCC disassociated tumor cells (DTCs). FIG.6B shows Representative histograms of ENPP3 expression in two of the positive ccRCC DTCs. FIG.6C show an IHC image from a ccRCC tissue section at a 5x magnification with no ENPP3 expression. FIG.6D shows an IHC image from a ccRCC tissue section at a 5x magnification with high ENPP3 expression. FIG.6E shows an IHC image from a ccRCC tissue section at a 5x magnification with high ENPP3 expression. [0039] FIGs.7A-D provides ENPP3 expression levels in a panel of cancer cell lines (HepG2-liver cancer; H1975 – non-small cell lung cancer (NSCLC); VMRCRCW – renal cell carcinoma; Example cell line 1TUHR10TKB -clear cell renal cell carcinoma (ccRCC); A704 kidney adenocarcinoma) FIG.7A shows Flow-cytometry-based membrane ENPP3 detection and receptor occupancy quantification measured using a commercial ENPP3 antibody on a panel of cancer cell lines with endogenous and overexpressing (OE) ENPP3. FIG 7B-7D shows representative histograms for ENPP3 expression for three cell lines shown in the bar charts in FIG.7A. [0040] FIG.8 provides ENPP3 expression in patient derived xenograft (PDX) model systems from ex vivo tumors. Flow-cytometry and IHC-based evaluation of ENPP3 expression in and 3 PDX models, i.e., RCC1, RCC2, and NSCLC. Magnification is 30× for all images. [0041] FIG.9 shows ADC1 binding to ENPP3-expressing tumor cell lines. Example cell line 1 (ENPP3 medium), HepG2 Knock Out (KO) – huENPP3 over expression (OE) (liver cancer), HepG2 KO – cyENPP3 OE (liver cancer), and HepG2 ENPP3 KO (liver cancer, ENPP3 negative) cells were treated with ADC1 and isotype control ADC (HIVB60-Dola) and binding was evaluated by flow cytometry. [0042] FIG.10 shows ENPP3 specific binding of ADC1. CHO K1 parental (ENPP3 negative), CHO K1 ENPP1 over expression (OE), CHO K1 ENPP2 OE, and CHO K1 ENPP3 OE cell were treated with ADC1 and an isotype control ADC (HIVB60-Dola) and binding was evaluated by flow cytometry. [0043] FIG.11 shows ADC1 internalization in ENPP3-expressing cell lines. A cell line with endogenous medium levels of ENPP3 expression and VMRCRCW – huENPP3 High OE (RCC, ENPP3 high overexpression) cells were treated with ADC1 and an isotype control ADC (B23B251-Dola). The results were evaluated with evaluated by confocal microscopy. [0044] FIGs.12A-12B shows ADC1 internalization, phenotypic changes, and cytotoxicity in VMRCRCW–huENPP3 High OE cells (RCC). FIG.12A shows immunofluorescence of ADC1 and an isotype control ADC. FIG.12B shows internalization as measured by immunofluorescence, as mean intensity of the cells, normalized to percent of the medium control. Phenotypic similarity to auristatin payload (auristatin F hydroxypropyl amide (AF-HPA)) represents Pearson correlation to the best matching MMAE concentration at the same time point. The cytotoxic phenotype graph represents Euclidean distance from medium control in phenotypic space; values of ≥10 indicate the radical phenotypic change that occurs for apoptotic cells. The tumor cell loss graph is represented as percent of medium control. [0045] FIG.13 shows the effect of ADC1 on tumor cell viability. Example Cell line 1, Example Cell line 2, HepG2 huENPP3 Over Expression (OE) (liver cancer), VMRCRCW huENPP3 OE (RCC), HepG2 Knock Out (KO) (liver cancer), and H1975 huENPP3 OE (NSCLC) cell lines were treated with ADC1, Isotype-ADC (HIVB60-Dola), auristatin F hydroxypropyl amide (AF-HPA) (ADC1 payload), and auristatin F (AF) (metabolite of AF-HPA).Data plotted at 6 days post treatment. Error bars are standard error of the mean (SEM). [0046] FIG.14 shows the effect of ADC1 on tumor cell viability upon 2 hour or 6 day drug exposure. HepG2 huENPP3 Over expression (OE) (liver cancer) cells were treated with ADC1, Isotype-ADC (HIVB60-Dola), auristatin F hydroxypropyl amide (AF-HPA) (ADC1 payload), and auristatin F (AF) (metabolite of AF-HPA). Error bars are standard error of the mean (SEM). [0047] FIGs.15A-C shows ENPP3- induced bystander tumor cell cytotoxicity of ENPP3- expressing tumor cell lines. FIG.15A shows the tumor cell loss and IHC staining after treatment of HepG2 huENPP3 Over Expression (OE) (liver cancer) cells with ADC1, Isotype-ADC (HIVB60-Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF-conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days. FIG.15B shows the tumor cell loss and IHC staining after treatment of HepG2 huENPP3 Knock Out (KO) (liver cancer) cells with ADC1, Isotype- ADC (HIVB60-Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF-conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days. FIG.15C shows the tumor cell loss and IHC staining after treatment of a 1:1 coculture of HepG2 huENPP3 Over Expression (OE) (liver cancer) cells and HepG2 huENPP3 Knock Out (KO) (liver cancer) cells with ADC1, Isotype-ADC (HIVB60- Dola), AF HPA (ADC payload), and AF (metabolite of AF HPA), or vcMMAF- conjugated ENPP3 antibody (vcMMAF-conjugated ENPP3 Antibody 1) for 6 days. [0048] FIGs.16A-B shows the effect of ADC1 on tumor volume in a subcutaneous (SC) renal cell carcinoma (RCC) PDX models in NSG mice. In FIG.16A, tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 21 (dosing indicated by red arrow). * Denotes significant difference of the ADC1 treatment group versus the Isotype-ADC control group on Day 38 (p<0.001, n=12/group). Group tumor volumes are graphed as mean ± standard error of the mean (SEM). In FIG.16B, Tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 22 (dosing indicated by red arrow). * Denotes significant difference of the ADC1 treatment group versus the Isotype-ADC control group on Day 45 (p<0.001, n=11/group). Group tumor volumes are graphed as mean ± standard error of the mean (SEM). [0049] FIG.17 shows the effect of ADC1 on tumor volume in a subcutaneous (SC) non- small cell lung cancer (NSCLC) PDX in NMRI nude mice. Tumor fragments were implanted on Day 0, followed by treatment with an Isotype-ADC control, ADC1 at Dose A, ADC1 at Dose B, ADC at Dose C or ADC1 at Dose D on Day 13 (dosing indicated by red arrow). * Denotes significant difference of ADC1 treatment group versus the Isotype- ADC control group on Day 31 (p<0.001, n=12/group). Group tumor volumes are graphed as mean ± standard error of the mean SEM. DETAILED DESCRIPTION [0050] The function of ENPP3 in cancer development and progression is not well understood. ENPP3 was identified as an apically restricted cell surface protein in normal tissues by the inventors. The hypothesis was that these proteins would be protected in normal tissues from antibody-based targeting due to lack of access to the bloodstream. Cell surface apical proteins identified with high expression in specific cancers were further evaluated. In tumor tissues, the disruption of the apical-basal polarity results in disorganized expression of these proteins, enabling access to antibody-based therapeutics. This approach represents a unique tumor-specific targeting opportunity for solid tumors, where identifying an exclusive tumor-specific antigen has been a long-standing challenge. [0051] ENPP3 expression is an apically restricted cell surface protein in healthy tissues. In cancer, however, ENPP3 shows non-apical expression. For example, ENPP3 is highly expressed in several solid tumors, including renal cell carcinoma (RCC), endometrial cancer, CRC, hepatocellular carcinoma (HCC), lung adenocarcinoma, and some hematologic tumors like acute basophilic leukemia and neoplastic mast cells (The Human Protein Atlas. ENPP3. https://www.proteinatlas.org/ENSG00000154269-ENPP3. Accessed 17 June 2022.; Hauswirth AW, Escribano L, Prados A, et al. CD203c is overexpressed on neoplastic mast cells in systemic mastocytosis and is upregulated upon IgE receptor cross-linking. Int J Immunopathol Pharmacol.2008;21(4):797-806. doi:10.1177/039463200802100404; Staal-Viliare A, Latger-Cannard V, Didion J, et al. CD203c /CD117-, an useful phenotype profile for acute basophilic leukaemia diagnosis in cases of undifferentiated blasts. Leuk Lymphoma.2007;48(2):439-441. doi:10.1080/10428190601072293; Yano Y, Hayashi Y, Sano K, et al. Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-3 (E- NPP3/CD203c/PD-I beta/B10/gp130RB13-6) in human colon carcinoma. Int J Mol Med. 2003;12(5):763-766). [0052] In some embodiments, provided herein are antibody drug conjugates (ADC) comprising an antibody or antigen binding fragment thereof that bind to ENPP3 conjugated to an auristatin. As shown herein ENPP3 is a tumor antigen that is apically restricted in normal cells, that is therefore not typically accessible to the blood stream. Thus therapies, such as ADCs that target ENPP3 may be especially effective for treating tumor cells that express ENPP3 while avoiding normal cells. Thus, in some aspects, the ADCs provided herein may provide more targeted cancer therapies while avoiding side effects caused by targeting normal tissues. [0053] In some embodiments, the ADC advantageously binds specifically to ENPP3 on the surface of tumor tissues and can kill the ENPP3-positive cells at concentrations with low toxicity toward ENPP3 negative cells. Without wishing to be bound by theory, the cytotoxicity of the ADC provided herein may be mediated by its internalization, processing, and cytotoxic release in the ENPP3 -expressing tumor cells. Additionally, or alternatively, the cytotoxicity may be mediated by a bystander effect allowing the auristatin to diffuse to neighboring ENPP3 negative tumor cells, resulting in cell killing. In some embodiments, the bystander effect allows the payload to diffuse from antigen- positive tumor cells to adjacent antigen-negative tumor cells, resulting in cell killing. In some embodiments, the present ADCs show binding, internalization, and cytotoxicity in ENPP3 positive cancer cells lines (chronic myelogenous leukemia, acute myeloid leukemia, clear cell renal carcinoma, liver cancer, non-small cell lung cancer, kidney adenocarcinoma). In some embodiments, the present ADCs show antitumor efficacy in acute myeloid leukemia, renal cell carcinoma, and non-small cell lung cancer mouse models. [0054] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. I. Definitions [0055] Unless otherwise required by context or expressly indicated, singular terms shall include pluralities and plural terms shall include the singular. [0056] It is understood that aspect and embodiments of the invention described herein include “comprising”, “consisting”, and/or “consisting essentially of” aspects and embodiments. [0057] As used herein, the singular form “a”, “an”, and “the” should be understood to refer to “one or more” of any recited or enumerated component unless indicated otherwise. [0058] The term “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [0059] The term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0060] When a trade name is used herein, reference to the trade name also refers to the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context. [0061] An “antibody” may be a natural or conventional antibody in which two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (l) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains or regions, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties, such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N- terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs therefore refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated CDRL1, CDRL2, CDRL3 and CDRH1, CDRH2, CDRH3, respectively. A conventional antibody antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain variable region. [0062] “Framework Regions” (FRs) refer to amino acid sequences interposed between CDRs, i.e. to those portions of immunoglobulin light and heavy chain variable regions that are relatively conserved among different immunoglobulins in a single species. The light and heavy chains of an immunoglobulin each have four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L, and FR1-H, FR2-H, FR3-H, FR4-H, respectively. [0063] As used herein, a “human framework region” is a framework region that is substantially identical (about 85%, or more, for instance 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the framework region of a naturally occurring human antibody. In the context of the invention, CDR/FR definition in an immunoglobulin light or heavy chain is to be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org). [0064] As used herein, the term “antibody” denotes conventional antibodies and fragments thereof, as well as single domain antibodies and fragments thereof, in particular variable heavy chain of single domain antibodies, and chimeric or humanized.. [0065] The term “monoclonal antibody” or “mAb” as used herein refers to an antibody molecule of a single amino acid sequence, which is directed against a specific antigen, and is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be produced by a single clone of B cells or hybridoma, but may also be recombinant, i.e produced by protein engineering. [0066] The term “chimeric antibody” refers to an engineered antibody which, in its broadest sense, contains one or more regions from one antibody and one or more regions from one or more other antibodies. In an embodiment, a chimeric antibody comprises a VH domain and a VL domain of an antibody derived from a non-human animal, in association with a CH domain and a CL domain of another antibody, in an embodiment, a human antibody. As the non-human animal, any animal such as mouse, rat, hamster, rabbit, or the like can be used. [0067] The term “humanized antibody” refers to an antibody which is wholly or partially of non-human origin and which has been modified to replace certain amino acids, for instance in the framework regions of the VH and VL domains, in order to avoid or minimize an immune response in humans. [0068] The term “human antibody” to an antibody having variable and constant regions derived from human immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by human immunoglobulin sequences (for example mutations introduced by site-specific mutagenesis in vitro), for example in CDRs. However, a “human antibody” does not include antibodies that contain CDR sequences obtained from other species (such as mice) inserted into human frameworks. Human antibodies may be isolated from a donor, produced by recombinant means and/or produced by a rodent that comprises a modified immune system. This definition of a human antibody includes intact or full-length antibodies, fragments thereof, and/or antibodies comprising at least one human heavy and/or light chain polypeptide. [0069] “Fragments” of (conventional) antibodies comprise a portion of an intact antibody, in particular the antigen binding region or variable region of the intact antibody. Examples of antibody fragments include Fv, Fab, F(ab’)2, Fab’, dsFv, (dsFv)2, scFv, sc(Fv)2, diabodies, antibodies formed from antibody fragments. A fragment of a conventional antibody may also be a single domain antibody, such as a heavy chain antibody or VHH. [0070] The term “Fab” denotes an antibody fragment having a molecular weight of about 50,000 and antigen binding activity, in which about a half of the N-terminal side of the heavy chain and the entire light chain are bound together through a disulfide bond. [0071] The term “F(ab’)2” refers to an antibody fragment having a molecular weight of about 100,000 and antigen binding activity, which is slightly larger than 2 identical Fab fragments bound via a disulfide bond of the hinge region. It is usually obtained among fragments by treating IgG with a protease, pepsin. [0072] A single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide-encoding linker. Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2. “dsFv” is a VH::VL heterodimer stabilised by a disulphide bond. “(dsFv)2” denotes two dsFv coupled by a peptide linker. [0073] The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains of the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. [0074] The term “hybridoma” denotes a cell, which is obtained by subjecting a B cell prepared by immunizing a non-human mammal with an antigen to cell fusion with a myeloma cell derived from a mouse or the like which produces a desired monoclonal antibody having an antigen specificity. [0075] By “purified” and “isolated” it is meant, when referring to a polypeptide (i.e. the antibody of the invention) or a nucleotide sequence, that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type. The term “purified” as used herein means at least 75%, 85%, 95%, 96%, 97%, or 98% by weight, of biological macromolecules of the same type are present. An “isolated” nucleic acid molecule which encodes a particular polypeptide refers to a nucleic acid molecule which is substantially free of other nucleic acid molecules that do not encode the subject polypeptide; however, the molecule may include some additional bases or moieties which do not deleteriously affect the basic characteristics of the composition. Similarly, the term “isolated” as used herein can refer to a molecule that has been separated from at least some of the components with which it is typically found in nature or produced. For example, a polypeptide is referred to as “isolated” when it is separated from at least some of the components of the cell in which it was produced. Where a polypeptide is secreted by a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produced it is considered to be “isolating” the polypeptide. Similarly, a polynucleotide is referred to as “isolated” when it is not part of the larger polynucleotide (such as, for example, genomic DNA or mitochondrial DNA, in the case of a DNA polynucleotide) in which it is typically found in nature or is separated from at least some of the components of the cell in which it was produced, e.g., in the case of an RNA polynucleotide. Thus, a DNA polynucleotide that is contained in a vector inside a host cell may be referred to as “isolated”. [0076] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues can contain natural or non-natural amino acid residues, and include, but are not limited to, dimers, trimers, peptides, oligopeptides, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. The term “polypeptide” also refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, so long as the protein maintains the desired activity. The terms “polypeptide” and “protein” encompass ENPP3 antigen binding proteins, including antibodies, antibody fragments, or sequences that have deletions from, additions to, and/or substitutions of one or more amino acids of the antigen binding protein. [0077] A “native sequence” or a “naturally-occurring” polypeptide comprises a polypeptide having the same amino acid sequence as a polypeptide found in nature. Thus, a native sequence polypeptide can have the amino acid sequence of naturally-occurring polypeptide from any mammal. Such native sequence polypeptide can be isolated from nature or can be produced by recombinant or synthetic means. The term “native sequence” polypeptide specifically encompasses naturally-occurring truncated or secreted forms of the polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. [0078] A polypeptide “variant” means a biologically active polypeptide (e.g., an antigen binding protein or antibody) having at least about 70%, 80%, or 90% amino acid sequence identity with the native or a reference sequence polypeptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Such variants include, for instance, polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the polypeptide. In some embodiments, a variant will have at least about 80% amino acid sequence identity. In some embodiments, a variant will have at least about 90% amino acid sequence identity. In some embodiments, a variant will have at least about 95% amino acid sequence identity with the native sequence polypeptide. [0079] As used herein, “Percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antigen binding protein (e.g., antibody) sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are calculated according to this formula using the ALIGN-2 computer program. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not equal the % sequence identity of B to A. [0080] The term “leader sequence” refers to a sequence of amino acid residues located at the N-terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein. Leader sequences can be natural or synthetic, and they can be heterologous or homologous to the protein to which they are attached. [0081] The term “immunoglobulin” refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for instance, Fundamental Immunology (Paul, W., ed., 7th ed. Raven Press, N .Y. (2013)). Briefly, each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region typically is comprised of three domains, CH1, CH2, and CH3. The heavy chains are generally inter- connected via disulfide bonds in the so-called “hinge region.” Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL or VL) and a light chain constant region (CL or CL). The light chain constant region typically is comprised of one domain, CL. The CL can be of κ (kappa) or λ (lambda) isotype. The terms “constant domain” and “constant region” are used interchangeably herein. An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3 and IgG4. “Isotype” refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes. [0082] As used herein, the terms “hypervariable region,” “HVR,” “Complementarity Determining Region,” and “CDR” are used interchangeably. A “CDR” refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL β-sheet framework. CDR1, CDR2 and CDR3 in VH domain are also referred to as HCDR1, HCDR2 and HCDR3, respectively. CDR1, CDR2 and CDR3 in VL domain are also referred to as LCDR1, LCDR2 and LCDR3, respectively. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. [0083] CDR regions are well known to those skilled in the art and have been defined by well- known numbering systems. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed.1991); Nick Deschacht et al., J Immunol 2010; 184:5696-5704). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol.196:901-17 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol.2 (Kontermann and Dübel eds., 2d ed.2010)). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev. Comp. Immunol.27(1):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Plückthun, J. Mol. Biol.309: 657-70 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). [0084] The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the terms “CDR” and “complementary determining region” of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, Chothia, or Contact method. In other cases, the particular amino acid sequence of a CDR is given. It should be noted CDR regions may also be defined by a combination of various numbering systems, e.g., a combination of Kabat and Chothia numbering systems, or a combination of Kabat and IMGT numbering systems. Therefore, the term such as “a CDR1 as set forth in a specific VH” includes any CDR1 as defined by the exemplary CDR numbering systems described above, but is not limited thereby. Once a variable region (e.g., a VH or VL) is given, those skilled in the art would understand that CDRs within the region can be defined by different numbering systems or combinations thereof. [0085] Unless otherwise specified, the terms “CDR” and “complementary determining region” of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., “CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, AbM, Chothia, or Contact method. In other instances, the particular amino acid sequence of a CDR is given. [0086] Thus, in some embodiments, the antigen binding protein comprises CDRs and/or HVRs as defined by the IMGT system. In other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Kabat system. In still other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the AbM system. In further embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Chothia system. In yet other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the IMGT system. [0087] The term “variable region” or “variable domain” refers to the domain of an antigen binding protein (e.g., an antibody) heavy or light chain that is involved in binding the antigen binding protein (e.g., antibody) to antigen. The variable regions or domains of the heavy chain and light chain (VH and VL, respectively) of an antigen binding protein such as an antibody can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and/or form of structurally defined loops), such as complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). [0088] The term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, CH1, CH2, and CH3. Nonlimiting exemplary heavy chain constant regions include γ, δ, and α. Nonlimiting exemplary heavy chain constant regions also include ε and μ. Each heavy constant region corresponds to an antibody isotype. For example, an antibody comprising a γ constant region is an IgG antibody, an antibody comprising a δ constant region is an IgD antibody, and an antibody comprising an α constant region is an IgA antibody. Further, an antibody comprising a μ constant region is an IgM antibody, and an antibody comprising an ε constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (comprising a γ1 constant region), IgG2 (comprising a γ2 constant region), IgG3 (comprising a γ3 constant region), and IgG4 (comprising a γ4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (comprising an α1 constant region) and IgA2 (comprising an α2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2. [0089] The term “heavy chain” (HC) as used herein refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” as used herein refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence. [0090] The term “light chain constant region” as used herein refers to a region comprising a light chain constant domain, CL. Nonlimiting exemplary light chain constant regions include λ and κ. [0091] The term “light chain” (LC) as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full- length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence. [0092] The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU numbering system. [0093] As used herein, the term “epitope” refers to a site on an antigen (e.g., ENPP3), to which an antigen-binding protein (e.g., an antibody or fragments thereof) that targets that antigen. The epitope can comprise amino acids residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues that are not directly involved in the binding, including amino acid residues that are effectively blocked or covered by the antigen binding molecule (i.e., the amino acids are within the footprint of the antigen binding molecule). Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography, two-dimensional nuclear magnetic resonance, and HDX-MS (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol.66, G.E. Morris, Ed. (1996)). Once a desired epitope of an antigen is determined, antigen binding proteins (e.g., antibodies or fragments thereof) to that epitope can be generated using established techniques. It is then possible to screen the resulting antigen binding proteins in competition assays to identify antigen binding proteins that bind the same or overlapping epitopes. Methods for binning antibodies based upon cross-competition studies are described in WO 03/48731. [0094] A “nonlinear epitope,” “discontinuous,” or “conformational epitope” comprises noncontiguous polypeptides, amino acids, and/or sugars within the antigenic protein to which an antibody specific to the epitope binds. [0095] A “linear epitope” or a “continuous epitope” comprises contiguous polypeptides, amino acids, and/or sugars within the antigenic protein to which an antigen binding protein (e.g., an antibody or fragment thereof) specific to the epitope binds. [0096] A “paratope” or “antigen binding site” is the site on the antigen binding protein (e.g., antibody or fragment thereof) that binds the epitope and typically includes the amino acids that are in close proximity to the epitope once the antibody is bound (see, e.g., Sela- Culang et al., 2013, Front Immunol.4:302). [0097] “Affinity” refers to the strength of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. [0098] As used herein, the term “specifically binds”, “binding” or simply “binds” or other related terms in the context of the binding of an antigen binding protein to its target antigen means that the antigen binding protein exhibits essentially background binding to non-target molecules. An antigen binding protein that specifically binds the target antigen (e.g., ENPP3) may, however, cross-react with ENPP3 proteins from different species. Typically, a ENPP3 antigen binding protein specifically binds human ENPP3 when the dissociation constant (KD) is 10-7 M or less, such as about 10-8 M or less, such as about 10-9 M or less, about 10-10 M or less, or about 10-11 M or even less as measured via a surface plasma resonance (SPR) technique (e.g., BIACore, GE-Healthcare Uppsala, Sweden) using the antibody as the ligand and the antigen as the analyte. [0099] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antigen binding protein-antigen interaction (e.g., antibody-antigen interaction). Affinity, as used herein, and KD are inversely related, such that higher affinity is intended to refer to lower KD, and lower affinity is intended to refer to higher KD. [0100] An “antibody-drug-conjugate” or simply “ADC” refers to an antibody conjugated to a drug such as an auristatin. An antibody-drug-conjugate typically binds to the target antigen (e.g., ENPP3) on a cell surface followed by internalization of the antibody-drug- conjugate into the cell where the drug is released. An antibody-drug-conjugate as used herein, include antibody drug conjugates in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms. The term “antibody-drug conjugate (ADC)” as used throughout the present specification refers to an antibody as defined hereinabove, to which one or more therapeutic moieties are conjugated via a linker (linker drugs). [0101] A “drug-to-antibody ratio” (DAR) refers to the number of linker drugs conjugated to the antibody. Conjugation processes typically yield a heterogeneous mixture of different ADC molecules, i.e. different DAR species having different drug-to-antibody ratios. Therefore, the term “ADC” also refers to such mixtures of DAR species. The term “average DAR” refers to the average DAR of the population of such DAR species. [0102] A “cytotoxic effect” refers to the depletion, elimination and/or killing of a target cell. [0103] A “cytostatic effect” refers to the inhibition of cell proliferation. [0104] “Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. In some embodiments, an FcγR is a native human FcR. In some embodiments, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of those receptors. FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see, e.g., Daeron, Annu. Rev. Immunol.15:203-234 (1997)). FcRs are reviewed, for example, in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term “Fc receptor” or “FcR” also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol.117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) and regulation of homeostasis of immunoglobulins. Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward., Immunol. Today 18(12):592-598 (1997); Ghetie et al., Nature Biotechnology, 15(7):637-640 (1997); Hinton et al., J. Biol. Chem.279(8):6213-6216 (2004); WO 2004/92219 (Hinton et al.). [0105] “Effector functions” refer to biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation. Such functions can be affected by, for example, binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system. Typically, the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of the CD33 targeted cell. Fc regions of antibodies can recruit Fc receptor (FcR)-expressing cells and juxtapose them with antibody-coated target cells. Cells expressing surface FcR for IgGs including FcγRIII (CD16), FcγRII (CD32) and FcγRIII (CD64) can act as effector cells for the destruction of IgG-coated cells. Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils and eosinophils. Engagement of FcγR by IgG activates antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). ADCC is mediated by CD16+ effector cells through the secretion of membrane pore- forming proteins and proteases, while phagocytosis is mediated by CD32+ and CD64+ effector cells (see, e.g., Fundamental Immunology, 4th ed., Paul ed., Lippincott-Raven, N.Y., 1997, Chapters 3, 17 and 30; Uchida et al., 2004, J. Exp. Med.199:1659-69; Akewanlop et al., 2001, Cancer Res.61:4061-65; Watanabe et al., 1999, Breast Cancer Res. Treat.53:199-207. [0106] “Human effector cells” are leukocytes which express one or more FcRs and perform effector functions. In certain embodiments, the cells express at least FcγRIII and perform ADCC effector function(s). Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils. The effector cells may be isolated from a native source, e.g., from blood. [0107] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a mechanism of cytotoxicity in which the Fc region of antibodies bound to antigen on the cell surface of target cells interact with Fc receptors (FcRs) present on certain cytotoxic effector cells (e.g. NK cells, neutrophils, and macrophages). This interaction enables these cytotoxic effector cells to subsequently kill the target cell with cytotoxins. The primary cells for mediating ADCC, NK cells, express FcγRIII only, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). [0108] “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to the Fc region of antibodies (of the appropriate subclass), which are bound to their cognate antigen on a target cell. This binding activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane and subsequent cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed. Polypeptide variants with altered Fc region amino acid sequences (polypeptides such as an antibody with a variant Fc region) and increased or decreased C1q binding capability are described, e.g., in U.S. Pat. No.6,194,551 B1, U.S. Pat. No.7,923,538, U.S. Pat. No.7,994,290 and WO 1999/51642. See also, e.g., Idusogie et al., J. Immunol.164: 4178-4184 (2000). [0109] The term “antibody-dependent cellular phagocytosis”, or simply “ADCP”, refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils and dendritic cells) that bind to an Fc region of Ig. [0110] The terms “nucleic acid molecule”, “nucleic acid” and “polynucleotide” are used interchangeably herein and refer to a polymer of nucleotides of any length. Such polymers of nucleotides can contain natural and/or non-natural nucleotides, and include, but are not limited to, DNA, RNA, and PNA. “Nucleic acid sequence” refers to the linear sequence of nucleotides that comprise the nucleic acid molecule or polynucleotide. [0111] The term “vector” means any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage or virus) used to transfer a nucleic acid molecule into a host cell. A vector typically includes a nucleic acid molecule engineered to contain a cloned polynucleotide or polynucleotides encoding a polypeptide or polypeptides of interest that can be propagated in a host cell. A vector may include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and/or enhancers) that regulate the expression of the polypeptide of interest, and/or one or more selectable marker genes. The term includes vectors which are self- replicating nucleic acid molecules as well as vectors incorporated into the genome of a host cell into which it has been introduced. [0112] The term “expression vector” refers to a vector that is suitable for transformation of a host cell and that can be used to express a polypeptide of interest in a host cell. [0113] The terms “host cell” or “host cell line” are used interchangeably herein and refer to a cell or population of cells that may be or has been a recipient of a vector or isolated polynucleotide. Host cells can be prokaryotic cells or eukaryotic cells. [0114] As used herein, “operably linked” means that the components to which the term is applied are in a relationship that allows them to carry out their inherent functions under suitable conditions. For example, a control sequence in a vector that is “operably linked” to a protein coding sequence is ligated thereto such that expression of the protein coding sequence is achieved under conditions compatible with the transcriptional activity of the control sequences. In the case in which two encoding sequences are operably linked, the phrase means that the two DNA fragments or encoding sequences are joined such that the amino acid sequences encoded by the two fragments remain in-frame. [0115] The term “transfection” means the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham et al., 1973, Virology 52:456; Sambrook et al., 2001, Molecular Cloning: A Laboratory Manual, supra; Davis et al., 1986, Basic Methods in Molecular Biology, Elsevier; Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host cells. [0116] The term “transformation” refers to a change in a cell’s genetic characteristics, and a cell has been transformed when it has been modified to contain new DNA or RNA. For example, a cell is transformed where it is genetically modified from its native state by introducing new genetic material via transfection, transduction, or other techniques. Following transfection or transduction, the transforming DNA can recombine with that of the cell by physically integrating into a chromosome of the cell or can be maintained transiently as an episomal element without being replicated or can replicate independently as a plasmid. A cell is considered to have been "stably transformed” when the transforming DNA is replicated with the division of the cell. [0117] A “disease” or “disorder” as used herein refers to a condition where treatment is needed, such as cancer. [0118] “Cancer” and “tumor,” as used herein, are interchangeable terms that refer to any abnormal cell or tissue growth or proliferation in an animal including solid tumors and leukemias. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. [0119] In the context of cancer, the term “treating” includes, but is not limited to, any or all of: inhibiting growth of cancer cells, inhibiting replication of cancer cells, reducing the number of cancer cells, and lessening of overall tumor burden. [0120] A “reference” as used herein, refers to any sample, standard, or level that is used for comparison purposes. A reference can be obtained from a healthy and/or non-diseased sample. In some examples, a reference can be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased on non-treated sample of a subject individual. In some examples, a reference is obtained from one or more healthy individuals who are not the subject or patient. [0121] As used herein, to “suppress” a function or activity is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another condition. For example, an antibody which suppresses tumor growth reduces the rate of growth of the tumor compared to the rate of growth of the tumor in the absence of the antibody. [0122] An “effective amount” or “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent (such as an ADC) is any amount of the drug or agent that, when used alone or in combination provides a treatment effect. [0123] “Administering” or “administration” refer to the physical introduction of a therapeutic agent (such as an ADC) to a subject, using any of the various methods and delivery systems known to those skilled in the art. [0124] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile. [0125] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent (such as an ADC) that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. [0126] The term “sugar” refers to a monosaccharide, for example glucose (Glc), galactose (Gal), mannose (Man) and fucose (Fuc). The term “sugar derivative” refers to a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and/or functional groups. Examples of a sugar derivative include, but are not limited to, amino sugars and sugar acids. Examples of a sugar derivative also include compounds denoted as S’(F’)X1, wherein S’ is a sugar or a sugar derivative, F’ is a functional group and x1 indicates the number of functional groups. [0127] The term “core-GlcNAc moiety”, as used herein, refers to a monosaccharide, polysaccharide, or oligosaccharide moiety comprising a GlcNAc (e.g., a core-GlcNAc) which is attached to an antibody (e.g., via the C1 position of the GlcNAc). In some embodiments, the GlcNAc is attached to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody. In some embodiments, the core-GlcNAc moiety is present at a native glycosylation site of an antibody or is introduced on a different site on the antibody. In some embodiments, the core-GlcNAc moiety is a monosaccharide (e.g., the core-GlcNAc moiety is also a terminal-GlcNAc moiety). In some embodiments, the core-GlcNAc moiety further comprises a fucose, e.g., the core-GlcNAc moiety is a disaccharide core-GlcNAc-(α1-6- Fuc) moiety (which may be referred to as GlcNAc(Fuc)). Thus, when antibody comprises a core-GlcNAc moiety, the antibody may comprise a monosaccharide or a disaccharide core-GlcNAc moiety, and the core-GlcNAc moiety may further comprise a fucose (e.g., a disaccharide core-GlcNAc(Fuc) moiety). If the core-GlcNAc moiety further comprises a fucose, the fucose may be linked α-1,6 to O-6 of the core-GlcNAc moiety. A core- GlcNAc moiety further comprising a fucose may be referred to as core-GlcNAc(Fuc). [0128] The term “core-GlcNAc” refers to the inner GlcNAc that is a portion of a polysaccharide or oligosaccharide, wherein the polysaccharide or oligosaccharide is attached to an antibody via the inner GlcNAc. [0129] The term “terminal-GlcNAc moiety”, as used herein, refers to a moiety comprising a GlcNAc which is attached to an antibody and has a terminal functional group being available for further modification (e.g., with a compound of P”-S”-A”). In some embodiments, the terminal-GlcNAc moiety further comprises a fucose. In some embodiments, the terminal-GlcNAc moiety is formed by reacting the core-GlcNAc moiety of a glycoprotein (e.g., an antibody glycan) with an endoglycosidase. [0130] The term "glycoprotein" is herein used in its normal scientific meaning and refers to a protein comprising one or more monosaccharide or oligosaccharide chains ("glycans") covalently bonded to the protein. A glycan may be attached to a hydroxyl group on the protein (O-linked-glycan), to an amide function on the protein (N-glycoprotein), or to a carbon on the protein (C-glycoprotein). A glycoprotein may comprise more than one glycan, may comprise a combination of one or more monosaccharide and one or more oligosaccharide glycans, and may comprise a combination of N-linked, O-linked and C- linked glycans. It is estimated that more than 50% of all proteins have some form of glycosylation and therefore qualify as glycoprotein. [0131] The term "glycan" is herein used in its normal scientific meaning and refers to a monosaccharide or oligosaccharide chain that is linked to a protein. Glycan thus refers to the carbohydrate-part of a glycoprotein. The glycan is attached to a protein via the C-1 carbon of one sugar, which may be without further substitution (monosaccharide) or may be further substituted at one or more of its hydroxyl groups (oligosaccharide). A naturally occurring glycan typically comprises 1 to about 10 saccharide moieties. However, when a longer saccharide chain is linked to a protein, said saccharide chain is also considered a glycan. A glycan of a glycoprotein may be a monosaccharide. A glycan may also be an oligosaccharide. An oligosaccharide chain of a glycoprotein may be linear or branched. In an oligosaccharide, the sugar that is directly attached to the protein is called the core sugar. In an oligosaccharide, a sugar that is not directly attached to the protein and is attached to at least two other sugars is called an internal sugar. In an oligosaccharide, a sugar that is not directly attached to the protein but to a single other sugar, i.e. carrying no further sugar substituents at one or more of its other hydroxyl groups, is called the terminal sugar. For the avoidance of doubt, there may exist multiple terminal sugars in an oligosaccharide of a glycoprotein, but only one core sugar. A glycan may be an O-linked glycan, an N-linked glycan, or a C-linked glycan. In a delinked glycan, a monosaccharide or oligosaccharide glycan is bonded to a C-atom in an amino acid of the protein. [0132] The term “glycosyltransferase” refers to a superfamily of enzymes that are involved in the synthesis of complex carbohydrates present on glycoproteins and glycolipids. [0133] The term “N-acetylgalactosaminyl transferase” (GalNAc-T or GalNAc transferase) is a N-acetyl-D-galactosamine transferase enzyme that catalyzes the addition of N-acetyl-D- galactosamine to proteins. [0134] In some embodiments, conjugates of the disclosure, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt form thereof are useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as solid tumors or leukemias. [0135] Accordingly, included within the present disclosure are the ADCs as disclosure herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the ADCs of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes. [0136] “Anti-ENPP3 antibody,” “antibody that binds to ENPP3,” “ENPP3 antibody” and “antibody or antigen binding fragment thereof that binds to ENPP3” are used interchangeably herein to refer to an antibody or antigen binding fragment thereof that specifically binds to ENPP3. [0137] Various aspects of the disclosure are described in further detail in the following sections. II. ENPP3 Antibodies [0138] In some aspects, provided herein are antibodies or antigen binding fragment thereof that bind to ENPP3. In some embodiments, the isolated antibody of this invention is specific to human and cynomolgus monkey ENPP3 proteins. In some embodiments, the isolated antibody of this invention binds to ENPP3 and does not bind to cells expressing other forms of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family members. [0139] In some embodiments, provided herein are isolated anti-ENPP3 antibodies that bind to the extracellular region of ENPP3. In some embodiments, the isolated antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the isolated antibody or antibody fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232. [0140] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the isolated anti- ENPP3 antibody or antigen binding fragment thereof is human. In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof is chimeric. In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof is humanized. [0141] In some embodiments, the isolated anti-ENPP3 antibody comprises a Fc region. In some embodiments, the anti-ENPP3 Fc region has been mutated to abolish interactions with Fcγ receptors. In some embodiments, the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the isolated antibody comprises an L234A mutation. In some embodiments, the isolated antibody comprises an L235 mutation. In some embodiments, the isolated antibody comprises a D265S mutation. In some embodiments, the isolated antibody comprises L234A, L235A, and D265S mutations. [0142] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in any of SEQ ID NO: 1, 32, 38, 44, 50, or 56 a CDRH2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 2, 33, 39, 45, 51, or 57 a CDRH3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 3, 34, 40, 46, 52, or 58, a CDRL1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 4, 35, 41, 47, 53, or 59 a CDRL2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 5, 36, 42, 48, 54, or 60 and a CDRL3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 6, 37, 43, 43, 49, 66 or 61. [0143] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. [0144] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37. [0145] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43. [0146] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49. [0147] In some embodiments, isolated the anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55. [0148] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. [0149] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26. In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. [0150] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:7. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. [0151] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:22 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:22. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27. [0152] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:23 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:23. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28. [0153] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:24 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:24. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 29. [0154] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:25 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:25. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. [0155] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:26 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the anti-ENPP3 antibody or antigen binding fragment thereof comprises a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:26. In some embodiments the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 31. [0156] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8. [0157] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27. [0158] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28. [0159] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29. [0160] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30. [0161] In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31. In some embodiments, the antigen binding protein comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31. [0162] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:3 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:5; and a CDR3-L comprising the amino acid sequence set forth in SE Q ID NO:6 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:8. [0163] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:32; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:33; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:35; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:36; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:37 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:27. [0164] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:38; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:39; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:40 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:41; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:42; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:43 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:28. [0165] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:44; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:45; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:46 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:47; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:48; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:49 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:29. [0166] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:50; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:51; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:52 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:53; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:54; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:55 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:30. [0167] In some embodiments, the isolated anti-ENPP3 antibody comprises one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:56; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:57; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:58 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:59; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:60; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:61 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity with the amino acid sequence set forth in SEQ ID NO:31. [0168] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:1, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:2 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:3. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0169] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:32, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:33 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:34. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0170] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:38, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:39 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:40. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0171] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:44, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:45 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:46. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0172] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:50, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:51 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:52. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0173] In some embodiments, the isolated antibody or antigen binding fragment thereof comprises a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:56, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:57 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:58. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0174] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:4, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:5 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:6. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0175] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:35, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:36 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:37. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0176] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:41, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:42 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:43. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0177] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:47, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:48 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:49. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0178] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:53, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:54 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:55. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0179] In other embodiments, the isolated antibody or antigen binding fragment thereof comprises a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:59, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:60 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:61. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0180] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:10 or 17-21. [0181] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10. [0182] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:12, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17. [0183] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:13, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:18. [0184] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:14, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:19. [0185] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:15, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:20. [0186] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and a light chain that has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21. [0187] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16 and the light chain comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21. [0188] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:9 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 10. [0189] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:12 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 17. [0190] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:13 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 18. [0191] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:14 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 19. [0192] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:15 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 20. [0193] In some embodiments, the isolated anti-ENPP3 antibody or antigen binding fragment thereof comprises a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:16 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 121. [0194] In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 of SEQ ID NO: 9. In some embodiments, a modified glycan is a non-native glycan. In some embodiments, the modified glycan is the native glycans on the antibody Fc at position N296 of SEQ ID NO 9. that has been enzymatically processed by an endoglycosidase (e.g. an EndoSH) to the core N- acetylglucosamine followed by attachment of an azido-modified N-acetylgalactosamine utilizing a glycosyl transferase (e.g., a GalNAc transferase). In some embodiments, the modified glycan is at a position corresponding to N296 of SEQ ID NO: 9. [0195] The antibody in any of the foregoing embodiments can be an antibody in any form. As such, the antibody described in any of the above embodiments can be, for example, a monoclonal antibody, a human, humanized or chimeric antibody, and antigen binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library. The antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. [0196] In certain embodiments, an isolated antibody or antigen binding fragment thereof with the HVR and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, CH3 and CL domains. Also included in the present disclosure are antigen-binding fragments comprising any combination of variable region(s) with a hinge region, CH1, CH2, CH3 and CL domains. [0197] In any of the embodiments described herein, one or several amino acids (e.g., 1, 2, 3 or 4) at the amino or carboxy terminus of the light and/or heavy chain, such as the C- terminal lysine of the heavy chain, may be missing or derivatized in some or all of the molecules in a composition. One specific example of such a modification, is an antibody or antigen binding fragment thereof in which the carboxy terminal lysine of the heavy chain is missing. [0198] In certain embodiments, the isolated antibody or antigen binding fragment thereof is a human antibody that binds ENPP3. In some embodiments, the human antibody that binds to ENPP3 is generated by a rodent with a modified immune system. In some embodiments, the human antibody that binds to ENPP3 is generated by a human immune system. [0199] In certain embodiments, the isolated antibody or antigen binding fragment thereof is a humanized antibody that binds ENPP3. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. A humanized antibody is a genetically engineered antibody in which the HVRs (e.g., CDRs) or portions thereof from a non-human “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539; Carter, US 6,407,213; Adair, US 5,859,205; and Foote, US 6,881,557). [0200] The acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence. Human acceptor sequences can be selected for a high degree of sequence identity in the variable region frameworks with donor sequences to match canonical forms between acceptor and donor HVRs or CDRs among other criteria. Thus, a humanized antibody is an antibody having HVRs or CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly, a humanized heavy chain typically has all three HVRs or CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences. Likewise, a humanized light chain usually has all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 80%, 85%, 90%, 95% or 100% of corresponding residues defined by Kabat are identical. [0201] Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on HVR (e.g,.CDR) conformation and/or binding to antigen. Investigation of such possible influences is by modeling, examination of the characteristics of the amino acids at particular locations, or empirical observation of the effects of substitution or mutagenesis of particular amino acids. [0202] For example, when an amino acid differs between a murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid can be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid: (1) noncovalently binds antigen directly, (2) is adjacent to an HVR or CDR region, (3) otherwise interacts with an HVR or CDR region (e.g. is within about 6 Å of such a region); (4) mediates interaction between the heavy and light chains, or (5) is the result of somatic mutation in the mouse chain. (6) is a site of glycosylation. [0203] Framework residues from classes (1)-(3) are sometimes alternately referred to as canonical and vernier residues. Canonical residues refer to framework residues defining the canonical class of the donor CDR loops determining the conformation of a CDR loop (Chothia and Lesk, J. Mol. Biol.196, 901-917 (1987), Thornton & Martin, J. Mol. Biol., 263, 800-815, 1996). Vernier residues refer to a layer of framework residues that support antigen-binding loop conformations and play a role in fine-tuning the fit of an antibody to antigen (Foote & Winter, 1992, J Mol Bio.224, 487-499). [0204] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, (2008) Front. Biosci.13: 1619-1633, and are further described, e.g., in Riechmann et al., (1988) Nature 332:323-329; Queen et al., (1989) Proc. Natl Acad. Sci. USA 86: 10029-10033; US Patent Nos.5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., (2005) Methods 36:25-34 (describing specificity determining region (SDR) grafting); Padlan, (1991) Mol. Immunol.28:489-498 (describing “resurfacing”); Dall'Acqua et al., (2005) Methods 36:43-60 (describing “FR shuffling”); and Osbourn et al., (2005) Methods 36:61-68 and Klimka et al., (2000) Br. J. Cancer, 83:252-260 (describing the “guided selection” approach to FR shuffling). [0205] Human framework regions that may be used for humanization include, but are not limited to, framework regions selected using the “best-fit” method (see, e.g., Sims et al. (1993) J. Immunol.151 :2296); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. (1992) Proc. Natl. Acad. Sci. USA, 89:4285; and Presta et al. (1993) J. Immunol, 151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633); and framework regions derived from screening FR libraries (see, e.g., Baca et al., (1997) J. Biol. Chem.272: 10678-10684 and Rosok et al., (1996) J. Biol. Chem.271 :22611-22618). [0206] In some embodiments, the heavy and light chain variable regions of isolated antibodies described herein can be linked to at least a portion of a human constant region. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from κ and λ. In some embodiments, an isolated antibody described herein comprises a human IgG constant region. In some embodiments, an isolated antibody described herein comprises a human IgG4 heavy chain constant region. In some of these embodiments, an isolated antibody described herein comprises an S241P mutation in the human IgG4 constant region. In some embodiments, an isolated antibody described herein comprises a human IgG4 constant region and a human κ light chain. [0207] Throughout the present specification and claims unless explicitly stated or known to one skilled in the art, the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference. The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. [0208] Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype binds to a non-polymorphic region of a one or more other isotypes. Reference to a human constant region includes a constant region with any natural allotype or any permutation of residues occupying polymorphic positions in natural allotypes. Also, up to 1, 2, 5, or 10 mutations may be present relative to a natural human constant region, such as those indicated above to reduce Fcγ receptor binding. In some embodiments, the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody comprises an L234A mutation. In some embodiments, the antibody comprises an L235 mutation. In some embodiments, the antibody comprises a D265S mutation. In some embodiments, the antibody comprises L234A, L235A, and D265S mutations. [0209] In some embodiments, one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. [0210] The choice of constant region depends, in part, whether antibody-dependent cell- mediated cytotoxicity, antibody dependent cellular phagocytosis and/or complement dependent cytotoxicity are desired. For example, human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotype IgG2 weak complement- dependent cytotoxicity and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4. Light chain constant regions can be lambda or kappa. [0211] In some embodiments, the isolated antibody comprises one or more (e.g., one) core- GlcNAc moiety on each heavy chain, said core-GlcNAc moiety being optionally fucosylated. In some embodiments, the whole antibody comprises two or more (e.g., two) optionally fucosylated, core-GlcNAc moieties. In some embodiments, said core-GlcNAc moiety is present at a native N-glycosylation site of the antibody. In some embodiments, the antibody comprises, or is engineered to comprise, at least one chemically reactive group or a chemically reactive amino acid moiety or side chains. In some embodiments, said core-GlcNAc moiety is present at position N296 according to SEQ ID NO: 9. In some embodiments, position N296 according to SEQ ID NO:9 corresponds to position N297 according to EU numbering. III. Modified anti-ENPP3 Antibodies [0212] In some embodiments, the anti-ENPP3 antibody is a modified anti-ENPP3 antibody. A “modified antibody” or “modified anti-ENPP3 antibody” as used herein is an antibody which has been post-translationally modified. In some embodiments, the modified antibody is an intermediate in a process to produce an antibody drug conjugate. In some embodiments, the modified antibody comprises processed or non-native glycans. [0213] In some embodiments of the modified anti-ENPP3 antibody, * denotes a direct or indirect attachment to the rest of the modified anti-ENPP3 antibody. In some embodiments, S” is a sugar or a derivatized sugar. In some embodiments, A” is a functional group being capable of forming a covalent bond with a functional group of the Linker-Drug moiety, [0214] In some embodiments, the modified anti-ENPP3 antibody, prior to conjugation, comprises a sugar-derivative moiety of * S A . [0215] In some embodiments, the modified anti-ENPP3 antibody comprises an asparagine group in the region 290-305 (e.g., at N297; EU numbering). In some embodiments, the sugar-derivative moiety is directly or indirectly attached to the asparagine group (e.g., at N297; EU numbering). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest (5th ed.1991)). [0216] In some embodiments, the modified anti-ENPP3 antibody, prior to conjugation, * omprises a modified-GlcNAc moiety, Glc S" A" c NAc , wherein GlcNAc is N- acetylglucosamine. [0217] In some embodiments, the modified-GlcNAc moiety is connected to the rest of the modified anti-ENPP3 antibody via the C1 position of the GlcNAc. In some embodiments, the modified-GlcNAc moiety further comprises a fucose. [0218] In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to the asparagine group (e.g., at N297, EU Numbering). In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to N297. In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached at position N180 of SEQ ID NO: 11, a position corresponding to N297 (as numbered by EU numbering). In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to the antibody at position N296 of SEQ ID NO: 9 a position corresponding to N297 (as numbered by EU numbering). [0219] In some embodiments, the modified anti-ENPP3 antibody is conjugated to the Linker- Drug moiety via a covalent bond formed between A” and a functional group of the Linker-Drug moiety. [0220] In some embodiments, the modified antibody that binds to ENPP3 of the present disclosure is obtained by a process comprising: a. contacting an antibody that binds to ENPP3 and a core-GlcNAc moiety with an endoglycosidase, thereby forming an intermediate antibody comprising the antibody and a terminal-GlcNAc moiety and, optionally, the terminal-GlcNAc moiety further comprises a fucose; and b. contacting the intermediate antibody with a compound having the structure of P S A , in the presence of a glycosyltransferase, thereby forming the modified antibody that binds to ENPP3 comprising the antibody and the modified-GlcNAc moiety, , and, optionally, the modified-GlcNAc moiety is attached to the rest of the modified anti-ENPP3 antibody the C1 position of the GlcNAc; wherein GlcNAc is N-acetylglucosamine; S” is a sugar or a derivatized sugar; A” is azido, keto, or alkynyl; and P” is uridine diphosphate (UDP), guanosine diphosphate (GDP) or cytidine diphosphate (CDP). [0221] In some embodiments, steps (a) and (b) are conducted sequentially. In some embodiments, steps (a) and (b) are conducted concurrently. [0222] In some embodiments, the antibody is a monoclonal antibody (mAb). [0223] In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. [0224] In some embodiments, the antibody is an IgG antibody, e.g., an IgGl, IgG2, IgG3, or IgG4 antibody. In some embodiments, the antibody is an IgGl antibody. [0225] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety. [0226] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety connected to each heavy chain of the antibody. [0227] In some embodiments, the core-GlcNAc moiety further comprises a fucose. [0228] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises two or more core-GlcNAc moiety connected to the full-length antibody. [0229] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises two core-GlcNAc moieties connected to the full-length antibody. [0230] In some embodiments, at least one of the two or more core-GlcNAc moieties further comprises a fucose. [0231] In some embodiments, each of the two or more core-GlcNAc moiety further comprises a fucose. [0232] In some embodiments, the antibody is a single chain antibody or an antibody that binds to ENPP3 fragment (e.g., a Fab or Fc fragment), the antibody glycan comprises one or more core-GlcNAc moiety (which optionally further comprises fucose) connected to the antibody. [0233] In some embodiments, the core-GlcNAc moiety is connected to a position of the antibody, wherein the core-GlcNAc moiety does not substantially hinder the antigen- binding site of the antibody. [0234] In some embodiments, the core-GlcNAc moiety is connected to the Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the CH domain. In some embodiments, the core-GlcNAc moiety is connected to the Fab or Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody. In some embodiments, the core-GlcNAc moiety is connected to a native N-glycosylation site of the antibody. [0235] In some embodiments, the antibody is an IgG, antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG. [0236] In some embodiments, the antibody is an IgG, antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG (e.g., the N297 N-glycosylation site of IgG; EU numbering). In some embodiments, the N297 N-glycosylation site is present in the conserved Fc region of the heavy chain of an IgG antibody at asparagine in the region 290-305 (e.g., at N297; EU numbering). [0237] In some embodiments, the intermediate antibody is of Formula (XXII): wherein: Ab is an antibody that binds to ENPP3; GlcNAc is N-acetylglucosamine; Fuc is fucose; u3 is 0 or 1; and u4 is an integer ranging from is 1 to 16. [0238] In some embodiments, u4 is an integer ranging from 1 to 10. In some embodiments, u4 is 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, u4 is 1, 2, 3, 4, 5 or 6. In some embodiments, u4 is 1, 2, 3 or 4. In some embodiments, u4 is 2 or 4. In some embodiments, u4 is 1 or 2. In some embodiments, u4 is 1. In some embodiments, u4 is 2. [0239] In some embodiments, the antibody comprises one core-GlcNAc moiety (e.g., u4 is 1). In some embodiments, the antibody comprises two core-GlcNAc moieties (e.g., u4 is 2). [0240] In some embodiments, the modified antibody that binds to ENPP3 is obtained by the process outlined in Scheme 1. As shown below, contacting an intermediate antibody of Formula (XXIII) comprising one terminal-GlcNAc moiety with a compound having the structure of P" S" A" , in the presence of a glycosyltransferase, provides a modified anti-ENPP3 antibody comprising one modified-GlcNAc moiety (e.g., the modified anti-ENPP3 antibody of Formula (XXIIIa)). [0241] In some embodiments, the modified antibody that binds to ENPP3 is obtained by contacting an intermediate antibody of Formula (XXIV) comprising two terminal-GlcNAc moieties with a compound having the structure of P" S" A" , in the presence of a glycosyltransferase, provides a modified anti-ENPP3 antibody comprising two modified- GlcNAc moieties (e.g., the modified anti-ENPP3 antibody of Formula (XXIVa)). Scheme 1 Ab GlcNAc Glycosyl Transferase (XXIII) (XXIV) (XXIVa) wherein u3, Ab, S”, A”, and P” are as defined herein. [0242] In some embodiments, the antibody glycan to be modified in the process according to the present disclosure comprises a glycan, said glycan comprising a core-GlcNAc moiety, i.e., a GlcNAc moiety that is present at the non-reducing end of the glycan. In some embodiments, the glycan comprises one or more saccharide moieties and may be linear or branched. [0243] In some embodiments, upon reacting with endoglycosidase, the intermediate antibody may be formed, which comprises a terminal GlcNAc moiety (e.g., the intermediate antibody of Formula (XXIII) or (XXIV)). [0244] In some embodiments, the endoglycosidase is endoglycosidase Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof. [0245] In some embodiments, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof. [0246] In some embodiments the endoglycosidase is Endo S or Endo SH, or a combination thereof. In some embodiments the endoglycosidase is Endo SH. [0247] In some embodiments, step (b) of the process (the formation of the modified antibody that binds to ENPP3 is as shown in FIG.1, wherein the intermediate antibody comprises a monoclonal antibody (mAb) and a terminal GlcNAc moiety (which optionally comprises a fucose (e.g., u3 is 0 or 1)) on each heavy chain of the monoclonal antibody (mAb). In some embodiments, in step (b), the terminal-GlcNAc moiety is converted into modified-GlcNAc moiety. In some embodiments, said conversion may be executed via reaction of the terminal GlcNAc moiety with the compound of the presence of a glycosyltransferase. [0248] In some embodiments, the compound of P" S" A" is GalNAz-UDP (e.g., 4- AzGalNAc-UDP). In some embodiments, the terminal-GlcNAc moiety is *-GlcNAc- GalNAz or *-GlcNAc(Fuc)-GalNAz, wherein * denotes the attachment to the rest of the modified antibody that binds to ENPP3. [0249] In some embodiments, the steps of the deglycosylation/trimming step and the formation of the modified antibody that binds to ENPP3 are conducted sequentially. [0250] In some embodiments, the steps of the deglycosylation/trimming step and the formation of the modified antibody that binds to ENPP3 are conducted simultaneously. [0251] In some embodiments, the process for the preparation of a modified antibody that binds to ENPP3 is performed in a suitable buffer solution, e.g., buffered saline (e.g. phosphate-buffered saline, Tris-buffered saline), citrate, HEPES, Tris and glycine. In some embodiments, the buffer solution is phosphate-buffered saline (PBS) or Tris buffered saline. In some embodiments, the buffer solution is phosphate-buffered saline (PBS). [0252] In some embodiments, the process is performed at a temperature ranging from about 4 to about 50 °C. In some embodiments, the process is performed at a temperature ranging from about 10 to about 45 °C. In some embodiments, the process is performed at a temperature ranging from about 20 to about 40 °C. In some embodiments, the process is performed at a temperature ranging from about 30 to about 37 °C. In some embodiments, the process is performed at a temperature of about 30 °C. In some embodiments, the process is performed at a temperature of 30 °C. [0253] In some embodiments, the process is performed at a pH value ranging from about 5 to about 9 (e.g., from about 5.5 to about 8.5, from about 6 to about 8, or from about 7 to about 8). In some embodiments, the process is performed at a pH value of about 7.4. [0254] In some embodiments, the process for the preparation of a modified antibody that binds to ENPP3 is as shown in FIG.2. [0255] In some embodiments, the process for the preparation of a modified antibody that binds to ENPP3 comprises: (a) contacting a glycoprotein (e.g., an anti-ENPP3 antibody glycan) comprising an antibody that binds to ENPP3 and core-GlcNAc moiety connected to site N297; EU numbering, of the antibody, with endoglycosidase Endo SH, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and (b) contacting the intermediate antibody with 4-AzGalNAc-UDP in the presence of a β-(l,4)-GalNAcT enzyme, thereby forming the modified anti-ENPP3 antibody comprising the modified-GlcNAc moiety; wherein steps (a) and (b) are conducted concurrently. [0256] In some embodiments, the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa. [0257] In some embodiments, the β-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa. In some embodiments, the β-(l,4)-GalNAcT enzyme containing an N-terminal 6xHis tag (SEQ ID NO: 233) is derived from Trichopulsia ni. [0258] In some embodiments, the process is conducted in PBS buffer at pH value of about 7.4 and at a temperature of about 30 oC. Endoglycosidases [0259] Endoglycosidases are enzymes that are capable of cleaving internal glycosidic linkages in glycan structures, thereby remodeling or trimming the glycan structure. For example, endoglycosidases can be used for the facile homogenization of heterogeneous glycan populations, when they cleave at predictable sites within conserved glycan regions. One class of endoglycosidases comprises the endo-β-N-acetylglucosaminidases (EC 3.2.1.96, commonly known as Endo S or ENGases), a class of hydrolytic enzymes that removes N-glycans from glycoproteins by hydrolyzing the β-l,4-glycosidic bond in the Ν,Ν'-diacetylchitobiose core (as described in Wong et al. Chem. Rev.2011, 111, 4259, which is incorporated herein by reference in its entirety), leaving a single core N- linked GlcNAc residue. Endo-β-N-acetylglucosaminidases are widely found in nature with common chemoenzymatic variants including Endo D, which is specific for paucimannose; Endo A and Endo H, which are specific for high mannose; Endo F subtypes, which range from high mannose to biantennary complex; and Endo M, which can cleave most N-glycan structures (high mannose/complex-type/hybrid-type), except fucosylated glycans, and the hydrolytic activity for the high-mannose type oligosaccharides is significantly higher than that for the complex-and hybrid-type oligosaccharides. In some embodiments, these ENGases show specificity toward the distal N-glycan structure and not the protein displaying it, making them useful for cleaving most N-linked glycans from glycoproteins under native conditions. [0260] In some embodiments, endoglycosidases Fl, F2, and F3 are suitable for deglycosylation of native proteins. The linkage specificities of Endo Fl, F2, and F3 suggest a general strategy for deglycosylation of proteins that may remove all classes of N-linked oligosaccharides without denaturing the protein. In some embodiments, biantennary and triantennary structures can be immediately removed by endoglycosidases F2 and F3, respectively. In some embodiments, oligo-mannose and hybrid structures can be removed by Endo Fl. [0261] Endo S is a secreted endoglycosidase from Streptococcus pyogenes, and also belongs to the glycoside hydrolase family 18, as disclosed by Collin et al. (EMBO J., 2001, 20, 3046), which is incorporated by reference herein in its entirety. In contrast to the ENGases mentioned above, Endo S has a more defined specificity and is specific for cleaving only the conserved N-glycan in the Fc domain of human IgGs (no other substrate has been identified to date), suggesting that a protein-protein interaction between the enzyme and IgG provides this specificity. [0262] Endo S49, also known as Endo S2, is described in WO 2013/037824, incorporated by reference herein in its entirety, is isolated from Streptococcus pyogenes NZ131 and is a homologue of Endo S. Endo S49 has a specific endoglycosidase activity on native IgG and cleaves a larger variety of Fc glycans than Endo S. [0263] Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer. Endo SH specifically cleaves the N-linked glycans between two N- acetylglucosame (GluNAc) moieties in the core region of the glycan chain. [0264] In some embodiments, the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, Endo M, Endo A, or a combination thereof. In some embodiments, the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, or a combination thereof. In some embodiments, the endoglycosidase is Endo S, Endo SH, Endo S2, or Endo S49. [0265] In some embodiments, when the glycan to be trimmed is a diantennary structure of the complex type, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof. In some embodiments, endoglycosidases Fl, F2, and F3 are suitable for deglycosylation of native proteins. The linkage specificities of Endo Fl, F2, and F3 suggest a general strategy for deglycosylation of proteins that may remove all classes of N-linked oligosaccharides without denaturing the protein. In some embodiments, biantennary and triantennary structures can be immediately removed by endoglycosidases F2 and F3, respectively. In some embodiments, oligo-mannose and hybrid structures can be removed by Endo Fl. [0266] Endo S is a secreted endoglycosidase from Streptococcus pyogenes, and also belongs to the glycoside hydrolase family 18, as disclosed by Collin et al. (EMBO J., 2001, 20, 3046), which is incorporated by reference herein in its entirety. In contrast to the ENGases mentioned above, Endo S has a more defined specificity and is specific for cleaving only the conserved N-glycan in the Fc domain of human IgGs (no other substrate has been identified to date), suggesting that a protein-protein interaction between the enzyme and IgG provides this specificity. [0267] Endo S49, also known as Endo S2, is described in WO 2013/037824, incorporated by reference herein in its entirety, is isolated from Streptococcus pyogenes NZ131 and is a homologue of Endo S. Endo S49 has a specific endoglycosidase activity on native IgG and cleaves a larger variety of Fc glycans than Endo S. [0268] Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer. Endo SH specifically cleaves the N-linked glycans between two N- acetylglucosame (GluNAc) moieties in the core region of the glycan chain. [0269] In some embodiments, the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, Endo M, Endo A, or a combination thereof. In some embodiments, the endoglycosidase for deglycosylating the antibody is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, Endo H, or a combination thereof. In some embodiments, the endoglycosidase is Endo S, Endo SH, Endo S2, or Endo S49. [0270] In some embodiments, when the glycan to be trimmed is a diantennary structure of the complex type, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof. [0271] In some embodiments, when the glycoprotein is an anti-ENPP3 antibody and the oligosaccharide to be trimmed is a diantennary structure of the complex type and is present at the IgG conserved N-glycosylation site at N297, EU numbering, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, Endo Fl, Endo F2, Endo F3, or a combination thereof. In some embodiments the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof. [0272] In some embodiments, when the glycoprotein is an anti-ENPP3 antibody and the glycan to be trimmed is a diantennary structure of the complex type, and is not present at the IgG conserved N-glycosylation site at N297, EU numbering, the endoglycosidase is Endo Fl, Endo F2, Endo F3, or a combination thereof. [0273] In some embodiments, when the glycan to be trimmed is a high mannose, the endoglycosidase is Endo H, Endo M, Endo A, Endo F1, or a combination thereof. [0274] In some embodiments, when the glycoprotein is an anti-ENPP3 antibody and the oligosaccharide to be trimmed is a high mannose in addition to having a diantennary structure of the complex type is present at the IgG conserved N-glycosylation site at N297, EU numbering, the endoglycosidase is Endo S, Endo SH, Endo S2, Endo S49, or a combination thereof. In some embodiments, the endoglycosidase is Endo S or Endo SH. In some embodiments, the endoglycosidase is Endo SH. [0275] In some embodiments, the endoglycosidase enzyme as defined herein comprises a sequence encoding a tag for ease of purification. In some embodiments, said tag includes, but is not limited to, a FLAG-tag, poly(His)-tag, HA-tag, Myc-tag, SUMO-tag, GST-tag, MBP-tag, or a CBP-tag. In some embodiments, said tag is a 6xHis tag (SEQ ID NO: 233). In some embodiments, said tag is covalently linked to the endoglycoside enzyme at the C- terminus of the enzyme or at an internal residue. In some embodiments, said tag is covalently linked to the endoglycoside enzyme at the N-terminus of the enzyme. [0276] In some embodiments, the Endo SH is a fusion between the two endoglycosidases, Endo S and Endo H linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa. Glycosyltransferase [0277] The process to form a modified antibody that binds to ENPP3 comprises treating the deglycosylated/trimmed antibody having an optionally fucosylated terminal N- acetylglucosamine (Gal-NAc) moiety with a compound of Formula S’’(A’’)-P’’ in the presence of a glycosyltransferase to form the modified antibody that binds to ENPP3 having a GlcNAc-S’’(A’’) substituent bonded to the antibody at C1 of the GalNAc moiety via a β-1,4-O-glycosidic bond. [0278] In some embodiments, the glycosyltransferases is a β-l,4-galactosyltransferases (4Gal-T), a β-(1,4)-Acetylgalactosaminyltransferase (β-(l,4)-GalNAcT or GalNAcT) or a mutant thereof. [0279] β-(1,4)-Acetylgalactosaminyltransferases (β-(l,4)-GalNAcTs or GalNAcTs) have been identified in a number of organisms, including humans, Caenorhabditis elegans (Kawar et al, J. Biol. Chem.2002, 277, 34924, incorporated by reference herein in its entirety), Drosophila melanogaster (Hoskins et al. Science 2007, 316, 1625, incorporated by reference herein in its entirety) and Trichoplusia ni (Vadaie et al, J. Biol. Chem.2004, 279, 33501, incorporated by reference herein in its entirety). [0280] β-(l,4)-N-Acetylgalactosaminyltransferases (β-(l,4)-GalNAcTs) are known in the art. In some embodiments, a β-(l,4)-GalNAcT is an enzyme that catalyzes the transfer of N- acetylgalactosamine (GalNAc) from uridine diphosphate-GalNAc (UDP-GalNAc, also referred to as GalNAc-UDP) to a terminal GlcNAc moiety of a glycoprotein glycan, wherein C1 of the GalNAc moiety is attached to the antibody via a β-1,4-O-glycosidic bond. In some embodiments. the terminal GlcNAc moiety is fucosylated. [0281] In some embodiments, the β-(l,4)-GalNAcT enzyme used in the process of the invention is or is derived from an invertebrate β-(l,4)-GalNAcT enzyme, such as, for example, is or is derived from a β-(l,4)-GalNAcT that originates from invertebrate animal species. The β-(1,4)-GalNAcT enzyme can be or can be derived from any invertebrate β- (l,4)-GalNAcT enzyme known by one skilled in the art. In some embodiments, the β- (l,4)-GalNAcT enzyme is or is derived from a β-(l,4)-GalNAcT enzyme that originates from the phylum of Nematoda, such as, for example, of the class of Chromadorea or Secernentea, or of the phylum of Arthropoda, such as, for example, of the class of Insecta. In some embodiments, the β-(l,4)-GalNAcT enzyme is or is derived from a β- (l,4)-GalNAcT enzyme that originates from Caenorhabditis elegans, Caenorhabditis remanei, Caenorhabditis briggsae, Ascaris suum, Trichoplusia ni, Drosophila melanogaster, Wuchereria bancrofti, Loa loa, Cerapachys biroi, Zootermopsis nevadensis, Camponotus floridanus, Crassostrea gigas or Danaus plexippus, (e.g., from Caenorhabditis elegans, Ascaris suum, Trichoplusia ni or Drosophila melanogaster). In some embodiments, the β-(l,4)-GalNAcT enzyme is, or is derived from, a β-(l,4)- GalNAcT enzyme that originates from Caenorhabditis elegans, Ascaris suum or Trichoplusia ni. In other embodiments, the β-(l,4)-GalNAcT enzyme is, or is derived from, a β-(l,4)-GalNAcT enzyme that originates from Trichoplusia ni. [0282] The term "derived from" comprises e.g. truncated enzymes, mutant enzymes, enzymes comprising a tag for ease of purification or a combination of these modifications. Derived from thus refers to as having an amino acid sequence that is altered from a naturally occurring β-(l,4)-GalNAcT enzyme by substituting, inserting, deleting, or adding one or more, (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or more) amino acids, respectively. A β-(l,4)-GalNAcT enzyme that is derived from a β- (l,4)-GalNAcT enzyme is herein also referred to as a derived β-(1,4)-GalNAcT enzyme or a modified β -(l,4)-GalNAcT enzyme or a β-(l,4)-GalNAcT mutant enzyme. [0283] In some embodiments, the derived β-(l,4)-GalNAcT enzyme is modified by adding additional N- or C- terminal amino acids or chemical moieties or by deleting N- or C- terminal amino acids to increase stability, solubility, activity and/or ease of purification. [0284] In some embodiments, the β-(l,4)-GalNAcT enzyme is modified by deleting the N- terminal cytoplasmic domain and transmembrane domain, referred to as a truncated enzyme. [0285] A β-(l,4)-GalNAcT enzyme wherein one or more amino acid has been substituted, added or deleted is herein also referred to as a mutant β-(l,4)-GalNAcT enzyme or a derived β-(l,4)-GalNAcT enzyme. In some embodiments, the β-(l,4)-GalNAcT enzyme is modified by deleting the N-terminal cytoplasmic domain and transmembrane domain and mutated by substituting one or more amino acids. A substitution of one or more amino acids is herein also referred to as a mutation. An enzyme comprising one or more substituted amino acids is also referred to as a mutant enzyme. [0286] In some embodiments, when the glycosyltransferase is a β-(l,4)-GalNAcT enzyme or truncated β-(l,4)-GalNAcT enzyme, the enzyme further comprises one or more mutations. In some embodiments, these mutations include, but are not limited to, substitution of the isoleucine (He, also referred to as I) at position 257 by leucine (Leu, also referred to as L), methionine (Met, also referred to as M), or alanine (Ala, also referred to as A). In some embodiments, substitution of the methionine (Met, also referred to as M) at position 312 by histidine (His, also referred to as H) is also included. It should be noted that the numbering of amino acid position is herein based on the numbering of amino acid position in the wild-type β-(l,4)-GalNAcT enzyme. When a β-(l,4)-GalNAcT enzyme is, for example, a truncated enzyme, the number used herein to indicate the position of an amino acid substitution corresponds to the numbering of amino acid position in the corresponding wild-type β-(l,4)-GalNAcT enzyme. [0287] In some embodiments, the glycosyltransferase is a β(l,4)-GalT enzyme comprising a mutant catalytic domain. [0288] A catalytic domain may have an amino acid sequence as found in a wild-type enzyme or have an amino acid sequence that is different from that of a wild-type sequence. A catalytic domain having an amino acid sequence that is different from a wild-type sequence is herein referred to as a mutant catalytic domain. In some embodiments, the mutation may comprise a single amino acid change (for example, a point mutation), or multiple amino acids changes (for example, 1 to 10, or 1 to 6, or 1, 2, 3 or 4, or 1 or 2 amino acids), or a deletion or insertion of one or more amino acids (for example, 1 to 10, or 1 to 6, or 1, 2, 3 or 4,or 1 or 2) amino acids. In some embodiments, said mutant catalytic domain may be present in a full-length enzyme, for example, β(l,4)- galactosyltransferase or α(l,3)-N-galactosyltransferase, but also in a polypeptide fragment or a recombinant polypeptide comprising said mutant catalytic domain, optionally linked to additional amino acids. [0289] β(l,4)-galactosyltransferase I is herein referred to as GalT. Such mutant GalT catalytic domains are disclosed in, for example, WO 2004/063344, which is incorporated by reference herein in its entirety. WO 2004/063344 also discloses Tyr- 289 mutants of GalT and their methods of preparation. These mutants are referred to as Y289L, Y289N or Y289I. [0290] In some embodiments, the GalT mutant catalytic domain is Y289L, Y289N, Y289I, Y284L, or R228K. In some embodiments, the GalT mutant catalytic domain is Y289L. [0291] In some embodiments, the GalT Y289F, GalT Y289M, GalT Y289V, GalT Y289G, GalT Y289I, GalT Y289A, GalT Y289N, and GalT Y289L mutants may be produced via site-directed mutagenesis processes, described in, for example, WO2004063344, Qasba et al, Prot. Expr. Pur.2003, 30, 219 and Qasba et al, J. Biol. Chem.2002, 277, 20833 (all incorporated by reference herein in their entirety). In GalT Y289F the tyrosine amino acid (Y) at position 289 is replaced by a phenyl alanine (F) amino acid, in GalT Y289M said tyrosine is replaced by a methionine (M) amino acid, in GalT Y289V by a valine (V) amino acid, in GalT Y289G by a glycine (G) amino acid, in GalT Y289I by an isoleucine (I) amino acid and in Y289A by an analine (A) amino acid. [0292] In some embodiments, the β-(l,4)-GalNAcT enzyme comprises a sequence encoding a tag for ease of purification. In some embodiments, said tag includes, but is not limited to, a FLAG-tag, poly(His)-tag, HA-tag, Myc-tag, SUMO-tag, GST-tag, MBP-tag, or a CBP- tag. In other embodiments, said tag is a 6xHis tag (SEQ ID NO: 233). In some embodiments, said tag is covalently linked to the β-(l,4)-GalNAcT enzyme at the C- terminus of the enzyme. In some embodiments, said tag is covalently linked to the β-(l,4)- GalNAcT enzyme at the N-terminus of the enzyme. [0293] In some embodiments, β-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa. In some embodiments, the β-(l,4)-GalNAcT enzyme containing an N-terminal 6xHis tag (SEQ ID NO: 233) is derived from Trichopulsia ni. Molecules of P”-S”-A” [0294] In some embodiments, the molecule of P”-S”-A”, for use in the process of preparing a modified antibody that binds to ENPP3 of the present disclosure, may be any sugar derivative nucleotide that is a substrate for a suitable galactosyltransferase catalyst. [0295] In some embodiments, S”-A” is a sugar derivative moiety, wherein: [0296] S” is a sugar or a derivatized sugar; and A” is a functional group being capable of forming a covalent bond with a functional group of the Linker-Drug moiety. [0297] In some embodiments, A” is an azido, keto, or alkynyl moiety. In some embodiments, A” is an azido or keto moiety. In some embodiments, A” is an azido moiety. In some embodiments, A” is -N3. In some embodiments, A” is a keto moiety. [0298] In some embodiments, A” is -[C(R8k)2]x2C(O)R9k, wherein: R9k is methyl or optionally substituted C2-24 alkyl; each R8k independently is a hydrogen, halogen, or R9k; and x2 is an integer ranging from 0 to 24. [0299] In some embodiments, x2 is an integer ranging from 0 to 10. In some embodiments, x2 is 0, 1, 2, 3, 4, 5, or 6. [0300] In some embodiments, each R8k is hydrogen. [0301] In some embodiments, A” is an alkynyl moiety. In some embodiments, A” is terminal alkynyl, cycloalkynyl, or heterocycloalkynyl moiety. In some embodiments, A” is terminal alkynyl moiety. In some embodiments, A” is cycloalkynyl moiety. In some embodiments, A” is heterocycloalkynyl moiety. [0302] In some embodiments, A” is -[C(R8k)2]x2-C≡C-R8k group, wherein R8k and x2 are as defined herein. In some embodiments, A” is -[CH2]x2-C≡CH. [0303] In some embodiments, S”-A” is derived from a sugar or a derivatized sugar, e.g., an amino sugar or an otherwise derivatized sugar. In some embodiments, examples of sugars and derivatized sugars include, but are not limited to, galactose (Gal), mannose (Man), glucose (Glc), glucuronic acid (Gcu), and fucose (Fuc). It is understood that an amino sugar is a sugar wherein a hydroxyl (OH) group is replaced by an amine group. Examples of amino sugars include, but are not limited to, N-acetylglucosamine (GlcNAc), and N- acetylgalactosamine (GalNAc). Examples of otherwise derivatized sugars include, but are not limited to, glucuronic acid (Gcu), and N-acetylneuraminic acid (sialic acid). [0304] In some embodiments, S”-A” is derived from galactose (Gal), mannose (Man), N- acetylglucosamine (GlcNAc), glucose (Glc), N-acetylgalactosamine (GalNAc), glucuronic acid (Gcu), fucose (Fuc), or N-acetylneuraminic acid (sialic acid). In some embodiments, S”-A” is derived from GlcNAc, Glc, Gal, or GalNAc. In some embodiments, S”-A” is derived from GlcNAc. In some embodiments, S”-A” is derived from Glc. In some embodiments, S”-A” is derived from Gal or GalNAc. In some embodiments, S”-A” is derived from Gal. In some embodiments, S”-A” is derived from GalNAc. [0305] In some embodiments, the functional group A” may be attached to S” in various ways. [0306] In some embodiments, A” is directly attached to the carbon atom at C2, C3, C4, or C6 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position). [0307] In some embodiments, S” is a fucose or a derivatized fucose, which lacks any hydroxyl C6 position. In some embodiments, when A” is attached to C6 position of the fucose or derivatized fucose, A” is directly attached to the carbon atom at the C6 position. [0308] In some embodiments, A” is an azido moiety, and A” is attached to C2, C4, or C6 position of the sugar or derivatized sugar of S”. [0309] In some embodiments, A” is an azido moiety, and A” is directly attached to the carbon atom at C2, C3, C4 or C6 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position). In some embodiments, S”-A” is 6- azidofucose (6-AzFuc). In some embodiments, A” is an azido moiety, and A” is attached to the N-acetyl moiety of an amino sugar or a derivatized amino sugar (e.g., by replacing the acetyl moiety with an azidoacetyl moiety). In some embodiments, S”-A” is 2- azidoacetamidogalactose (GalNAz), 6-azido-6-deoxygalactose (6-AzGal), 6-azido-6- deoxy-2-acetamidogalactose (6-AzGalNAc), 4-azido-4-deoxy-2- acetamidogalactose (4- AzGalNAc), 6-azido-6-deoxy-2-azidoacetamidogalactose (6- AzGalNAz), 2- azidoacetamidoglucose (GlcNAz), 6-azido-6-deoxyglucose (6-AzGlc), 6-azido-6-deoxy- 2-acetamidoglucose (6-AzGlcNAc), 4-azido-4-deoxy-2- acetamidoglucose (4- AzGlcNAc), or 6-azido-6-deoxy-2-azidoacetamidoglucose (6- AzGlcNAz). In some embodiments, S”-A” is GalNAz, 4-AzGalNAc, GlcNAz, or 6-AzGlcNAc. [0310] In some embodiments, P”-S”-A” is a compound of Formula (XXIVb), (XXXIVc), or (XXIVd), or a salt thereof. [0311] In some embodiments, A” keto, and A’’ is directly attached to the carbon atom at C2 position of the sugar or derivatized sugar of S” (e.g., instead of the hydroxyl at the corresponding position). [0312] In some embodiments, A” is attached to the nitrogen atom of an amino sugar or derivatized amino sugar, e.g., a C2-derivatized amino sugar. In some embodiments, the derivatized amino sugar comprises a moiety of -NC(O)-R9k, wherein R9k is methyl or optionally substituted C2-24 alkyl (e.g., ethyl). [0313] In some embodiments, R9k is ethyl. [0314] In some embodiments, S”-A” is 2-deoxy-(2-oxopropyl)-galactose (2-keto-Gal), 2-N- propionyl-galactosamine (2-N-propionylGal-NAc), 2-N-(4-oxopentanoyl)-galactosamine (2-N-Lev-Gal), or 2-N-butyryl-galactosamine (2-N-butyryl-GalNAc). In some embodiments, S”-A” is 2- ketoGalNAc or 2-N-propionyl-GalNAc. [0315] In some embodiments, P”-S”-A” is a compound of Formula (XXIVe) or (XXIVf), or a salt thereof. [0316] In some embodiments, A” is terminal alkynyl, cycloalkynyl, or heterocycloalkynyl. In some embodiments, A” is attached to a C2-derivatized amino sugar of S”. [0317] In some embodiments, S”-A” is 2-(but-3-ynoic acid amido)-2-deoxy-galactose. [0318] In some embodiments, P”-S”-A” is a compound of Formula (XXIVg) or a salt thereof. In some embodiments, P”-S”-A” is a compound of Formula (XXIVd) or a salt thereof. [0319] In some embodiments, compounds of P”-S”-A” may be synthesized according to various methods known in the art. In some embodiments, the compound is synthesized by linking a nucleoside monophosphate or a nucleoside diphosphate P” to a sugar derivative , e.g., as disclosed in Wang et al. (Chem. Eur. J. 16:13343-13345 (2010)), Piller et al. (ACS Chem. Biol.7:753 (2012)), Piller et al. (Bioorg. Med. Chem. Lett. 15:5459-5462 (2005), and PCT Appl’n Pub. No. WO/2009/102820, each of which are incorporated by reference herein in their entireties. [0320] In some embodiments, P” is a nucleoside mono- or diphosphate. In some embodiments, P” is uridine diphosphate (UDP), guanosine diphosphate (GDP), thymidine diphosphate (TDP), cytidine diphosphate (CDP), or cytidine monophosphate (CMP). In some embodiments, P” is uridine diphosphate (UDP). [0321] In some embodiments, P”-S”-A” is a compound of Formula (XXIVb), (XXIVc), (XXIVd), (XXIVe), (XXIVf), or (XXIVg): (XXIVe) (XXIVf) (XXIVg) or a salt thereof, wherein: R9k is a C2-24 alkyl group. [0322] In some embodiments, P”-S”-A” is GalNAz-UDP (e.g., Formula (XXIVb)), 6- AzGal-UDP (e.g., Formula (XXIVc)), 6-AzGalNAc-UDP (e.g., Formula (XXIVd)), 4- AzGalNAz-UDP, 6-AzGalNAz-UDP, 6- AzGlc-UDP, 6-AzGlcNAz-UDP, 2-ketoGal- UDP (e.g., Formula (XXIVe)), 2-N-propionylGalNAc-UDP (e.g., Formula (XXIVf), wherein R9k is ethyl), or 2-(but-3-ynoic acid amido)-2-deoxy-galactose-UDP (e.g., Formula (XXIVg)). [0323] In some embodiments, P”-S”-A” is GalNAz-UDP or 4-AzGalNAc-UDP. In some embodiments, P”-S”-A” is a compound of Formula (XXIVb) or (XXIVd). The syntheses of GalNAz-UDP (e.g., Formula (XXIVb)) and 6-AzGalNAc-UDP (e.g., Formula (XXIVd)) are disclosed in Piller et al. (Bioorg. Med. Chem. Lett.15:5459-5462 (2005)) and Wang et al. (Chem. Eur. J.16:13343-13345 (2010)), each of which is incorporated by reference herein in its entirety. [0324] In some embodiments, P”-S”-A” is 4-AzGalNAc-UDP. In some embodiments, P”- S”-A” is a compound of Formula (XXIVd) or a salt thereof. The synthesis of 2-ketoGal- UDP (XXIVe) is disclosed in Qasba et al. (J. Am. Chem. Soc.125:16162 (2003)), and in the supporting information thereof, both of which are incorporated by reference herein in their entireties. [0325] The synthesis of 2-(but-3-ynoic acid amido)-2-deoxy-galactose-UDP is disclosed in PCT Appl’n Pub. No. WO/2009/102820, which is incorporated by reference herein in its entirety. IV. Anti-ENPP3 ADCs [0326] In some embodiments, provided herein is an antibody-drug conjugate (ADC) comprising one or more Linker-Drug moieties covalently bonded to an antibody or antigen binding fragment thereof that binds to ENPP3 (Ab), wherein each Linker-Drug moiety comprises a multifunctional linker that connect Ab to one or more drugs (e.g., an auristatin). [0327] In some embodiments, an ADC has the structure: Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and LA, LA is a divalent moiety connecting L to D, D is a drug. In some embodiments, n is an integer 1, 2, or 3 and m is an integer 1, 2, or 3. In some embodiments, the antibody comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31. In some embodiments, the drug (D) is an auristatin. In some embodiments, the ADC provided herein, has certain advantages over other ADCs including increased anti-tumor activity and decreased toxicity. In some embodiments, the drug is an auristatin (i.e., D is an auristatin). In some embodiments, n=3 and m=2. In some embodiments, the DAR is 6. In some embodiments, n=3 and m=1. In some embodiments, the DAR is 3. [0328] It is understood that an ADC is typically produced as a composition containing a population of ADCs, i.e., a mixture of ADCs that are essentially identical, except for the drug load. In some embodiments, an ADC can be characterized by a drug-to-antibody ratio (DAR). In some embodiments, the DAR is the number of drug moieties conjugated to an antibody moiety in an ADC molecule. Thus, in some aspects, the present disclosure provides an ADC composition comprising a mixture of ADCs, wherein each antibody in the mixture is identical, except that the number of drugs or drug-linkers that are conjugated to each antibody can vary. [0329] In some embodiments, the antibody drug conjugate (ADC) comprises an antibody that binds to human and cynomolgus monkey ENPP3 proteins. In some embodiments, the ADC comprises an antibody that binds to ENPP3 and does not bind to cells expressing other forms of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family members. [0330] In some embodiments, provided herein are ADCs comprising anti-ENPP3 antibodies that bind to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232. [0331] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof is human, chimeric or humanized. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is human. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is chimeric. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof that is humanized. [0332] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising a Fc region. In some embodiments, the anti-ENPP3 Fc region has been mutated to abolish interactions with Fcγ receptors. In some embodiments, the mutations comprise amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody comprises an L234A mutation. In some embodiments, the antibody comprises an L235 mutation. In some embodiments, the antibody comprises a D265S mutation. In some embodiments, the antibody comprises L234A, L235A, and D265S mutations. [0333] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 1, 32, 38, 44, 50, or 56, a CDRH2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 2, 33, 39, 45, 51, or 57, a CDRH3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 3, 34, 40, 46, 52, or 58, a CDRL1 comprising the amino acid sequence set forth in any one of SEQ ID NO: 4, 35, 41, 47, 53, or 59, a CDRL2 comprising the amino acid sequence set forth in any one of SEQ ID NO: 5, 36, 42, 48, 54, or 60, and a CDRL3 comprising the amino acid sequence set forth in any one of SEQ ID NO: 6, 37, 43, 43, 49, 66 or 61. [0334] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. [0335] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37. [0336] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43. [0337] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49. [0338] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55. [0339] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. [0340] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. [0341] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. [0342] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:22 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27. [0343] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:23 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28. [0344] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:24 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 29. [0345] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:25 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. [0346] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:26 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VH comprising at least 80%, 85%, 90%, 95% or 99% sequence identity the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a VL comprising at least 80%, 85%, 90%, 95% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 31. [0347] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8. [0348] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:22 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:27. [0349] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:23 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:28. [0350] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:24 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:29. [0351] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:25 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:30. [0352] In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31. In some embodiments, the ADC comprises an antigen binding protein comprising a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:31. [0353] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:3 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:5; and a CDR3-L comprising the amino acid sequence set forth in S E Q ID NO:6 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:8. [0354] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:32; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:33; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:35; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:36; and a CDR3-L comprising the amino acid sequence set forth in S EQ ID NO:37 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:27. [0355] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:38; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:39; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:40 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:23. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:41; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:42; and a CDR3-L comprising the amino acid sequence set forth in S EQ ID NO:43 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:28. [0356] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:44; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:45; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:46 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:47; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:48; and a CDR3-L comprising the amino acid sequence set forth in S EQ ID NO:49 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:29. [0357] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:50; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:51; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:52 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:25. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:53; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:54; and a CDR3-L comprising the amino acid sequence set forth in S EQ ID NO:55 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:30. [0358] In some embodiments, the ADC comprises an anti-ENPP3 antibody comprising one or more of a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:56; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:57; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:58 and a VH comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to with the amino acid sequence set forth in SEQ ID NO:26. In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:59; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:60; and a CDR3-L comprising the amino acid sequence set forth in S EQ ID NO:61 and a VL comprising at least 80%, 85%, 90%, 95% or 99% amino acid sequence similarity to the amino acid sequence set forth in SEQ ID NO:31. [0359] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:1, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:2 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:3. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0360] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:32, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:33 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:34. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0361] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:38, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:39 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:40. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0362] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:44, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:45 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:46. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0363] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:50, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:51 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:52. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0364] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VH comprising a CDRH1, a CDRH2, and a CDRH3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRH1 reference sequence has the amino acid sequence of SEQ ID NO:56, the CDRH2 has the amino acid sequence set forth in SEQ ID NO:57 and the CDRH3 has the amino acid sequence set forth in SEQ ID NO:58. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0365] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:4, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:5 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:6. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0366] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:35, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:36 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:37. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0367] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:41, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:42 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:43. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0368] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:47, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:48 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:49. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0369] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:53, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:54 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:55. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0370] In other embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a VL comprising a CDRL1, an CDRL2, and an CDRL3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDRL1 reference sequence has the amino acid sequence of SEQ ID NO:59, the CDRL2 has the amino acid sequence set forth in SEQ ID NO:60 and the CDRL3 has the amino acid sequence set forth in SEQ ID NO:61. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0371] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in any one of SEQ ID NO:10 or 17-21. [0372] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10. [0373] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:12, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:17. [0374] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:23, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:18. [0375] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:14, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:19. [0376] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:15, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:20. [0377] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:16, and a light chain that has at least 80%, 85%, 90%, 95% or 99% similarity to the amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:21. [0378] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in any one of SEQ ID NO:9 or 12-16 and the light chain comprising the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21. [0379] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:9 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 10. [0380] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:12 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 17. [0381] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:13 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 18. [0382] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:14 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 19. [0383] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:15 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 20. [0384] In some embodiments, the ADC comprises an anti-ENPP3 antibody or antigen binding fragment thereof comprising a heavy chain comprises the amino acid sequence set forth in SEQ ID NO:16 and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 21. [0385] In some embodiments, the ADC comprises an antibody or antigen binding fragment thereof comprising a modified glycan at position N296 according to SEQ ID NO:9 (position N297 according to EU numbering). In some embodiments, a modified glycan is a non-native glycan. In some embodiments, the modified glycan is the native glycans on the antibody Fc at site N296 according to SEQ ID NO:9 (position N297 according to EU numbering). that has been enzymatically processed by an endoglycosidase to the core N acetylglucosamine followed by attachment of an azido-modified N acetylgalactosamine utilizing a glycosyl transferase. [0386] In some embodiments, the ADC comprises an antigen binding protein in any of the foregoing embodiments in any form. As such, the ADC may comprise an antigen binding protein described in any of the above embodiments can be, for example, a monoclonal antibody, , a human, humanized or chimeric antibody, and antigen binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library. The antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. [0387] In any of the embodiments described herein, the ADC comprises an antibody with one or several amino acids (e.g., 1, 2, 3 or 4) at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivitized in some or all of the molecules in a composition. One specific example of such a modification, is an antibody or antigen binding fragment thereof in which the carboxy terminal lysine of the heavy chain is missing (e.g., as part of a post-translational modification). Furthermore, it should be understood that any of the sequences described herein include post-translational modifications to the specified sequence during expression of the antibody or antigen binding fragment thereof in cell culture (e.g., a CHO cell culture). A. Drugs and Linkers [0388] In some embodiments, the anti-ENPP3 antibody or modified anti-ENPP3 antibody is conjugated to one or more Linker-Drug moieties. In some embodiments, the anti-ENPP3 antibody or modified anti-ENPP3 antibody is conjugated to a m number of Linker-Drug moieties, wherein m is 1, 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, each Linker-Drug moiety is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. In some embodiments, Linker-Drug moiety is attached at position 296 according to SEQ ID NO:9 (position N297 according to EU numbering). In some embodiments, Linker-Drug moiety is attached at position 296 of SEQ ID NO:9 (position N297 according to EU numbering). [0389] In some embodiments, each Linker-Drug moiety comprises a multifunctional linker that connect Ab to one or more drugs (D). In some embodiments, each Linker-Drug moiety has the structure -L-(LA-D)n, in which the multifunctional linker comprises LA connecting each D directly to the rest (L) of the multifunctional linker. In some embodiments, each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. In some embodiments, L is attached at position 296 at SEQ ID NO:9. In some embodiments, L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan. In some embodiments, L covalently bonds to Ab via a glycan on a Fc constant region of the Ab. [0390] In some embodiments, L comprises , wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to LA. e embodiments, L comprises , wherein the wavy line denotes attachment to the glycan and * denotes attachment to LA. Cleavable Bonds [0391] The LA-D moiety can comprise a cleavable bond. Exemplary cleavable bonds are described in WO2018098269 and WO2021/142199, which are incorporated herein in their entireties by reference. [0392] In some embodiments, the LA-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect. [0393] Functional groups for forming moieties comprising a cleavable bond can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone moieties, hydroxyl amine groups to form oxime moieties, carboxylic or amino groups to form amide moieties, carboxylic or hydroxy groups to form ester moieites, aminocarbonyl groups or oxycarbonyl to form carbamate groups, and sugars to form glycosidic bonds. In some embodiments, LA comprises a disulfide bond that is cleavable through disulfide exchange, an acid-labile bond that is cleavable at acidic pH, and/or bonds that are cleavable by hydrolases (e.g., peptidases, esterases, and glucuronidases). In some embodiments, LA comprises a carbamate group (i.e., -O-C(O)- NR-, in which R is H or alkyl or the like). [0394] The structure and sequence of the cleavable bond(s) in the LA-D moiety can be such that the bond(s) is cleaved by the action of enzymes present at the target site. In other embodiments, the cleavable bond(s) can be cleavable by other mechanisms. [0395] In some embodiments, the cleavable bond(s) can be enzymatically cleaved by one or more enzymes, including a tumor- associated protease, to liberate the drug(s), which in one embodiment is protonated in vivo upon release to provide a drug. [0396] In certain embodiments, LA can comprise one or more amino acids. For example, each amino acid in LA can be natural or unnatural and/or a D- or L- isomer provided that there is a cleavable bond. In some embodiments, LA comprising an alpha, beta, or gamma amino acid that can be natural or non-natural. In some embodiments, LA comprises 1 to 12 (e.g., 1 to 6, or 1 to 4, or 1 to 3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) amino acids in contiguous sequence. [0397] In certain embodiments, LA can comprise only natural amino acids. In other embodiments, LA can comprise only non-natural amino acids. In some embodiments, LD can comprise a natural amino acid linked to a non-natural amino acid. In some embodiments, LD can comprise a natural amino acid linked to a D-isomer of a natural amino acid. An exemplary LA comprises a dipeptide such as -Val-Cit-, -Phe-Lys- or -Val- Ala-. [0398] In some embodiments, LA comprises a monopeptide, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, a decapeptide, an undecapeptide or a dodecapeptide unit. [0399] In some embodiments, LA comprises a peptide (e.g., of 1 to 12 amino acids), which is conjugated directly to one or more drugs. In some such embodiments, the peptide is a single amino acid or a dipeptide. [0400] In some embodiments, each amino acid in LA is independently selected from alanine, β-alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino-heterocyclo- alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof. [0401] In some embodiments, each amino acid is independently selected from alanine, β- alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, citrulline and selenocysteine. [0402] In some embodiments, each amino acid is independently selected from the group consisting of alanine, β-alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, citrulline and derivatives thereof. [0403] In some embodiments, each amino acid is selected from the proteinogenic or the non- proteinogenic amino acids. [0404] In some embodiments, each amino acid in LA can be independently selected from L- or D-isomers of the following amino acids: alanine, β-alanine, arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aniinoalkanedioic acid, heterocyclo- carboxylic acid, citrulline, statine, diaminoalkanoic acid, valine, citrulline or derivatives thereof. [0405] In certain embodiments, LA can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, e.g., a tumor-associated protease. [0406] In some embodiments, LA is , wherein p is an integer from 1 to 25, q is an integer from 1 to 25, wherein the LD-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L. [0407] In some embodiments, p is 4. [0408] In some embodiments, q is 8. [0409] In some embodiments, the LD-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect. [0410] Functional groups for forming moieties comprising a cleavable bond can include, for example, sulfhydryl groups to form disulfide bonds, aldehyde, ketone, or hydrazine groups to form hydrazone moieties, hydroxyl amine groups to form oxime moieties, carboxylic or amino groups to form amide moieties, carboxylic or hydroxy groups to form ester moieties, aminocarbonyl groups or oxycarbonyl to form carbamate groups, and sugars to form glycosidic bonds. In some embodiments, LD comprises a disulfide bond that is cleavable through disulfide exchange, an acid-labile bond that is cleavable at acidic pH, and/or bonds that are cleavable by hydrolases (e.g., peptidases, esterases, and glucuronidases). In some embodiments, LD comprises an aminocarbonyl group (i.e., - C(O)-NR-, in which R is H or alkyl or the like). [0411] The structure and sequence of the cleavable bond(s) in the LD-D moiety can be such that the bond(s) is cleaved by the action of enzymes present at the target site. In other embodiments, the cleavable bond(s) can be cleavable by other mechanisms. [0412] In some embodiments, the cleavable bond(s) can be enzymatically cleaved by one or more enzymes, including a tumor- associated protease, to liberate the drug(s), which in one embodiment is protonated in vivo upon release to provide a drug. [0413] In certain embodiments, LD can comprise one or more amino acids. For example, each amino acid in LD can be natural or unnatural and/or a D- or L- isomer provided that there is a cleavable bond. In some embodiments, LD comprising an alpha, beta, or gamma amino acid that can be natural or non-natural. In some embodiments, LD comprises 1 to 12 (e.g., 1 to 6, or 1 to 4, or 1 to 3, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) amino acids in contiguous sequence. [0414] In certain embodiments, LD can comprise only natural amino acids. In other embodiments, LD can comprise only non-natural amino acids. In some embodiments, LD can comprise a natural amino acid linked to a non-natural amino acid. In some embodiments, LD can comprise a natural amino acid linked to a D-isomer of a natural amino acid. [0415] In some embodiments, LD comprises a peptide (e.g., of 1 to 12 amino acids), which is conjugated directly to one or more drugs. In some such embodiments, the peptide is a single amino acid or a dipeptide. [0416] In some embodiments, each amino acid in LD can be independently selected from L- or D-isomers of the following amino acids: alanine, β-alanine, arginine, aspartic acid, asparagine, cysteine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, methionine, serine, tyrosine, threonine, tryptophan, proline, ornithine, penicillamine, aminoalkynoic acid, aminoalkanoic acid, heterocyclo- carboxylic acid, citrulline, statine, diaminoalkanoic acid, valine, citrulline or derivatives thereof. [0417] In some embodiments, each amino acid in LD is independently cysteine, homocysteine, penicillamine, ornithine, lysine, serine, threonine, glycine, glutamine, alanine, aspartic acid, glutamic acid, selenocysteine, proline, glycine, isoleucine, leucine, methionine, valine, citrulline or alanine. [0418] In certain embodiments, LD can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, e.g., a tumor-associated protease. Drugs [0419] In some embodiments, conjugates of the disclosure comprise one or more occurrences of D, wherein D is a drug (e.g., an auristatin drug moiety), wherein the one or more occurrences of D may be the same or different. [0420] In some embodiments, D is an auristatin. Exemplary auristatins include auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin. In some embodiments, the auristatin is auristatin F hydroxypropylamide (AF HPA).Suitable auristatins are also described in U.S. Publication Nos.2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/117,531, WO 2005/081711, WO 04/010957; WO 02/088172 and WO01/24763, and U.S. Pat. Nos. 7,498,298; 6,884,869; 6,323,315; 6,239,104; 6,124,431; 6,034,065; 5,780,588; 5,767,237; 5,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, the disclosures of which are incorporated herein by reference in their entirety. [0421] In some embodiments, the auristatin drug moiety is or comprises a compound of Formula (XIIa), (XIIc), or (XIIe):
[0422] In some embodiments, the auristatin drug moiety (D) is or comprises: [0423] In some embodiments, LA-D is
[0424] In some embodiments, one or more occurrences of the antibody that binds to ENPP3 or modified antibody that binds to ENPP3 is attached to the Linker-Drug moiety, wherein the one or more occurrences of antibody that binds to ENPP3 or modified antibody that binds to ENPP3 may be the same or different. [0425] In some embodiments, one or more Linker-Drug moieties that comprises one or more occurrences of D are connected to one antibody that binds to ENPP3 or modified antibody that binds to ENPP3. In some embodiments, each Linker-Drug moiety has the structure -L-(LA-D)n as described herein and an ADC has the structure Ab-(L-(LA-D)n)m, wherein m is an integer ranging from about 1 to about 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. [0426] In some embodiments, the targeting ligands, the linkers and the drug or prodrug fragments described herein can be assembled into the conjugate or scaffold of the disclosure, for example according to the disclosed techniques and methods. Therapeutic and targeting conjugates of the disclosure, and methods for producing them, are described below by way of non-limiting example. [0427] In some embodiments, the disclosure also relates to a Linker-Drug moiety comprising or the cysteine engineered antibody that binds to ENPP3 at least two moieties, wherein each moiety is capable of conjugation to a thiol group in an antibody that binds to ENPP3 so as to form a protein-Linker-Drug conjugate. [0428] In some embodiments, one or more thiol groups of the antibody that binds to ENPP3 or the cysteine engineered antibody that binds to ENPP3are produced by reducing a protein. The one or more thiol groups of the antibody that binds to ENPP3or the cysteine engineered antibody that binds to ENPP3 may then react with one or more Linker-Drug moieties that are capable of conjugation to a thiol group from the antibody that binds to ENPP3, or the cysteine engineered antibody that binds to ENPP3 with the Linker-Drug moiety. In some embodiments, the at least two moieties connected to the antibody that binds to ENPP3 or the cysteine engineered antibody that binds to ENPP3 are maleimide groups. [0429] In some embodiments, the antibodies may be activated for conjugation with Linker- Drug moiety by treatment with a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride). In some embodiments, full length, monoclonal antibodies can be reduced with an excess of TCEP to reduce disulfide bonds (e.g., between the cysteine present in the corresponding parent antibodies or the cysteine engineered antibody) to yield a reduced form of the antibody. The newly introduced and unpaired cysteine may remain available for reaction with Linker-Drug moiety to form the antibody conjugates of the present disclosure. In some embodiments, an excess of Linker-drug moiety is added to effect conjugation and form the ADC, and the conjugation mixture is purified to remove excess Linker-drug intermediate and other impurities. [0430] Conjugates disclosed herein can be purified (i.e., removal of any starting materials) by extensive diafiltration. If necessary, additional purification by size exclusion chromatography can be conducted to remove any aggregated conjugates. In general, the conjugates as purified typically contain less than 5% (e.g., <2% w/w) aggregated conjugates as determined by SEC; less than 0.5% (e.g., <0.1% w/w) free (unconjugated) drug as determined by RP-HPLC; less than 1% drug carrying-peptide-containing scaffolds as determined by SEC and less than 2% (e.g., <1% w/w) unconjugated antibody that binds to ENPP3 as determined by HIC-HPLC. [0431] In some embodiments, modified ENPP3 ADCs of the present disclosure may be obtained by reacting the modified antibody that binds to ENPP3 of the present disclosure with a Linker-Drug moiety comprising a functional group (e.g., WP), which is capable of forming one or more covalent bond(s) with the functional group A” of the modified- * GlcNAc moiety, GlcNAc S" A" , in the modified antibody that binds to ENPP3. [0432] In some embodiments, WP comprises alkynyl e.g., cycloalkynyl, heterocycloalkynyl, or terminal alkynyl. [0433] In some embodiments, the functional group A” of the modified antibody that binds to ENPP3 is azido, keto, or alkynyl. In some embodiments, the functional group A” of the modified antibody that binds to ENPP3 is azido. In some embodiments, the azido functional group A” of the modified anti-ENPP3 antibody reacts with the alkynyl of WP (e.g., the cycloalkynyl, heterocycloalkynyl, or terminal alkynyl) of the Linker-Drug moiety to form a triazole moiety (e.g., via a cycloaddition reaction). The cycloaddition reaction of an azido group and an alkynyl group is known in the art as “click chemistry”. [0434] In some embodiments, WP of the Linker-Drug moiety comprises a terminal alkynyl, and the cycloaddition reaction may be performed in the presence of a catalyst (e.g., a Cu(I) catalyst). [0435] In some embodiments, WP of the Linker-Drug moiety comprises cycloalkynyl or heterocycloalkynyl (e.g., strained cycloalkynyl or heterocycloalkynyl). [0436] In some embodiments, WP of the Linker-Drug moiety comprises a strained cycloalkynyl or heterocycloalkynyl, and the cycloaddition reaction may be performed in the presence or absence of a catalyst. In some embodiments, the cycloaddition reaction may occur spontaneously by a reaction called strain-promoted azide-alkyne cycloaddition (SPAAC), which is known in the art as “metal-free click chemistry”. In some embodiments, the strained cycloalkynyl or heterocycloalkynyl is as described herein. [0437] In some embodiments, upon conjugation, the functional group A” of the modified antibody that binds to ENPP3 and WP of the Linker-Drug moiety forms a triazole moiety. [0438] In some embodiments, upon conjugation, the functional group A” of the modified antibody that binds to ENPP3 and WP of the Linker-Drug moiety forms a triazole moiety of Formula wherein * denotes a direct or indirect attachment to the rest of the modified anti-ENPP3 antibody; and ** indicates attachment to the rest of the Linker-Drug moiety. [0439] In some embodiments, when an azide-modified antibody that binds to ENPP3 of the present disclosure is reacted with a Linker-Drug moiety comprising an alkynyl group to form an ADC via a cycloaddition reaction, the formed triazole moiety in ADC may be resistant to hydrolysis and/or other degradation pathways. [0440] In some embodiments, when an aldehyde or ketone-modified antibody that binds to ENPP3 of the present disclosure is reacted with a Linker-Drug moiety comprising a hydroxylamine or a hydrazine, the resulting oxime or hydrazone moiety in the modified ENPP3 ADC may be relatively inert at neutral conditions. [0441] In some embodiments, the modified antibody that binds to ENPP3 and modified ENPP3 ADC of the present disclosure may be synthesized by practical synthetic routes, as the process for introducing the functional group A” (e.g., azido, keto, or alkynyl) into the antibody is straightforward and generally applicable. [0442] In some embodiments, a site-specific ENPP3 ADC of the present disclosure is obtained by a process comprising reacting a modified antibody that binds to ENPP3with a Linker-Drug moiety, wherein: [0443] the Linker-Drug moiety comprises cycloalkynyl or heterocycloalkynyl, [0444] the modified antibody that binds to ENPP3, prior to conjugation, comprises an * antibody that binds to ENPP3 and a modified GlcNAc moiety of GlcNAc S" A" attached to an antibody that binds to ENPP3 via the C1 position of the GlcNAc; GlcNAc is N-acetylglucosamine; S” is a sugar or a derivatized sugar; and A” is azido. [0445] In some embodiments, A” is cycloalkynyl or heterocycloalkynyl. In some embodiments, A” is cycloalkynyl. In some embodiments, A” is heterocycloalkynyl. [0446] In some embodiments, A” is strained cycloalkynyl or heterocycloalkynyl. In some embodiments, A” is strained cycloalkynyl. In some embodiments, A” is strained heterocycloalkynyl. [0447] In some embodiments, a site-specific an ENPP3 ADC of the present disclosure is obtained by a process comprising the steps of: (a) contacting an intermediate antibody of Formula (XXII); wherein: Ab is an antibody that binds to ENPP3; GlcNAc is N-acetylglucosamine; Fuc is fucose; u3 is 0 or 1; and d13 is an integer ranging from 1 to 12; with a compound , wherein: S” is a sugar or a derivatized sugar; A” is azido; and P is uridine diphosphate (UDP), guanosine diphosphate (GDP), or cytidine diphosphate (CDP); in the presence of an galactosyltransferase, thereby forming a modified antibody that * binds to ENPP3 comprising the modified-GlcNAc moiety, GlcNAc S" A" , (optionally, the modified-GlcNAc moiety is attached to the rest of the modified antibody the C1 position of the GlcNAc); and (b) reacting the modified anti-ENPP3 antibody with a Linker-Drug moiety comprising a strained cycloalkynyl or heterocycloalkynyl, thereby forming the antibody-drug conjugate. [0448] In some embodiments, the process for preparing a site-specific ENPP3 ADC is as depicted in FIGs.3A-3B. [0449] In some embodiments, the modified antibody that binds to ENPP3 comprising an azido at each amino acid N297, EU numbering, of the antibody is conjugated with a Linker-drug moiety comprising strained cycloalkynyl or heterocycloalkynyl by metal-free click chemistry to form the site-specific antibody-drug conjugate of the present disclosure. [0450] In some embodiments, when the modified antibody that binds to ENPP3 comprises at least one azido moiety and the Linker-drug moiety comprises a strained cycloalkynyl, the presence of a copper catalyst is not necessary for the cycloaddition reaction between the azido in the modified antibody and the strained cycloalkynyl or heterocycloalkynyl of the Linker-Drug moiety. In some embodiments, the cycloaddition reaction proceeds in the absence of a copper catalyst, which may alleviate several possible disadvantages of using a copper catalyst in the process. [0451] In some embodiments, a Cu(I) catalyst is generally required in the cycloaddition of an azido moiety of an antibody and a terminal alkyne moiety. In some embodiments, extensive optimization and fine-tuning of conditions may be required to find the optimal parameters for efficient conversion. Nevertheless, even under such conditions, the concomitant formation of reactive oxygen species cannot always be fully avoided, which in turn may induce oxidative damage to the antibody/protein (e.g., oxidation of methionine, histidine, cysteine or disulfide bonds). Other protocols have employed Cu(I) sources such as CuBr for labeling fixed cells and synthesizing glycoproteins. In these cases, the instability of Cu(I) in air imposes a requirement for large excesses of Cu (e.g., greater than 4 mm) and ligand for efficient reactions, which could also raise the risk of antibody/protein damage or precipitation, plus the presence of residual metal after purification. Thus, the conjugation of an azido-containing antibody to a terminal alkyne in the presence of a copper catalyst can lead to extensive side-product formation by undesired amino acid oxidation. [0452] In some embodiments, the modified antibody that binds to ENPP3 comprising an azido (e.g., at each amino acid N297, EU numbering, of the antibody) is conjugated with a Linker-Drug moiety comprising strained cycloalkynyl or heterocycloalkynyl (e.g., by metal-free click chemistry). [0453] In some embodiments, upon conjugation, the azido moiety of the modified antibody that binds to ENPP3 and the strained cycloalkynyl or heterocycloalkynyl of the Linker- Drug moiety forms a triazole moiety of Formula XXXV), wherein * denotes a direct or indirect attachment to the rest of the modified antibody; and ** indicates attachment to the rest of the Linker-Drug moiety. [0454] In some embodiments, the ENPP3 ADC of the present disclosure comprises one or more occurrences of D, wherein each D independently is a drug (e.g., an auristatin drug moiety), wherein the one or more occurrences of D may be the same or different. [0455] In some embodiments, one or more specific sites of the antibody that binds to ENPP3 is attached to the Linker-Drug moiety, wherein the Linker-Drug moieties attached to the one or more specific sites may be the same or different. In some embodiments, one or more Linker-Drug moieties that comprises one or more occurrences of D (i.e. an auristatin drug moiety) are attached to one anti-ENPP3 antibody. [0456] In some embodiments, D is or comprises an auristatin drug moiety, for example an auristatin, for example auristatin F (AF), for example auristatin F hydroxypropylamide (AF-HPA). [0457] In some embodiments, the modified antibody that binds to ENPP3 is modified at the amino acid N297, EU numbering. [0458] In some embodiments, the total number of specific bonds formed between the Linker- Drug moiety and the modified anti-ENPP3 antibody (or total number of attachment points) is 12 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 10 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 8 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 6 or less. In some embodiments, the total number of specific bonds formed between the Linker- Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 4 or less. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 2 or less. [0459] In some embodiments, the total number of specific bonds formed between the Linker- Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 2. In some embodiments, the total number of specific bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 1. [0460] In some embodiments, the modified antibody that binds to ENPP3, linker, or drug described herein may be assembled into the conjugate or scaffold of the present disclosure according to various techniques and methods known in the art. The conjugate of the present disclosure, and method for producing the conjugate, are described herein (e.g., by way of non-limiting embodiments and examples). [0461] In some embodiments, the total number of bonds formed between the Linker-Drug moiety and the modified antibody that binds to ENPP3 (or total number of attachment points) is 12 or less. [0462] In some embodiments, the ratio between the Linker-Drug moiety and the modified antibody that binds to ENPP3 is greater than 1:1 and less than or equal to 12:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 12:1, about 11:1, about 10;1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, or about 1:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is between 2:1 and 10:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is between about 2:1 and about 4:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 4:1, about 3:1, or about 2:1. In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 2:1, or 1:1. [0463] In some embodiments, the ratio between Linker-Drug moiety and the modified antibody that binds to ENPP3 is about 2:1. In some embodiments, each half antibody is conjugated to a Linker-Drug moiety. [0464] In some embodiments, the antibody comprises an asparagine group in the region 290- 305 (e.g., at N297, EU numbering) attached to the sugar-derivative moiety, which comprises a functional group A”; and the modified antibody that binds to ENPP3 is conjugated to the Linker-Drug moiety by a covalent bond formed between A” and a functional group of the Linker-Drug moiety. [0465] In some embodiments, the Linker-Drug moiety comprises at least two functional groups, each of which is capable of forming a covalent bond with a functional group A” of the sugar-derivative moiety of the modified antibody that binds to ENPP3 (e.g., at amino acid N297, EU numbering, of the antibody) to form an antibody-drug conjugate. [0466] In some embodiments, the ratio between the modified antibody that binds to ENPP3 and the Linker-Drug moiety is between about 1:1 and about 1:2. [0467] In some embodiments, the modified antibody that binds to ENPP3 drug conjugate and scaffold of the present disclosure can be purified (e.g., to remove any starting materials) by extensive diafiltration. If necessary, additional purification by size exclusion chromatography can be conducted to remove any aggregated conjugates. In some embodiments, the purified conjugate or scaffold comprises less than 5% w/w (e.g., <2% w/w) aggregated conjugates as determined by SEC; less than 0.5% w/w (e.g., <0.1% w/w) free (unconjugated) drug as determined by RP-HPLC; less than 1% w/w drug carrying-peptide-containing scaffolds as determined by SEC; and/or less than 2% w/w (e.g., <1% w/w) unconjugated antibodies as determined by HIC-HPLC. [0468] The conjugate described herein is an ENPP3 ADC comprising a modified antibody that binds to ENPP3 and two molecules of a fully synthetic macromolecular linker- payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA). The fully synthetic macromolecular linker-payload is conjugated to the modified anti-ENPP3 antibody in a site-specific manner enabled by glycan remodeling of the antibody at the asparagine group at position 297 of the antibody according to EU numbering. [0469] The average drug-to-antibody ratio (DAR) of the ENPP3 antibody-drug conjugate is about 6. [0470] In some embodiments, the ENPP3 antibody-drug conjugate is a conjugate of Formula (I): Formula (I): a. d13 is about 2 b. the ANTIBODY binds ENPP3 and comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and CDRL3 of a variable light chain domain (VL0 comprising the amino acid sequence set forth in SEQ ID NO:8. c. the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; and d. is GlcNAc; is Fuc; and is GalNAc. [0471] It is understood that, unless stated otherwise, the symbol of refers to GlcNAc in the present disclosure. It is understood that, unless stated otherwise, the symbol of refers to fucose in the present disclosure. It is understood that, unless stated otherwise, the symbol of refers to GalNAc in the present disclosure. [0472] GlcNAc refers to N-acetylglucosamine (i.e., β-D-(Acetylamino)-2-deoxy- glucopyranose or N-Acetyl-D-glucosamine). [0473] Fuc refers to fucose (i.e., (2S,3R,4R,5S)-6-Methyltetrahydro-2H-pyran-2,3,4,5-tetraol or 6-Deoxy-l-galactose). [0474] GalNAc refers to N-acetylgalactosamine (i.e., 2-(Acetylamino)-2-deoxy-D-galactose, 2-Acetamido-2-deoxy-D-galactose, N-Acetylchondrosamine, 2-Acetamido-2-deoxy-D- galactopyranose, or N-Acetyl-D-galactosamine). [0475] In some embodiments, the GlcNAc is bonded to the conjugate through a reactive moiety of GlcNAc. [0476] In some embodiments, the Fuc is bonded to the conjugate through a reactive moiety of Fuc. [0477] In some embodiments, the GalNAc is bonded to the conjugate through a reactive moiety of GalNAc. [0478] In some embodiments, the Linker-Drug moiety is attached to the antibody at position N180 of SEQ ID NO: 11, a position corresponding to N297 (as numbered by EU numbering). [0479] In some embodiments the Linker-Drug moiety is attached to the antibody at a position corresponding to N180 of SEQ ID NO: 11. Corresponding positions are determined, for example, using a sequence alignment tool. [0480] In some embodiments, the Linker-Drug moiety is attached to the antibody at position N296 of SEQ ID NO: 9 a position corresponding to N297 (as numbered by EU numbering). [0481] In some embodiments, the Linker-Drug moiety is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 9. In some embodiments, the Linker- Drug moiety is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 9. Corresponding positions are determined, for example, using a sequence alignment tool. In some embodiments, the antibody binds to ENPP3. In some embodiments, the antibody comprises a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in SEQ ID NO:7 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in SEQ ID NO:8. [0482] In some embodiments, the process for the preparation of an antibody that binds to ENPP3 comprises: (a) contacting a glycoprotein (e.g., an antibody that binds to ENPP3 glycan) comprising an antibody that binds to ENPP3 and core-GlcNAc moiety connected to site N297 (according to EU numbering) of the antibody, with endoglycosidase Endo SH, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and (b) contacting the intermediate antibody with 4-AzGalNAc-UDP in the presence of a β-(l,4)-GalNAcT enzyme, thereby forming the modified antibody that binds to ENPP3 comprising the modified-GlcNAc moiety; wherein steps (a) and (b) are conducted concurrently. [0483] In some embodiments, the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag (SEQ ID NO: 233) resulting in an overall molecular weight of 139 kDa. [0484] In some embodiments, the β-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) and has an overall molecular weight of 45.7 kDa. In some embodiments, the β-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag (SEQ ID NO: 233) is derived from Trichopulsia ni. [0485] In some embodiments, the process is conducted in PBS buffer at pH value of about 7.4 and at a temperature of about 30 oC. [0486] The ENPP3 antibody-drug conjugate can be generated and purified by well-known techniques e.g., WO 2018098269 and US 17/568,378, each of which is incorporated herein in its entirety by reference. [0487] In some embodiments, the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-a): wherein is GalNAc; and d13 is about 2. [0488] In some embodiments, the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-b):
(I-b) wherein is GlcNAc; and d13 is about 2. [0489] In some embodiments, the ENPP3 antibody-drug conjugate of Formula (I) is of Formula (I-c):
d13 is about 2. [0490] In some embodiments, the ENPP3 antibody-drug conjugate is a conjugate of Formula (IA):
(IA). [0491] The conjugate described herein is a ENPP3 antibody-drug conjugate comprising a modified antibody that binds to ENPP3 and two molecules of a fully synthetic macromolecular linker-payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA). In some embodiments, the free auristatin payload, auristatin F hydroxypropyl amide (AF-HPA) comprises: [0492] In some embodiments, the primary AF-HPA metabolite, Auristatin F (AF), comprises: . V. Antigen Binding Protein Expression and Production A. Nucleic Acid Molecules Encoding Antigen Binding Proteins [0493] Nucleic acid molecules that encode for the antigen binding proteins described herein, or portions thereof, are also provided. [0494] The nucleic acid molecules can be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form. A nucleic acid is "isolated" or "rendered substantially pure" when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids (e.g., other chromosomal DNA, e.g., the chromosomal DNA that is linked to the isolated DNA in nature) or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, restriction enzymes, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York. A nucleic acid described herein can be, for example, DNA or RNA and may or may not contain intronic sequences. [0495] Thus, nucleic acid molecules comprising polynucleotides that encode one or more chains of an anti-ENPP3 antibodies, provided herein. In some embodiments, a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of an anti-ENPP3 antibody. In some embodiments, a nucleic acid molecule comprises both a polynucleotide sequence that encodes a heavy chain and a polynucleotide sequence that encodes a light chain, of an anti-ENPP3 antibody. In some embodiments, a first nucleic acid molecule comprises a first polynucleotide sequence that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide sequence that encodes a light chain. In some embodiments, the polynucleotides are codon optimized. [0496] In one embodiment, the nucleic acid molecule comprises a polynucleotide encoding the VH of one of the antibodies provided herein. In another embodiment, the nucleic acid comprises a polynucleotide encoding the VL of one of the antibodies provided herein. In still another embodiment, the nucleic acid encodes both the VH and the VL of one of the antibodies provided herein. In some embodiments, the nucleic acid encodes an antibody VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8. [0497] In a particular embodiment, the nucleic acid encodes a variant of one or more of the above amino acid sequences (e.g., the heavy chain and/or light chain amino acid sequences, or the VH and/or VL amino acid sequences disclosed herein), wherein the variants has at most 25 amino acid modifications, such as at most 20, such as at most 15, 14, 13, 12 or 11 amino acid modifications, such as 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino-acid modifications, such as deletions or insertions, preferably substitutions, such as conservative substitutions. [0498] Once nucleic acids encoding VH and VL segments are obtained, these nucleic acids can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene. In these manipulations, a VL- or VH-encoding nucleic acid is operatively linked to another nucleic acid encoding another polypeptide, such as an antibody constant region or a flexible linker. [0499] The isolated nucleic acid encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding nucleic acid to another nucleic acid molecule encoding heavy chain constant regions (hinge, CH1, CH2 and/or CH3). The sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242) and nucleic acid fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, for example, an IgG1 region. For a Fab fragment heavy chain gene, the VH-encoding nucleic can be operatively linked to another nucleic acid molecule encoding only the heavy chain CH1 constant region. [0500] The isolated nucleic acid molecule encoding the VL region can be converted to a full- length light chain gene (as well as a Fab light chain gene) by operatively linking the VL- encoding nucleic acid molecule to another nucleic acid molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242) and nucleic acid fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region. [0501] To create a scFv gene, the VH- and VL-encoding nucleic acid fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3 (SEQ ID NO: 234), such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554). [0502] In another aspect, nucleic acid molecules that are suitable for use as primers or hybridization probes for the detection of nucleic acid sequences are also provided. A nucleic acid molecule can comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion (e.g., ENPP3 binding portion) of a polypeptide. [0503] Vectors, including expression vectors, comprising one or more nucleic acids encoding one or more components of the antibody or antigen binding fragment thereof (e.g. VH and/or VL; and light chains, and/or heavy chains) are also provided. An expression vector can include, but is not limited to, sequences that affect or control transcription, translation, and, if introns are present, affect RNA splicing of a coding region operably linked thereto. Nucleic acid sequences necessary for expression in prokaryotes include a promoter, optionally an operator sequence, a ribosome binding site and possibly other sequences. Eukaryotic cells are known to utilize promoters, enhancers, and termination and polyadenylation signals. [0504] The expression vector can also include a secretory signal peptide sequence that is operably linked to the coding sequence of interest, such that the expressed polypeptide can be secreted by the recombinant host cell, for more facile isolation of the polypeptide of interest from the cell, if desired. Other signal or secretory peptides are known to those of skill in the art and may be fused to any of the variable region polypeptide chains, for example, to facilitate or optimize expression in particular host cells. [0505] Expression and cloning vectors of the invention will typically contain a promoter that is recognized by the host organism and operably linked to the molecule encoding the polypeptide. A large number of promoters, recognized by a variety of potential host cells, are well known. A suitable promoter is operably linked to the DNA encoding e.g., heavy chain, light chain, or other component of the antibodies and antigen-binding fragments of the invention, by removing the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into the vector. Suitable promoters for use with yeast hosts are also well known in the art. Yeast enhancers are advantageously used with yeast promoters. Suitable promoters for use with mammalian host cells are well known. In certain embodiments, nucleic acids encoding the different components of the antibody or antigen binding fragment thereof can be inserted into the same expression vector. For instance, the nucleic acid encoding an anti-ENPP3 antibody light chain or variable region, as provided herein can be cloned into the same vector as the nucleic acid encoding an anti-ENPP3 antibody heavy chain or variable region as provided herein. B. Host Cells [0506] After the vector has been constructed and the one or more nucleic acid molecules encoding the components of the antibody or antigen binding fragment thereof described herein has been inserted into the proper site(s) of the vector or vectors, the completed vector(s) may be inserted into a suitable host cell for amplification and/or polypeptide expression. [0507] Thus, in another aspect, host cells comprising nucleic acid molecules or vectors such as described herein are also provided. In various embodiments, antibody heavy chains and/or antilight chains can be expressed in prokaryotic cells, such as bacterial cells, or in eukaryotic cells. The selection of an appropriate host cell depends upon various factors, such as desired expression levels, polypeptide modifications that are desirable or necessary for activity (such as glycosylation or phosphorylation) and ease of folding into a biologically active molecule. [0508] Once a suitable host cell has been prepared, it can be used to express the desired antibody or antigen binding fragment thereof. Thus, in a further aspect, methods for producing an antibody or antigen binding fragment thereof as described herein are also provided. In general, such methods comprise culturing a host cell comprising one or more expression vectors as described herein in a culture medium under conditions permitting expression of the antibody or antigen binding fragment thereof as encoded by the one or more expression vectors; and recovering the antibody or antigen binding fragment thereof from the culture medium. [0509] In some embodiments, the antibody or antigen binding fragment thereof is produced in a cell-free system. VI. Therapeutic Applications A. Methods of Treatment [0510] In another aspect, methods of treating disorders associated with cells that express ENPP3, e.g., cancers, provided here. In certain exemplary embodiments, the method comprises treating cancer in a cell, tissue, organ, animal or human. Most typically, the treatment method comprises treating a cancer in a human. [0511] In some embodiments, methods of treating a solid tumor in an individual with the ADCs of the invention, provided herein. In some embodiments, the solid tumor is selected from the group consisting of kidney cancer, lung adenocarcinoma, endometrioid uterine cancer, ovarian cancer, and colorectal cancer (CRC). In some embodiments, the kidney cancer is of clear cell or papillary histology. [0512] In another aspect, methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate to the individual. [0513] In some embodiments, the tumor cells expresses ENPP3. In some embodiments the tumor cells does not express ENPP3. In some embodiments, the tumor cell does not express ENPP3 and is killed through a bystander effect. [0514] In some embodiments, the administration of the antibody-drug conjugate results in a strong bystander effect. In some embodiments, the bystander effect allows the payload to diffuse from antigen-positive tumor cells to adjacent antigen-negative tumor cells, resulting in cell killing. In some embodiments, the administration of the antibody-drug conjugate results in a low off-target effect. [0515] In some embodiments, disclosed herein is a method of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of the present invention. In some embodiments, the tumor cell expresses ENPP3. In some embodiments, the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, the antibody binds the extracellular region of ENPP3. In some embodiments, the ADC is internalized in the tumor cells. In some embodiments, following internalization, the drug is released from the antibody. In some embodiments, the drug is auristatin F. VII. Pharmaceutical compositions and formulations [0516] In some embodiments, the invention provides ADC or antibody mixtures and pharmaceutical compositions comprising any of the ADCs or antibodies as provided herein. [0517] In some embodiments, the compositions are pharmaceutical compositions comprising the ADCs or antibodies provided herein and a pharmaceutically acceptable carrier. In some of those embodiments, the pharmaceutical composition is in liquid form. In other of those embodiments, the pharmaceutical composition is a lyophilized powder. EXEMPLARY EMBODIMENTS [0518] In some embodiments, provided herein is an antibody drug conjugate having the structure Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and LA, LA is a divalent moiety connecting L and D, D is a drug; n is 1, 2 or 3; and m is 1, 2 or 3, wherein the antibody comprises: a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27-31. [0519] In some embodiments, provided here ins An antibody drug conjugate having the structure, Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3; L is a linker covalently bound to Ab and LA; LA is a divalent moiety connecting L and D; D is an auristatin; n is 1, 2 or 3; and m is 1, 2 or 3. In some embodiment, n is 2 or 3. In some embodiments, m is 1 or 2.. In some embodiments, n is 3 and m is 2. In some embodiments the drug to antibody ratio is 6. In some embodiments, n is 3 and m is 1. In some embodiments the drug to antibody ratio is 3. [0520] In some embodiments, the antibody or antigen binding fragment thereof comprises; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. [0521] In some embodiments, the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. [0522] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8, or 27-31. [0523] In some embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. [0524] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and the VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain (HC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or 12-16, and a light chain (LC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10 or 17-21. In some embodiments, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. In some embodiments, the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. [0525] In some embodiments, each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. In some embodiments, L is attached to the asparagine residue at position 296 according to SEQ ID NO:9. In some embodiments, L is attached to the asparagine residue at position 296 of SEQ ID NO:9. In some embodiments, the L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan. [0526] In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for a FcƔ receptor. In some embodiments, the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. In some embodiments, the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3. [0527] In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232. [0528] In some embodiments, the drug is an auristatin.In some embodiments, the auristatin is selected from the group consisting of auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin. In some embodiments, the auristatin is auristatin F hydroxypropylamide (AF HPA) comprising, . [0529] In some embodiments, L covalently bonds to Ab via a glycan on a Fc constant region of the Ab. In some embodiments, L comprises wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to LA. In some embodiments, LA is , wherein p is an integer from 1 to 25; q is an integer from 1 to 25; wherein the LD-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L. [0530] In some embodiments, p is 4. In some embodiments, q is 8. In some embodiments, LA- D is
[0531] In some embodiments, provided herein the antibody drug conjugate is of Formula (I): wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; [0532] In some embodiments, provided herein is an antibody drug conjugate having the Formula (I): wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; is GlcNAc; is Fuc; and is GalNAc, wherein the antibody comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; [0533] In some embodiments, the antibody drug conjugate is produced by a method comprising, processing a glycan at position N296 according to SEQ ID NO: 9 by incubating an antibody that binds to ENPP3 with an endoglycosidase, attaching an azido modified N-acetylglucosamine to position N296 according to SEQ ID NO:9 by providing glucosyl transferase, and attaching the linker and drug to the azido-modified N-acetyl glucosamine using a coper-free click chemistry. [0534] In some embodiments, provided herein is a composition comprising the antibody drug conjugate. In some embodiments, the composition comprises a heterogeneous mixture of different ADC molecules (i.e., different DAR species having different drug-to-antibody ratios). Therefore, in some embodiments, the term ADC also refers to such mixtures of DAR species. [0535] In some embodiments, provided herein is an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of claims SEQ ID NO:7 or 22-26; and CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8, or 27-31. In some embodiments, the isolated antibody or antigen binding fragment comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the VH has at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and the VL has at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. In some embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence identity the amino acid sequence set forth in SEQ ID NO: 8. [0536] In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 of SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises a modified glycan at position N296 according to SEQ ID NO:9. In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region. In some embodiments, the antibody or antigen binding fragment thereof is a full length antibody. In some embodiments, the HC comprises the amino acid sequence set forth in any one of SEQ ID NO:9, or 12-16 and the LC comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21.In some embodiments, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. In some embodiments, the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for an FcƔ receptor. In some embodiments the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. [0537] In some embodiments the antibody or antigen binding fragment thereof is human, chimeric, or humanized. In some embodiments, the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3 In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. In some embodiments, the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at residues 671-681 (VPPSESQKCSF (SEQ ID NO: 231)) and 762-780 (PDEITKHLANTDVPIPTHY (SEQ ID NO: 232)) [0538] In some embodiments, provided herein is an antibody drug conjugate comprising the antibody or antigen binding fragment of any of the embodiments herein covalently bound to one or more drug molecules. [0539] In some embodiments, provided herein are nucleic acid encoding the isolated antibody of any one of the embodiments provided herein. In some embodiments, provided herein are nucleic acid encoding a light chain, a heavy chain, or a light chain and heavy chain encoding the isolated antibody of any one of the embodiments described herein. In some embodiments, provided herein are vector comprising the nucleic acid of any the embodiments provided herein. In some embodiments, provided herein are host cells comprising the vector of any of the embodiments provided herein. [0540] Provided herein are methods of producing an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising culturing the host cell of the embodiments provided herein under conditions suitable for expressing the antibody or antigen binding fragment thereof. [0541] In some embodiments, provided herein are pharmaceutical compositions comprising the antibody drug conjugate of any one of the embodiments provided herein or the isolated antibody embodiments provided herein and a pharmaceutically acceptable carrier. [0542] In some embodiments, provided herein are methods of treating a solid tumor selected from the group consisting of kidney cancer of clear cell or papillary histologies, a lung adenocarcinoma, an endometrioid uterine cancer, ovarian cancers, or colorectal cancer (CRC) comprising administering the antibody-drug conjugate of any of the embodiments herein or the isolated antibody or antigen binding fragment embodiments provided herein. In some embodiments, treating a solid tumor comprises a change in tumor growth inhibition. In some embodiments, the tumor volume and/or the rate of tumor volume growth is decreased. [0543] In some embodiments, provided herein are methods of killing a tumor cell in an individual comprising administering the antibody drug conjugate of any of the embodiments provided herein. In some embodiments, the tumor cell expresses ENPP3. In some embodiments, the tumor cell is killed through a bystander effect. [0544] In some embodiments, provided herein are methods of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of any one of the embodiments provided herein to the individual. In some embodiments, the tumor cell expresses ENPP3. In some embodiments, the antibody binds to ENPP3 expressed on the surface of the tumor cell. In some embodiments, wherein the antibody drug conjugate is internalized in the tumor cell. In some embodiments, following internalization, the drug is released from the antibody. EXAMPLES Example 1: Antibody Screen Generation of antibodies specific to ENPP3 [0545] Transgenic Ablexis AJ mice expressing human variable regions were immunized using either full length ENPP3 amino acid sequence (SEQ ID NO: 62) (Table 1) or full length nucleic acid sequence. A total of 213 antibody clones were recovered and screened for binding to recombinant human ENPP3 and cells expressing ENPP3.90 antibody clones were selected based on binding affinity. The 90 antibody clones were evaluated based on biophysical properties, CDR sequence diversity, and potential post-translational modification (PTM) liabilities, yielding 53 antibodies. Variable regions (VH and VL) of each of the select 53 antibodies were engineered as human IgG1_G1m(17). Select panel of anti-ENPP3 antibody-drug conjugates exhibited potent cytotoxicity [0546] Each of the 53 antibodies was conjugated via a linker with antimitotic drug monomethylauristatin F (vcMMAF) to form antibody drug conjugates (ENPP3- vcMMAF). Cell lines expressing ENPP3 were treated with ENPP3-vcMMAF antibody drug conjugates or Isotype-vcMMAF as a control. Tumor cell cytotoxicity was measured using Cell-Titer-Glow Cell Viability Assay (Promega). Briefly, suspension cells were counted and plated in 96 well plates in 75uL of complete media. Cells were incubated overnight to allow for recovery. ADCs and compounds were prepared and 1:5 serial dilutions were performed in complete media.75uL of media + compound was added to each well and incubated for 3 or 6 days. Plates were read on either day 3 or day 6 via Cell Titer Glo 2.0 by adding 75uL of CTG reagent to each well. Plates were placed on a shaker for 2 minutes and then incubated at RT for 15 minutes before being read on an Envision plate reader. Raw data was exported from the plate reader to Excel and then analyzed in Prism Graph Pad. All 53 ENPP3-vcMMAF antibodies tested exhibited dose- dependent cytotoxicity in with varying sensitives.23 ENPP3-vcMMAF antibodies were selected for further analysis based on exhibiting the most potent cytotoxicity. [0547] Next, the selected 23 ENPP3 antibodies were evaluated for binding to Cynomolgus monkey ENPP3. Table 1: ENPP3 sequence used to immunize mice Anti Descri Sequence SEQ ID NO gen ption NPP His- HHHHHHHHHHGLNDIFEAQKIEWHERKLEKQGSCRKKCFD 3W6 Avi- ASFRGLENCRCDVACKDRGDCCWDFEDTCVESTRIWMCN hENP K P3 FRCGETRLEASLCSCSDDCLQRKDCCADYKSVCQGETSWL (46- EENCDTAQQSQCPEGFDLPPVILFSMDGFRAEYLYTWDTL 875) MPNINKLKTCGIHSKYMRAMYPTKTFPNHYTIVTGLYPESH GIIDNNMYDVNLNKNFSLSSKEQNNPAWWHGQPMWLTAM YQGLKAATYFWPGSEVAINGSFPSIYMPYNGSVPFEERISTL LKWLDLPKAERPRFYTMYFEEPDSSGHAGGPVSARVIK ALQVVDHAFGMLMEGLKQRNLHNCVNIILLADHGMDQTY CNKMEYMTDYFPRINFFYMYEGPAPRIRAHNIPHDFFSFNS SEQ ID NO: EEIVRNLSCRKPDQHFKPYLTPDLPKRLHYAKNVRIDKVHL 62 FVDQQWLAVRSKSNTNCGGGNHGYNNEFRSMEAIFLAHG PSFKEKTEVEPFENIEVYNLMCDLLRIQPAPNNGTHGSLNHL LKVPFYEPSHAEEVSKFSVCGFANPLPTESLDCFCPHL QNSTQLEQVNQMLNLTQEEITATVKVNLPFGRPRVLQKNV DHCLLYHREYVSGFGKAMRMPMWSSYTVPQLGDTSPLPPT VPDCLRADVRVPPSESQKCSFYLADKNITHGFLYPPASNRTS DSQYDALITSNLVPMYEEFRKMWDYFHSVLLIKHATER NGVNVVSGPIFDYNYDGHFDAPDEITKHLANTDVPIPTHYF VVLTSCKNKSHTPENCPGWLDVLPFIIPHRPTNVESCPE GKPEALWVEERFTAHIARVRDVELLTGLDFYQDKVQPVSEI LQLKTYLPTFETTI Example 2: Synthesis of the ENPP3 ADC1 [0548] The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list is not meant to be an all-inclusive list of abbreviations used in the application as additional standard abbreviations, which are readily understood by those skilled in the art of organic synthesis, can also be used in the synthetic schemes and examples. Abbreviations: ACN Acetonitrile AF Auristatin F AF-HPA Auristatin F hydroxypropyl amide aq Aqueous CE Capillary electrophoresis CR Complete regression DAD Diode array detector DAR Drug-to-antibody ratio DMEM Dulbecco’s Modified Eagle Medium ELISA Enzyme-linked immunosorbent assay Endo SH Endoglycosidase SH FBS Fetal bovine serum Fuc Fucose GalNAcT Glycosyltransferase HIC Hydrophobic interaction chromatography HRP Horse radish peroxidase IV Intravenous LC Liquid chromatography MS Mass spectrometry MTV Median tumor volume NMR Nuclear magnetic resonance PBS Phosphate buffered saline PBST Phosphate-buffered saline containing Tween PR Partial regression RP-HPLC Reverse-phase high performance liquid chromatography SEC Size exclusion chromatography TFS Tumor free survival TGI Tumor growth inhibition TCEP Tris[2-carboxyethyl] phosphine TEAA Triethylammonium acetate TMB Tetramethylbenzidine UDP Uridine diphosphate UF/DF Ultrafiltration/diafiltration WCX Weak cation exchange chromatography [0549] All reagents were purchased from relevant providers unless otherwise stated. Endo SH was prepared as described in PCT application WO 2017137459, the entire contents of which are incorporated herein by reference. UDP-azido sugar and GalNAcT were prepared as described in US 9,988,662, the entire contents of which is incorporated herein by reference. [0550] When applicable, the drug content of the conjugates was determined spectrophotometrically, otherwise RP-HPLC or LC/MS as performed for quantitative determination of the drug content. [0551] The protein content of the antibody-drug conjugates was determined spectrophotometrically or by ELISA. [0552] Antibody-drug conjugates, drug carrying scaffolds, or antibody scaffolds were purified (i.e., removal of residual unreacted drug, unconjugated antibody, enzymes or starting materials) by extensive diafiltration, CHT chromatography or HIC, as required. If necessary, additional purification by SEC or HIC were conducted to remove aggregated antibody-drug conjugates. In general, the antibody-drug conjugates, as purified, contained <5% (w/w) (e.g., <2% (w/w)) aggregated antibody-drug conjugates as determined by SEC; <0.5% (w/w) (e.g., <0.1% (w/w)) free (unconjugated) drug as determined by RP- HPLC and/or LC-MS/MS; <1% (w/w) of free drug conjugate as determined by SEC and/or RP-HPLC; and <10% (w/w) (e.g., <1% (w/w)) unconjugated antibody or antibody fragments as determined by HIC-HPLC and/or RP-HPLC. Reduced or partially reduced antibodies were prepared using procedures described in the literature, see, for example, Francisco et al., Blood 102 (4): 1458-1465 (2003). The total drug (conjugated and unconjugated) concentration was determined by UV-Vis spectrophotometry or RP-HPLC. [0553] The drug to antibody ratio (DAR) for conjugates comprising the auristatin drug moiety was determined by subjecting the antibody-drug conjugates to exhaustive base hydrolysis. The released AF-HPA was then quantified from a standard curve with RP- HPLC. The measured AF-HPA concentrations were correlated to the antibody content to determine DAR. Step 1. Azido-modified ENPP3 antibody [0554] To the antibody that binds to ENPP3 (12.71 mg, 0.088 µmole) in 50 mM Tris-HCl, pH 7.6, was added in the following order: Endo SH (0.127 mg, 1 w-%), GalNAcT (0.64 mg, 5 w-%), UDP-azido sugar (1.34 mg, 2.12 µmole), and MnCl2 (1.18 mg, 9.4 µmole), to achieve a final antibody concentration of 13.5 g/L. The reaction was stirred at 30 rpm for 17 hours at 30 °C. The crude azido-modified anti-ENPP3 antibody was purified by Protein A chromatography and dialysis to give the azido-modified antibody that binds to ENPP3 (10.53 mg, 83% yield). Step 2. ADC 1 [0555] Azido-modified antibody that binds to ENPP3 (10.03 mg, 0.070 µmole) in PBS, pH 7.2 and Scaffold 1A (4.25 mg, 0.67 µmole, prepared as described in US 17/144,378, US2021/0220477, WO2021142199A1) in water, were gently mixed, then left for 20 hours at 30 °C without shaking or rocking. The crude product was purified by UF/DF and HIC to give ADC1 (5.85 mg, 58% yield), that had a DAR of 5.9 as determined by reduced RP-HPLC. Example 3: Alternative Representative Synthetic Scheme for ADCs [0556] To generate AB1-AB23 (14.08 mg, 0.10 μmol) in 50 mM TBS, 150 mM NaCl, pH 7.6 were added the components in the following order: TBS, pH 7.6 (150.2 μL), EndoSH (0.070 mg, 0.5 w-%); GalNAcT (0.70 mg , 5 w-%); UDP-azidosugar (1.62 mg, 2.5 μmole, 25 equiv); MnCl2 (1.18 mg, 9.39 μmole) to achieve a final concentration of 10 mM in the reaction and the reaction was stirred at 30 ˚C for 17 h. The crude azido- modified AB1 was purified by protein A column chromatography and dialysis to give the azido-modified AB1 (12.9 mg, 88% yield). [0557] Azido-modified AB1 (12.88 mg, 0.09 µmole) in PBS, pH 7.2 and scaffold 1A (5.62 mg, 0.88 μmole, prepared as described in US 17/144,378) in water were gently mixed and, left for 20h at 30 °C. The crude product was purified by UF/DF and HIC to give conjugate ADC2 (8.74 mg, 66 % yield) that had a DAR of 5.95 as determined by RP- HPLC. The other ADCs were synthesized according to the same protocol with overall 40- 65% yields and DAR of 6. Example 4: Testing of ENPP3 ADCs [0558] Next, the select 23 ENPP3 antibodies from Example 1 were conjugated via a linker with antimitotic drug auristatin F hydroxypropyl amide (AF-HPA) (ENPP3-AF-HPA antibodies). The cytotoxicity of the ENPP3-AF-HPA antibodies was evaluated using the Cell Titer Glo 2.0 (Promega). Briefly, suspension cells were counted and plated in 96 well plates in 75uL of complete media. Cells were incubated overnight to allow for recovery. ENPP3-AF-HPA antibodies and compounds were prepared and 1:5 serial dilutions were performed in complete media.75uL of media + compound was added to each well and incubated for 3 or 6 days. Plates were read on either day 3 or day 6 via Cell Titer Glo 2.0 (Promega) by adding 75uL of CTG reagent to each well. Plates were placed on a shaker for 2 minutes and then incubated at RT for 15 minutes before being read on an Envision plate reader. Raw data was exported from the plate reader to Excel and then analyzed in Prism Graph Pad. All 23 ADCs tested exhibited potent dose-dependent cytotoxicity in ENPP3-positive cell lines with varying sensitives and EC50 values ranging from of 0.03 to 4 nM after 6 days of treatment. [0559] Six ENPP3 antibodies were selected for further analysis based on the most potent in vitro cytotoxicity across multiple cell lines and cross reactivity with the Cynomolgus monkey ENPP3. The sequences of the 6 select antibodies are shown in Tables 2-39. The cytotoxicity, binding, and internalization data for these antibodies conjugated with AF- HPA are shown in Table 40. Table 2: Heavy chains Amino Acid Sequence SEQ ID ENPP3 EVQLVESGGGLVKPGGSLRLSCAPSGFTFSDYSMNWVRQAPGR Antibody 1 GLEWVSSISSNSRYKYYADSVKGRFTISRDNAENSLYLQMNSL RAEDTALYFCARGLDYFDYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP SEQ ID KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV NO: 9 VVSVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK QVQLQESGPGLVKPSETLSLTCTVSGGSISNYYWSWIRQPAGKGLEWI SEQ ID ENPP3 GRIYASGSTNYNPSLKSRVTMSVDTSKNQFSLRLRSVTATDTAVYYC Antibody 2 AREGYSSTLYDNAFDFWGQGTMVTVSSASTKGPSVFPLAPSSKSTSG NO: 12 GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK ENPP3 EVQLVESGGGLVKPGGSLRLSCTASGFTFSRYSMDWVRQAPGKGLE Antibody 3 WVSSISSRSNYIYYATSVKGRFTISRDNAKNSLFLQMNSLRAEDSAVY YCARETSTFDAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAA SEQ ID GGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA NO: 13 LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK ENPP3 EVQLVESGGGLVKPGGSLRRSCVASGFTFSDYSMNWVRQAPGKGLE Antibody 4 WVSFISSRSNYMKYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARGHYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG SEQ ID PSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA NO: 14 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK ENPP3 EVQLVESGGGLVKPGGSLRLSCTASGFTFSRYSMDWVRQASGKGLE Antibody 5 WVSSISSRSNYIYYATSVKGRFTISRDNAKNSLFLQMNSLRAEDSAVY YCARETSTFDAFDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAA SEQ ID GGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA NO: 15 LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK ENPP3 EVQLVESGGGLVKPGGSLRLFCAASGFTFSDYSMNWVRQAPGKGLE Antibody 6 WVSLISSSSIYLYYVDSVKGRFTISRDNAKHSLYLQMNSLRVEDTAVY YCARGRDYLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SEQ ID SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEV NO: 16 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK Table 3: Constant region of Heavy chains ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT SEQ ENPP3 LMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKPRE ID Antibody EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS NO: 1-6 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW 11 ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Table 6B: Heavy Chain Nucleic Acids Nucleic Acid Sequence SEQ ID ENPP3 GAAGTTCAGCTGGTTGAATCTGGCGGAGGTCTTGTGAAACCCGGT Antibody 1 GGTTCTCTGCGACTTTCTTGTGCTCCATCTGGGTTTACCTTTAGCGA TTACAGCATGAACTGGGTTAGACAAGCACCCGGAAGGGGTCTGGA ATGGGTTTCAAGCATTTCCAGCAATTCTCGCTATAAGTACTACGCT GATTCAGTTAAAGGCAGATTCACAATCTCTCGCGACAATGCAGAG AATAGTCTGTATCTGCAAATGAACTCTCTTCGAGCAGAAGATACA GCTCTGTATTTCTGTGCAAGAGGTCTTGATTACTTCGACTACTGGG GACAAGGGACATTGGTGACAGTTTCTTCAGCCTCCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGG CACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC SEQ ID AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC NO: 63 ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCG TGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCC CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGG TCACATGCGTGGTGGTGAGCGTGAGCCACGAAGACCCTGAGGTCA AGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGT ACAAGTGCAAGGTGTCGAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGT GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAA GCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTC ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GTCTCTCTCCCTGTCTCCGGGAAAA CAAGTTCAACTGCAAGAATCTGGACCCGGCCTTGTGAAACCAAGC ENPP3 GAAACATTGTCTCTGACATGCACAGTTTCTGGAGGTTCTATCAGCA Antibody 2 ACTACTATTGGTCATGGATTAGACAGCCAGCTGGGAAAGGTCTGG AATGGATTGGCCGCATTTATGCTTCTGGCTCAACCAATTACAACCC ATCTCTTAAGTCAAGGGTGACAATGTCAGTTGACACATCTAAGAA CCAGTTTAGTCTGCGACTGAGAAGTGTTACTGCAACAGATACCGC AGTTTATTATTGCGCCAGAGAGGGTTATAGTTCTACCCTTTACGAT AATGCCTTTGACTTTTGGGGACAAGGAACAATGGTGACAGTTAGTT CAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTC CAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCT TGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCA ACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAA CTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGAC SEQ ID CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT NO: 64 CTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGAGCGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACA GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTG GCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCGAACAAAGCCCT CCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC CCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGA GAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTC CTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCA GCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGTCTCTCTCCCTGTCTCCGGGAAAA ENPP3 GAAGTCCAACTGGTTGAATCTGGTGGTGGTCTGGTGAAACCCGGT Antibody 3 GGTTCACTTAGACTCTCTTGTACAGCTAGTGGATTTACCTTCTCAA GATATTCCATGGATTGGGTTAGACAAGCTCCCGGGAAAGGACTTG AATGGGTTTCTTCCATTAGCTCTCGAAGCAACTACATCTACTACGC AACATCTGTGAAAGGAAGGTTTACCATTTCACGCGATAATGCCAA GAACTCTCTGTTCCTCCAAATGAACTCACTTCGCGCAGAAGATTCA GCTGTGTACTATTGTGCAAGAGAAACATCAACCTTTGACGCCTTTG SEQ ID ATATTTGGGGACAAGGGACAATGGTTACAGTTTCTTCTGCCTCCAC CAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC NO: 65 TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCT TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGAC CCCTGAGGTCACATGCGTGGTGGTGAGCGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAA TGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG CAAGGAGTACAAGTGCAAGGTGTCGAACAAAGCCCTCCCAGCCCC CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTA CAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC ACGCAGAAGTCTCTCTCCCTGTCTCCGGGAAAA ENPP3 GAGGTCCAGCTGGTAGAATCTGGAGGTGGCCTTGTTAAGCCCGGC Antibody 4 GGATCACTGAGGAGATCTTGTGTCGCTAGCGGGTTTACATTTTCCG ACTATAGCATGAACTGGGTCCGACAAGCACCCGGGAAAGGTCTGG AGTGGGTGTCCTTTATCTCCTCAAGAAGCAACTACATGAAGTACGC CGACAGCGTGAAAGGAAGGTTCACCATTTCCAGAGATAACGCCAA GAACAGTCTCTATCTGCAAATGAACTCACTCAGAGCTGAAGATAC TGCAGTGTATTATTGCGCCAGAGGCCACTACTTCGACTACTGGGGC CAAGGAACACTGGTGACTGTTAGTTCTGCCTCCACCAAGGGCCCAT CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGT GACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGTCCACCGTGCC SEQ ID CAGCACCTGAAGCAGCAGGGGGACCGTCAGTCTTCCTCTTCCCCCC AAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCAC NO: 66 ATGCGTGGTGGTGAGCGTGAGCCACGAAGACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAA GTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT CACCGTGGACAAGTCTAGATGGCAGCAGGGGAACGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAG CCTCTCCCTGTCTCCGGGTAAA ENPP3 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGG Antibody 5 GGGTCCCTGCGACTCTCCTGTACAGCCTCTGGATTCACCTTCAGTC GCTATAGCATGGACTGGGTCCGCCAGGCTTCAGGGAAGGGTCTGG SEQ ID AGTGGGTCTCGTCCATTAGTAGTAGGAGTAATTACATTTACTACGC NO: 67 AACCTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAA GAATTCACTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGACTC GGCTGTGTATTACTGTGCGAGAGAAACCTCAACTTTTGATGCTTTT GATATCTGGGGCCAAGGGACACTGGTCACCGTCTCTTCAGCCTCCA CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCT TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGAC CCCTGAGGTCACATGCGTGGTGGTGAGCGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAA TGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTA CAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAA CGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA ENPP3 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGG Antibody 6 GGGTCCCTGAGACTCTTCTGTGCAGCCTCTGGATTCACCTTCAGTG ACTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTCTCATTAATTAGTAGTAGTAGTATTTACTTATATTATGT AGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAA GCACTCGCTGTATCTGCAAATGAACAGCCTGAGAGTCGAGGACAC GGCTGTGTATTACTGTGCGAGAGGAAGGGACTACCTTGACTACTG GGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGG CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCA GCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCT ACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACA SEQ ID AGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC CGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTT NO: 68 CCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA GGTCACATGCGTGGTGGTGAGCGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG AAGAGCCTCTCCCTGTCTCCGGGTAAA Table 4: Light chains Amino Acid Sequence SEQ ID ENPP3 DIQLTQSPSFLSASVGDRVTITCRASQDISSNLAWYQQKPGKAP Antibody 1 KLLIYGASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFAIYHCQQ SEQ ID LNRYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL NO: 10 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC ENPP3 DIQMTQSPSSVSASVGGRVTITCRASQGISTWLAWYQQKPGKAPKLLI Antibody 2 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLT SEQ ID FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK NO: 17 VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC ENPP3 QLVLTQSPSASASLGASVKLTCTLNSGHSSYAIAWHQQQPEKGPRFL Antibody 3 MKVNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDETDYYCQTW GTGIHVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDF SEQ ID YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQW NO: 18 KSHRSYSCQVTHEGSTVEKTVAPTECS ENPP3 EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQRPGQAPRLLI Antibody 4 SDASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYYDWPR TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA SEQ ID KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK NO:19 VYACEVTHQGLSSPVTKSFNRGEC ENPP3 QLVLTQSPSASASLGASVKLTCTLNSGHSSYAIAWHQQQPEKGPRFL Antibody 5 MKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDETDYYCQTW GTGIHVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDF SEQ ID YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQW NO: 20 KSHRSYSCQVTHEGSTVEKTVAPTECS ENPP3 DIQMTQSPSFLSASVGDRVTITCRASQGISSNLAWYQQKPGKAPKLLI Antibody 6 YVTSTLQTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNNFPWT FGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK SEQ ID VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV NO: 21 YACEVTHQGLSSPVTKSFNRGEC Table 5 : Light chains Nucleic Acids Amino Acid Sequence SEQ ID ENPP3 GATATACAGCTGACTCAGTCACCCTCATTTCTCTCAGCTAGT Antibody 1 GTGGGCGACCGCGTGACAATTACATGCAGAGCAAGTCAAGA CATTTCCTCCAATCTGGCTTGGTATCAGCAGAAGCCCGGCAA GGCACCAAAGCTGCTGATTTATGGAGCTTCCACTCTTCAGAG TGGGGTGCCAAGTCGATTTTCTGGATCTGGGTCCGGTACAGA GTTTACACTAACCATCTCATCATTGCAACCAGAAGATTTCGC CATCTACCATTGTCAGCAGTTGAATCGGTATCCTCGGACTTT CGGCCAAGGCACCAAAGTTGAGATCAAGCGTACTGTGGCTG SEQ ID CACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA NO: 69 AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGC GAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAG CTTCAACAGGGGAGAGTGT ENPP3 GATATTCAGATGACACAGAGTCCTTCCTCAGTTTCAGCTTCA Antibody 2 GTTGGCGGGAGAGTGACAATCACTTGTCGCGCCTCTCAAGGC ATTTCCACATGGTTGGCTTGGTATCAGCAGAAGCCCGGGAAG GCACCAAAACTGCTGATCTATGCCGCATCTTCACTACAGTCT GGCGTGCCTTCAAGATTTAGTGGGAGTGGCTCCGGGACAGA CTTTACCCTTACTATCAGTTCCCTCCAGCCAGAAGATTTCGC AACATACTACTGTCAACAAGCCAATAGTTTCCCTCTGACCTT TGGAGGTGGTACCAAGGTCGAAATTAAGCGTACTGTGGCTG SEQ ID CACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT NO: 70 ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGC GAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAG CTTCAACAGGGGAGAGTGT ENPP3 CAACTGGTGCTGACACAGAGTCCATCAGCTTCTGCATCTCTT Antibody 3 GGGGCATCAGTTAAGCTGACTTGCACATTGAACTCCGGTCAC AGTTCATACGCTATCGCTTGGCATCAGCAGCAACCAGAGAA GGGACCCAGATTTCTCATGAAGGTGAACTCTGACGGCTCCCA TTCAAAAGGCGACGGTATTCCAGATCGATTTAGTGGGTCTTC CTCTGGCGCCGAACGGTATCTGACTATCAGTTCTCTGCAGTC SEQ ID AGAGGATGAAACCGACTATTACTGTCAGACTTGGGGCACCG GCATCCACGTGTTTGGAACCGGGACTAAAGTTACCGTGCTCG NO: 71 GTCAGCCCAAGGCTGCACCCAGTGTCACTCTGTTCCCGCCCT CCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTC TCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGA AGGCCGATAGCAGCCCCGTCAAGGCGGGAGTCGAAACCACC ACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAG CTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAA GCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAG AAGACAGTGGCCCCTACAGAATGTTCA ENPP3 GAAATCGTGATGACACAGAGCCCAGCCACACTTAGCGTTTCT Antibody 4 CCCGGGGAAAGGGCTACCCTCTCATGTCGCGCAAGTCAGTCT GTGTCCAGCAACTTTGCATGGTACCAACAGCGACCCGGTCAA GCTCCAAGGCTGCTGATTTCAGACGCCTCAACAAGAGCCACT GGCATCCCAGCAAGATTTTCCGGAAGTGGGTCTGGAACTGA ATTTACCCTCACAATTAGCTCTCTGCAGTCCGAGGACTTCGC TGTCTATTACTGCCAGCAGTACTATGATTGGCCTCGGACATT CGGCCAAGGCACTAAAGTGGAGATCAAGCGTACGGTGGCTG SEQ ID CACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT NO:72 ATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGC GAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAG CTTCAACAGGGGAGAGTGT ENPP3 CAGCTTGTGCTGACTCAATCGCCCTCTGCCTCTGCCTCCCTGG Antibody 5 GAGCCTCGGTCAAACTCACCTGCACTCTGAACAGTGGACAC AGCAGCTACGCCATCGCATGGCATCAGCAGCAGCCAGAGAA GGGCCCTCGGTTCTTGATGAAACTTAACAGTGATGGCAGCCA CAGCAAGGGGGACGGCATCCCTGATCGCTTCTCAGGCTCCA GCTCTGGGGCTGAGCGCTACCTCACCATCTCCAGCCTCCAGT CTGAGGATGAGACTGACTATTACTGTCAGACCTGGGGCACTG SEQ ID GCATTCATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTCG GTCAGCCCAAGGCTGCACCCAGTGTCACTCTGTTCCCGCCCT NO: 73 CCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTC TCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGA AGGCCGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACC ACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAG CTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAA GCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAG AAGACAGTGGCCCCTACAGAATGTTCA ENPP3 GACATCCAGATGACCCAGTCTCCATCCTTCCTGTCTGCATCT Antibody 6 GTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGG CATCAGCAGTAATTTAGCCTGGTATCAGCAAAAACCAGGGA AAGCCCCTAAGCTCCTGATCTATGTTACATCCACTTTACAAA CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACA SEQ ID GAATTCACTCTCACGATCAGCAGCCTGCAGCCTGAAGATTTT NO: 74 GCAACTTATTACTGTCAACAACTTAATAATTTCCCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGC TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC TATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGG ACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACG CTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTG CGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT Table 6: VH Amino Acid Sequence SEQ ID ENPP3 EVQLVESGGGLVKPGGSLRLSCAPSGFTFSDYSMNW SEQ ID Antibody VRQAPGR 1 GLEWVSSISSNSRYKYYADSVKGRFTISRDNAENSLYLQMNSL NO: 7 (VH1) RAEDTALYFCARGLDYFDYWGQGTLVTVSS ENPP3 QVQLQESGPGLVKPSETLSLTCTVSGGSISNYYWSWIRQPAGKG Antibody LEWIGRIYASGSTNYNPSLKSRVTMSVDTSKNQFSLRLRSVTAT SEQ ID 2 DTAVYYCAREGYSSTLYDNAFDFWGQGTMVTVSS NO: 22 ENPP3 EVQLVESGGGLVKPGGSLRLSCTASGFTFSRYSMDWVRQAPGK Antibody GLEWVSSISSRSNYIYYATSVKGRFTISRDNAKNSLFLQMNSLR SEQ ID 3 AEDSAVYYCARETSTFDAFDIWGQGTMVTVSS NO: 23 ENPP3 EVQLVESGGGLVKPGGSLRRSCVASGFTFSDYSMNWVRQAPG Antibody KGLEWVSFISSRSNYMKYADSVKGRFTISRDNAKNSLYLQMNS SEQ ID 4 LRAEDTAVYYCARGHYFDYWGQGTLVTVSS NO: 24 ENPP3 EVQLVESGGGLVKPGGSLRLSCTASGFTFSRYSMDWVRQASGK Antibody GLEWVSSISSRSNYIYYATSVKGRFTISRDNAKNSLFLQMNSLR SEQ ID 5 AEDSAVYYCARETSTFDAFDIWGQGTLVTVSS NO: 25 ENPP3 EVQLVESGGGLVKPGGSLRLFCAASGFTFSDYSMNWVRQAPG Antibody KGLEWVSLISSSSIYLYYVDSVKGRFTISRDNAKHSLYLQMNSL SEQ ID 6 RVEDTAVYYCARGRDYLDYWGQGTLVTVSS NO: 26 Table 7: VH Nucleic Acids Nucleic Acid Sequence SEQ ID ENPP3 GAAGTTCAGCTGGTTGAATCTGGCGGAGGTCTTGTGAAACCC Antibody GGTGGTTCTCTGCGACTTTCTTGTGCTCCATCTGGGTTTACCT SEQ ID 1 TTAGCGATTACAGCATGAACTGGGTTAGACAAGCACCCGGA (VH1) AGGGGTCTGGAATGGGTTTCAAGCATTTCCAGCAATTCTCGC NO: 75 TATAAGTACTACGCTGATTCAGTTAAAGGCAGATTCACAATC TCTCGCGACAATGCAGAGAATAGTCTGTATCTGCAAATGAAC TCTCTTCGAGCAGAAGATACAGCTCTGTATTTCTGTGCAAGA GGTCTTGATTACTTCGACTACTGGGGACAAGGGACATTGGTG ACAGTTTCTTCA ENPP3 CAAGTTCAACTGCAAGAATCTGGACCCGGCCTTGTGAAACC Antibody AAGCGAAACATTGTCTCTGACATGCACAGTTTCTGGAGGTTC 2 TATCAGCAACTACTATTGGTCATGGATTAGACAGCCAGCTGG GAAAGGTCTGGAATGGATTGGCCGCATTTATGCTTCTGGCTC SEQ ID AACCAATTACAACCCATCTCTTAAGTCAAGGGTGACAATGTC NO: 76 AGTTGACACATCTAAGAACCAGTTTAGTCTGCGACTGAGAA GTGTTACTGCAACAGATACCGCAGTTTATTATTGCGCCAGAG AGGGTTATAGTTCTACCCTTTACGATAATGCCTTTGACTTTTG GGGACAAGGAACAATGGTGACAGTTAGTTCA ENPP3 GAAGTCCAACTGGTTGAATCTGGTGGTGGTCTGGTGAAACCC Antibody GGTGGTTCACTTAGACTCTCTTGTACAGCTAGTGGATTTACC 3 TTCTCAAGATATTCCATGGATTGGGTTAGACAAGCTCCCGGG AAAGGACTTGAATGGGTTTCTTCCATTAGCTCTCGAAGCAAC SEQ ID TACATCTACTACGCAACATCTGTGAAAGGAAGGTTTACCATT NO: 77 TCACGCGATAATGCCAAGAACTCTCTGTTCCTCCAAATGAAC TCACTTCGCGCAGAAGATTCAGCTGTGTACTATTGTGCAAGA GAAACATCAACCTTTGACGCCTTTGATATTTGGGGACAAGGG ACAATGGTTACAGTTTCTTCT ENPP3 GAGGTCCAGCTGGTAGAATCTGGAGGTGGCCTTGTTAAGCCC Antibody GGCGGATCACTGAGGAGATCTTGTGTCGCTAGCGGGTTTACA 4 TTTTCCGACTATAGCATGAACTGGGTCCGACAAGCACCCGGG AAAGGTCTGGAGTGGGTGTCCTTTATCTCCTCAAGAAGCAAC SEQ ID TACATGAAGTACGCCGACAGCGTGAAAGGAAGGTTCACCAT NO: 78 TTCCAGAGATAACGCCAAGAACAGTCTCTATCTGCAAATGA ACTCACTCAGAGCTGAAGATACTGCAGTGTATTATTGCGCCA GAGGCCACTACTTCGACTACTGGGGCCAAGGAACACTGGTG ACTGTTAGTTCT ENPP3 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCC Antibody GGGGGGGTCCCTGCGACTCTCCTGTACAGCCTCTGGATTCAC 5 CTTCAGTCGCTATAGCATGGACTGGGTCCGCCAGGCTTCAGG GAAGGGTCTGGAGTGGGTCTCGTCCATTAGTAGTAGGAGTA SEQ ID ATTACATTTACTACGCAACCTCAGTGAAGGGCCGATTCACCA NO: 79 TCTCCAGAGACAACGCCAAGAATTCACTGTTTCTGCAAATGA ACAGCCTGAGAGCCGAGGACTCGGCTGTGTATTACTGTGCG AGAGAAACCTCAACTTTTGATGCTTTTGATATCTGGGGCCAA GGGACACTGGTCACCGTCTCTTCA ENPP3 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCC Antibody TGGGGGGTCCCTGAGACTCTTCTGTGCAGCCTCTGGATTCAC 6 CTTCAGTGACTATAGCATGAACTGGGTCCGCCAGGCTCCAGG GAAGGGGCTGGAGTGGGTCTCATTAATTAGTAGTAGTAGTAT SEQ ID TTACTTATATTATGTAGACTCAGTGAAGGGCCGATTCACCAT NO: 80 CTCCAGAGACAACGCCAAGCACTCGCTGTATCTGCAAATGA ACAGCCTGAGAGTCGAGGACACGGCTGTGTATTACTGTGCG AGAGGAAGGGACTACCTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA Table 8: VL Amino Acid Sequence SEQ ID ENPP3 Antibody DIQLTQSPSFLSASVGDRVTITCRASQDISSNLAWYQQKPGKAP SEQ ID 1 KLLIYGASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFAIYHCQQ NO: 8 LNRYPRTFGQGTKVEIK (VL1) ENPP3 DIQMTQSPSSVSASVGGRVTITCRASQGISTWLAWYQQKPGKA SEQ ID Antibody PKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 2 QQANSFPLTFGGGTKVEIK NO: 27 ENPP3 QLVLTQSPSASASLGASVKLTCTLNSGHSSYAIAWHQQQPEKGP SEQ ID Antibody RFLMKVNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDETD 3 YYCQTWGTGIHVFGTGTKVTVL NO: 28 ENPP3 EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQRPGQAP SEQ ID Antibody RLLISDASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQ 4 YYDWPRTFGQGTKVEIK NO: 29 ENPP3 QLVLTQSPSASASLGASVKLTCTLNSGHSSYAIAWHQQQPEKGP SEQ ID Antibody RFLMKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDETD 5 YYCQTWGTGIHVFGTGTKVTVL NO: 30 ENPP3 DIQMTQSPSFLSASVGDRVTITCRASQGISSNLAWYQQKPGKAP SEQ ID Antibody KLLIYVTSTLQTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQ 6 QLNNFPWTFGQGTKVEIK NO: 31 Table 9: VL Nucleic Acids Nucleic Acid Sequence SEQ ID ENPP3 GATATACAGCTGACTCAGTCACCCTCATTTCTCTCAGCTAGT Antibody 1 GTGGGCGACCGCGTGACAATTACATGCAGAGCAAGTCAAGA CATTTCCTCCAATCTGGCTTGGTATCAGCAGAAGCCCGGCAA (VL1) GGCACCAAAGCTGCTGATTTATGGAGCTTCCACTCTTCAGAG SEQ ID TGGGGTGCCAAGTCGATTTTCTGGATCTGGGTCCGGTACAGA NO: 81 GTTTACACTAACCATCTCATCATTGCAACCAGAAGATTTCGC CATCTACCATTGTCAGCAGTTGAATCGGTATCCTCGGACTTT CGGCCAAGGCACCAAAGTTGAGATCAAG ENPP3 GATATTCAGATGACACAGAGTCCTTCCTCAGTTTCAGCTTCA Antibody 2 GTTGGCGGGAGAGTGACAATCACTTGTCGCGCCTCTCAAGGC ATTTCCACATGGTTGGCTTGGTATCAGCAGAAGCCCGGGAAG GCACCAAAACTGCTGATCTATGCCGCATCTTCACTACAGTCT SEQ ID GGCGTGCCTTCAAGATTTAGTGGGAGTGGCTCCGGGACAGA NO: 82 CTTTACCCTTACTATCAGTTCCCTCCAGCCAGAAGATTTCGC AACATACTACTGTCAACAAGCCAATAGTTTCCCTCTGACCTT TGGAGGTGGTACCAAGGTCGAAATTAAG ENPP3 CAACTGGTGCTGACACAGAGTCCATCAGCTTCTGCATCTCTT Antibody 3 GGGGCATCAGTTAAGCTGACTTGCACATTGAACTCCGGTCAC AGTTCATACGCTATCGCTTGGCATCAGCAGCAACCAGAGAA GGGACCCAGATTTCTCATGAAGGTGAACTCTGACGGCTCCCA SEQ ID TTCAAAAGGCGACGGTATTCCAGATCGATTTAGTGGGTCTTC NO: 83 CTCTGGCGCCGAACGGTATCTGACTATCAGTTCTCTGCAGTC AGAGGATGAAACCGACTATTACTGTCAGACTTGGGGCACCG GCATCCACGTGTTTGGAACCGGGACTAAAGTTACCGTGCTC ENPP3 GAAATCGTGATGACACAGAGCCCAGCCACACTTAGCGTTTCT Antibody 4 CCCGGGGAAAGGGCTACCCTCTCATGTCGCGCAAGTCAGTCT GTGTCCAGCAACTTTGCATGGTACCAACAGCGACCCGGTCAA GCTCCAAGGCTGCTGATTTCAGACGCCTCAACAAGAGCCACT SEQ ID GGCATCCCAGCAAGATTTTCCGGAAGTGGGTCTGGAACTGA NO: 84 ATTTACCCTCACAATTAGCTCTCTGCAGTCCGAGGACTTCGC TGTCTATTACTGCCAGCAGTACTATGATTGGCCTCGGACATT CGGCCAAGGCACTAAAGTGGAGATCAAG ENPP3 CAGCTTGTGCTGACTCAATCGCCCTCTGCCTCTGCCTCCCTGG Antibody 5 GAGCCTCGGTCAAACTCACCTGCACTCTGAACAGTGGACAC AGCAGCTACGCCATCGCATGGCATCAGCAGCAGCCAGAGAA SEQ ID GGGCCCTCGGTTCTTGATGAAACTTAACAGTGATGGCAGCCA CAGCAAGGGGGACGGCATCCCTGATCGCTTCTCAGGCTCCA NO: 85 GCTCTGGGGCTGAGCGCTACCTCACCATCTCCAGCCTCCAGT CTGAGGATGAGACTGACTATTACTGTCAGACCTGGGGCACTG GCATTCATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTC ENPP3 Antibody 6 GACATCCAGATGACCCAGTCTCCATCCTTCCTGTCTGCATCT GTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGG CATCAGCAGTAATTTAGCCTGGTATCAGCAAAAACCAGGGA SEQ ID AAGCCCCTAAGCTCCTGATCTATGTTACATCCACTTTACAAA NO: 86 CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACA GAATTCACTCTCACGATCAGCAGCCTGCAGCCTGAAGATTTT GCAACTTATTACTGTCAACAACTTAATAATTTCCCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAA Table 10: ENPP3 Antibody 1 CDRs According to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 DYSMN SEQ ID NO: 1 CDRH2 SISSNSRYKYYADSVKG SEQ ID NO: 2 CDRH3 GLDYFDY SEQ ID NO: 3 CDRL1 RASQDISSNLA SEQ ID NO: 4 CDRL2 GASTLQS SEQ ID NO: 5 CDRL3 QQLNRYPRT SEQ ID NO: 6 Table 11: ENPP3 Antibody 1 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDY SEQ ID NO: 87 CDRH2 SSNSRY SEQ ID NO: 88 CDRH3 GLDYFDY SEQ ID NO: 89 CDRL1 RASQDISSNLA SEQ ID NO: 90 CDRL2 GASTLQS SEQ ID NO: 91 CDRL3 QQLNRYPRT SEQ ID NO: 92 Table 12: ENPP3 Antibody 1 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYSMN SEQ ID NO: 93 CDRH2 SISSNSRYKY SEQ ID NO: 94 CDRH3 GLDYFDY SEQ ID NO: 95 CDRL1 RASQDISSNLA SEQ ID NO: 96 CDRL2 GASTLQS SEQ ID NO: 97 CDRL3 QQLNRYPRT SEQ ID NO: 98 Table 13: ENPP3 Antibody 1 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SDYSMN SEQ ID NO: 99 CDRH2 WVSSISSNSRYKY SEQ ID NO: 100 CDRH3 ARGLDYFD SEQ ID NO: 101 CDRL1 SSNLAWY SEQ ID NO: 102 CDRL2 LLIYGASTLQ SEQ ID NO: 103 CDRL3 QQLNRYPR SEQ ID NO: 104 Table 14: ENPP3 Antibody 1 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYS SEQ ID NO: 105 CDRH2 ISSNSRYK SEQ ID NO: 106 CDRH3 ARGLDYFDY SEQ ID NO: 107 CDRL1 QDISSN SEQ ID NO: 108 CDRL2 GAS CDRL3 QQLNRYPRT SEQ ID NO: 110 Table 15: ENPP3 Antibody 2 CDRs According to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 NYYWS SEQ ID NO: 32 CDRH2 RIYASGSTNYNPSLKS SEQ ID NO: 33 CDRH3 EGYSSTLYDNAFDF SEQ ID NO: 34 CDRL1 RASQGISTWLA SEQ ID NO: 35 CDRL2 AASSLQS SEQ ID NO: 36 CDRL3 QQANSFPLT SEQ ID NO: 37 Table 16: ENPP3 Antibody 2 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GGSISNY SEQ ID NO: 111 CDRH2 YASGS SEQ ID NO: 112 CDRH3 EGYSSTLYDNAFDF SEQ ID NO: 113 CDRL1 RASQGISTWLA SEQ ID NO: 114 CDRL2 AASSLQS SEQ ID NO: 115 CDRL3 QQANSFPLT SEQ ID NO: 116 Table 17: ENPP3 Antibody 2 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GGSISNYYWS SEQ ID NO: 117 CDRH2 RIYASGSTN SEQ ID NO: 118 CDRH3 EGYSSTLYDNAFDF SEQ ID NO: 119 CDRL1 RASQGISTWLA SEQ ID NO: 120 CDRL2 AASSLQS SEQ ID NO: 121 CDRL3 QQANSFPLT SEQ ID NO: 122 Table 18: ENPP3 Antibody 2 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SNYYWS SEQ ID NO: 123 CDRH2 WIGRIYASGSTN SEQ ID NO: 124 CDRH3 AREGYSSTLYDNAFD SEQ ID NO: 125 CDRL1 STWLAWY SEQ ID NO: 126 CDRL2 LLIYAASSLQ SEQ ID NO: 127 CDRL3 QQANSFPL SEQ ID NO: 128 Table 19: ENPP3 Antibody 2 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GGSISNYY SEQ ID NO: 129 CDRH2 IYASGST SEQ ID NO: 130 CDRH3 AREGYSSTLYDNAFDF SEQ ID NO: 131 CDRL1 QGISTW SEQ ID NO: 132 CDRL2 AAS CDRL3 QQANSFPLT SEQ ID NO: 134 Table 20: ENPP3 Antibody 3 CDRs according to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 RYSMD SEQ ID NO: 38 CDRH2 SISSRSNYIYYATSVKG SEQ ID NO: 39 CDRH3 ETSTFDAFDI SEQ ID NO: 40 CDRL1 TLNSGHSSYAIA SEQ ID NO: 41 CDRL2 VNSDGSHSKGD SEQ ID NO: 42 CDRL3 QTWGTGIHV SEQ ID NO: 43 Table 21: ENPP3 Antibody 3 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRY SEQ ID NO: 135 CDRH2 SSRSNY SEQ ID NO: 136 CDRH3 ETSTFDAFDI SEQ ID NO: 137 CDRL1 TLNSGHSSYAIA SEQ ID NO: 138 CDRL2 VNSDGSHSKGD SEQ ID NO: 139 CDRL3 QTWGTGIHV SEQ ID NO: 140 Table 22: ENPP3 Antibody 3 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRYSMD SEQ ID NO: 141 CDRH2 SISSRSNYIY SEQ ID NO: 142 CDRH3 ETSTFDAFDI SEQ ID NO: 143 CDRL1 TLNSGHSSYAIA SEQ ID NO: 144 CDRL2 VNSDGSHSKGD SEQ ID NO: 145 CDRL3 QTWGTGIHV SEQ ID NO: 146 Table 23: ENPP3 Antibody 3 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SRYSMD SEQ ID NO: 147 CDRH2 WVSSISSRSNYIY SEQ ID NO: 148 CDRH3 ARETSTFDAFD SEQ ID NO: 149 CDRL1 SSYAIAWH SEQ ID NO: 150 CDRL2 FLMKVNSDGSHSKG SEQ ID NO: 151 CDRL3 QTWGTGIH SEQ ID NO: 152 Table 24: ENPP3 Antibody 3 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRYS SEQ ID NO: 153 CDRH2 ISSRSNYI SEQ ID NO: 154 CDRH3 ARETSTFDAFDI SEQ ID NO: 155 CDRL1 SGHSSYA SEQ ID NO: 156 CDRL2 VNSDGSH SEQ ID NO: 157 CDRL3 QTWGTGIHV SEQ ID NO: 158 Table 25: ENPP3 Antibody 4 CDRs according to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 DYSMN SEQ ID NO: 44 CDRH2 FISSRSNYMKYADSVKG SEQ ID NO: 45 CDRH3 ARGHYFD SEQ ID NO: 46 CDRL1 SSNFAWY SEQ ID NO: 47 CDRL2 LLISDASTRA SEQ ID NO: 48 CDRL3 QQYYDWPR SEQ ID NO: 49 Table 26: ENPP3 Antibody 4 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDY SEQ ID NO: 159 CDRH2 SSRSNY SEQ ID NO: 160 CDRH3 GHYFDY SEQ ID NO: 161 CDRL1 RASQSVSSNFA SEQ ID NO: 162 CDRL2 DASTRAT SEQ ID NO: 163 CDRL3 QQYYDWPRT SEQ ID NO: 164 Table 27: ENPP3 Antibody 4 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYSMN SEQ ID NO: 165 CDRH2 FISSRSNYMK SEQ ID NO: 166 CDRH3 GHYFDY SEQ ID NO: 167 CDRL1 RASQSVSSNFA SEQ ID NO: 168 CDRL2 DASTRAT SEQ ID NO: 169 CDRL3 QQYYDWPRT SEQ ID NO: 170 Table 28: ENPP3 Antibody 4 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SDYSMN SEQ ID NO: 171 CDRH2 WVSFISSRSNYMK SEQ ID NO: 172 CDRH3 ARGHYFD SEQ ID NO: 173 CDRL1 SSNFAWY SEQ ID NO: 174 CDRL2 LLISDASTRA SEQ ID NO: 175 CDRL3 QQYYDWPR SEQ ID NO: 176 Table 29: ENPP3 Antibody 4 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYS SEQ ID NO: 177 CDRH2 ISSRSNYM SEQ ID NO: 178 CDRH3 ARGHYFDY SEQ ID NO: 179 CDRL1 QSVSSN SEQ ID NO: 180 CDRL2 DAS CDRL3 QQYYDWPRT SEQ ID NO: 182 Table 30: ENPP3 Antibody 5 CDRs According to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 RYSMD SEQ ID NO: 50 CDRH2 SISSRSNYIYYATSVKG SEQ ID NO: 51 CDRH3 ETSTFDAFDI SEQ ID NO: 52 CDRL1 TLNSGHSSYAIA SEQ ID NO: 53 CDRL2 LNSDGSHSKGD SEQ ID NO: 54 CDRL3 QTWGTGIHV SEQ ID NO: 55 Table 31: ENPP3 Antibody 5 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRY SEQ ID NO: 183 CDRH2 SSRSNY SEQ ID NO: 184 CDRH3 ETSTFDAFDI SEQ ID NO: 185 CDRL1 TLNSGHSSYAIA SEQ ID NO: 186 CDRL2 LNSDGSHSKGD SEQ ID NO: 187 CDRL3 QTWGTGIHV SEQ ID NO: 188 Table 32: ENPP3 Antibody 5 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRYSMD SEQ ID NO: 189 CDRH2 SISSRSNYIY SEQ ID NO: 190 CDRH3 ETSTFDAFDI SEQ ID NO: 191 CDRL1 TLNSGHSSYAIA SEQ ID NO: 192 CDRL2 LNSDGSHSKGD SEQ ID NO: 193 CDRL3 QTWGTGIHV SEQ ID NO: 194 Table 33: ENPP3 Antibody 5 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SRYSMD SEQ ID NO: 195 CDRH2 WVSSISSRSNYIY SEQ ID NO: 196 CDRH3 ARETSTFDAFD SEQ ID NO: 197 CDRL1 SSYAIAWH SEQ ID NO: 198 CDRL2 FLMKLNSDGSHSKG SEQ ID NO: 199 CDRL3 QTWGTGIH SEQ ID NO: 200 Table 34: ENPP3 Antibody 5 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSRYS SEQ ID NO: 201 CDRH2 ISSRSNYI SEQ ID NO: 202 CDRH3 ARETSTFDAFDI SEQ ID NO: 203 CDRL1 SGHSSYA SEQ ID NO: 204 CDRL2 LNSDGSH SEQ ID NO: 205 CDRL3 QTWGTGIHV SEQ ID NO: 206 Table 35: ENPP3 Antibody 6 CDRs according to Kabat CDR Amino Acid Sequence SEQ ID NO CDRH1 DYSMN SEQ ID NO: 56 CDRH2 LISSSSIYLYYVDSVKG SEQ ID NO: 57 CDRH3 GRDYLDY SEQ ID NO: 58 CDRL1 RASQGISSNLA SEQ ID NO: 59 CDRL2 VTSTLQT SEQ ID NO: 60 CDRL3 QQLNNFPWT SEQ ID NO: 61 Table 36: ENPP3 Antibody 6 CDRs According to Chothia CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDY SEQ ID NO: 207 CDRH2 SSSSIY SEQ ID NO: 208 CDRH3 GRDYLDY SEQ ID NO: 209 CDRL1 RASQGISSNLA SEQ ID NO: 210 CDRL2 VTSTLQT SEQ ID NO: 211 CDRL3 QQLNNFPWT SEQ ID NO: 212 Table 37: ENPP3 Antibody 6 CDRs According to AbM CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYSMN SEQ ID NO: 213 CDRH2 LISSSSIYLY SEQ ID NO: 214 CDRH3 GRDYLDY SEQ ID NO: 215 CDRL1 RASQGISSNLA SEQ ID NO: 216 CDRL2 VTSTLQT SEQ ID NO: 217 CDRL3 QQLNNFPWT SEQ ID NO: 218 Table 38: ENPP3 Antibody 6 CDRs According to Contact CDR Amino Acid Sequence SEQ ID NO CDRH1 SDYSMN SEQ ID NO: 219 CDRH2 WVSLISSSSIYLY SEQ ID NO: 220 CDRH3 ARGRDYLD SEQ ID NO: 221 CDRL1 SSNLAWY SEQ ID NO: 222 CDRL2 LLIYVTSTLQ SEQ ID NO: 223 CDRL3 QQLNNFPW SEQ ID NO: 224 Table 39: ENPP3 Antibody 6 CDRs According to IMGT CDR Amino Acid Sequence SEQ ID NO CDRH1 GFTFSDYS SEQ ID NO: 225 CDRH2 ISSSSIYL SEQ ID NO: 226 CDRH3 ARGRDYLDY SEQ ID NO: 227 CDRL1 QGISSN SEQ ID NO: 228 CDRL2 VTS CDRL3 QQLNNFPWT SEQ ID NO: 230 Table 40: Cytotoxicity, binding and internalization data Cytotoxicity SPR Binding Cell Biding Internalization Fold Cell Cell Cell line 1 - Cell line2 Cell line 2 Human Cyno diff Binding Cell Bindin Fold diff Internalizing Cell line 1 - Dola - - Dola - - Dola - ENPP3, ENPP3, between – Cel Binding – g – between binding score DAY3 DAY6 DAY3 DAY6 KD nM KD nM cyno vs l Cell line 2 Cell line 3 cyno vs (all human line 1 (nM) KO cyno (nM) OE (nM) human concentrations) ENPP3 Antibody 0.13152 0.028692 0.08472 0.033672 0.23 Biphasic 0.30 0.38 1.50 4 195.85 1 ENPP3 Antibody 0.0816 0.015486 0.43704 0.0627 1.41 Biphasic 0.17 0.15 4.19 26 198.16 4 ENPP3 Antibody 1.3896 0.048378 0.8766 0.0633 0.13 11.16 85 0.51 0.57 1.55 3 203.49 6 ENPP3 Antibody 0.04647 0.01734 1.293 0.1899 0.34 1.21 4 0.44 0.53 1.09 2 223.14 5 ENPP3 Antibody 0.06395 0.02869 1.398 0.4203 0.33 0.91 3 0.39 0.52 0.85 2 3 ENPP3 Antibody 0.10662 0.01962 2.7228 0.51714 0.37 Biphasic 0.13 0.14 0.32 2 186.19 2 Treatment with select ENPP3-AF-HPA antibodies results in tumor regression in vivo [0560] Six ENPP3 antibodies were conjugated via a linker with AF-HPA (ENPP3-AF-HPA antibodies). Mice bearing established SC xenografts in female immune-compromised SCID-beige (ie, severe combined immunodeficiency – beige or CB17.Cg PrkdcscidLystbg J/Crl) mice were dosed once IV with 6 ENPP3-AF-HPA antibodies at Dose D or Isotype-AF-HPA at Dose D Tumor fragments were implanted on Day 0, followed by treatment on Day 13 (dosing indicated by arrow, FIG.4). Group tumor volumes are graphed as mean ± SEM. * Denotes significant difference of the ADC1 treatment group versus the Isotype-ADC control group on Day 30 (p<0.0001, n=8/group). Tumor ex vivo ENPP3 expression was measured by IHC and flow cytometry (dissociated tumors) at a tumor volume equivalent to that at randomization [Signals E168634, E102381]. IHC showed ENPP3 positivity in xenograft tumors and flow cytometry showed medium ENPP3 expression (110,000 receptors per cell). [0561] The results demonstrated tumor regression activity of the six ENPP3-AF-HPA antibodies (see FIG.4). ENPP3 Antibody 1 demonstrated the strongest tumor inhibition. Treatment with the select ENPP3-AF-HPA antibodies results in the dose-dependent tumor regression in vivo [0562] The effect of ENPP3-AF-HPA treatment on tumor growth in mice bearing xenograft tumors expressing ENPP3 was evaluated a different concentration of the select ENPP3- AF-HPA antibodies. Briefly, mice bearing established SC xenografts expressing ENPP3 in female immune-compromised SCID-beige (ie, severe combined immunodeficiency – beige or CB17.Cg PrkdcscidLystbg J/Crl) mice were dosed once IV with 3 ENPP3 ADCs, at Dose A, B, and D or Isotype-ADC (B23B251- AF-HPA) at Dose D. Tumor fragments were implanted on Day 0, followed by treatment on Day 13 (dosing indicated by red arrow). Group tumor volumes are graphed as mean ± SEM. * Denotes significant difference of the ADC1 treatment group versus the Isotype-ADC control group on Day 24 (p<0.0001, n=8/group). Tumor ex vivo ENPP3 expression was measured by IHC and flow cytometry (dissociated tumors) at a tumor volume equivalent to that at randomization [Signals E168634, E102381]. IHC showed ENPP3 positivity in xenograft tumors and flow cytometry showed medium ENPP3 expression (110,000 receptors per cell). The results show that ENPP3 Antibody 1-AF-HPA exhibited the most potent dose- dependent efficacy in xenograft tumor models expressing ENPP3 (Table 41). Table 41: Tumor growth inhibition by select ENPP3-AF-HPA antibodies. Treatment Day 24 %∆TGI p value CR, % regression ENPP3 Antibody 3-AF- 0 ns 0/8 HPA, Dose A ENPP3 Antibody 3-AF- 69 0.0003 3/8 HPA, Dose B ENPP3 Antibody 3-AF- 122 <0.0001 8/8, 100% HPA, Dose D ENPP3 Antibody 1- AF- 51 0.05 0/8 HPA, Dose A ENPP3 Antibody 1- - AF- 95 <0.0001 4/8 HPA, Dose B ENPP3 Antibody 1-- AF- 122 <0.0001 8/8, 100% HPA, Dose D ENPP3 Antibody 2- AF- 20 ns 0/8 HPA, Dose A ENPP3 Antibody 2- AF- 17 ns 1/8 HPA, Dose B ENPP3 Antibody 2- AF- 113 <0.0001 6/8, 75% HPA, Dose D Example 5: ENPP3 expression in solid tumors [0563] To better understand ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) expression and prevalence across tumors, an immunohistochemistry (IHC) assay was developed using the commercial mAb E5M2W, and staining was performed on ~1,500 tissues across 2 pan-cancer tissue microarrays (TMAs) and 11 tumor-specific TMAs. ENPP3 was highly expressed in several solid tumors including clear cell renal cell carcinoma (ccRCC) (93%), papillary renal cancer (78%), uterus endometrioid cancer (53%), colorectal cancer (CRC) (51%), lung adenocarcinoma (50%), the endometrioid subtype of ovarian and cancer (47%) (FIG.5). [0564] To quantify the expression level of ENPP3 in ccRCC tumors, flow-cytometry-based receptor density studies were performed using commercial ENPP3 antibody clone NP4D6. Of the 13 ccRCC dissociated tumor cells (DTCs) tested, 10 were positive for ENPP3.7 of the 10 samples exhibited a high level of expression (100,000 to >400,000 receptors/cell; FIG.6A-6B). Additionally, matched formalin-fixed, paraffin-embedded (FFPE) tissues from 3 DTCs were stained by IHC and results corroborated those obtained by flow cytometry (FIG.6C-6E). In addition, a tumor that showed very low ENPP3 expression by flow cytometry (7,000 receptors/cell) also stained negative (0 / 0% positivity) by IHC, while tumors that showed high expression by flow cytometry (170,000 and >470,000 receptors/cell) also stained moderate (Medium/ 100% positivity) by IHC. [0565] ENPP3 was identified as a unique tumor-targeting antigen with high expression in several solid tumors and apically restricted normal tissue expression. Example 6: ENPP3 expression in cancer cell lines [0566] ENPP3 surface expression and receptor density was evaluated on a panel of in vitro established renal cell carcinoma (RCC) and liver/hepatocellular carcinoma (HCC), cell lines with flow cytometry using a commercial ENPP3 antibody (clone NP4D6) binding to an epitope similar to ENPP3 binder arm within ADC1. Further, ENPP3 was overexpressed in several of these tumor cells to generate the overexpression cell lines, A704 huENPP3-OE, H1975 huENPP3-MedOE, H1975 huENPP3-HighOE, VMRCRCW huENPP3-MedOE and VMRC RCW huENPP3-HighOE. Endogenous ENPP3 was knocked out in the HepG2 cell line, generating the negative cell line HepG2 ENPP3 KO. Finally, human and cynomolgus monkey ENPP3 protein was overexpressed in the HepG2 ENPP3 KO cell line to generate HepG2 KO – huENPP3 OE and HepG2 KO – cyENPP3 OE cell lines, respectively. Cynomolgus monkey ENPP3 protein was also overexpressed in the ENPP3-negative cell line H1975, to generate the H1975 – cyENPP3 OE cell line. [0567] ENPP3 endogenous expression ranged from negative expression (determined as < lower limit of detection [LLOD], 7,646 receptors/cell) in the H1975 cell line, to low expression (<50,000 receptors/cell) in HepG2 and VMRC-RCW, medium expression (50,000-150,000 receptors/cell) in TUHR10TKB and Example Cell line 1, and high expression (>150,000 receptors/cell) in A704 cell lines (FIG.7A-D). Knock out and overexpression lines showed expected expression level changes (FIG.7A-D). Example 7: ENPP3 expression in tumor PDX models [0568] Ex vivo ENPP3 expression was also measured by IHC and flow cytometry in a NSCLC patient derived xenograft (PDX) model, and 2 RCC PDX models RCC1 and RCC2. All 3 PDX models exhibited high ENPP3 expression by IHC and receptor density measurements of 200,000 (NSCLSC), 310,000 (RCC1), and 410,000 (RCC2) receptors/cell (FIG.8). Example 8: Construction of ADC1 [0569] Antibody-drug conjugate 1 (ADC1) was constructed with a monoclonal antibody (mAb) that binds to ENPP3, ENPP3 Antibody 1, comprising the sequences set forth in Tables 2-14, conjugated to an auristatin and a branched linker. [0570] The mAb was generated by co-expression of the anti-ENPP3 heavy chain (HC) and light chain (LC) and binds to the extracellular region of ENPP3 at residues 671-681 (SEQ ID NO 231: VPPSESQKCSF) and 762-780 (SEQ ID NO 232: PDEITKHLANTDVPIPTHY). [0571] The auristatin and a branched linker platform consisted of a microtubule inhibitor payload and a branched hydrophilic linker enabling a drug-to-antibody (DAR) 6. The linker consists of branched scaffold to support 3 AF-HPA payloads per linker, and polyethylene glycol (PEG)8 groups for enhanced hydrophilicity. The payload was auristatin F hydroxypropyl amide (AF-HPA). [0572] Auristatin F hydroxypropyl amide (AF-HPA) has the formula . [0573] The drug-linker prior conjugation has the formula . [0574] The mAb was conjugated to an auristatin and a branched linker platform using the Synaffix GlycoConnect process. The native glycans on the antibody Fc at site N296 of SEQ ID NO: 9 was enzymatically processed by an endoglycosidase to the core N-acetylglucosamine followed by attachment of an azido-modified N-acetylgalactosamine utilizing a glycosyl transferase. The azido-modified antibody was then coupled to the Dolasythen payload-linker via copper-free click chemistry. Example 9: Biophysical assessment of ADC1 [0575] Binding and intrinsic properties of ADC1 were tested. ADC1 exhibited a favorable biophysical profile with high affinity (0.307 ± 0.005 nM) to human ENPP3, high purity, good conformational stability, low hydrophobicity, and low to no nonspecific binding. Furthermore, it also exhibited favorable stability profiles in human serum, under ex vivo physiological conditions, under degradation studies, and under thermal stress at high concentrations. Example 10: ADC1 binding in tumor cell lines [0576] In vitro cell binding of ADC1 was assessed on several cell lines with endogenous expression and overexpression of human or cynomolgus monkey ENPP3. ADC1 exhibited a dose-dependent binding to all ENPP3-positive cell lines tested, with endogenous expression (Example cell line 1, VMRCRCW, HepG2) and engineered overexpression (HepG2 KO – huENPP3 OE, VMRCRCW huENPP3 High OE, H1975 huENPP3 High OE) Results can be found in FIG.9 and Table 42. ADC1 binding 50% effective concentration (EC50) values for ENPP3 in the endogenously expressed ENPP3 cell lines were 0.27 to 0.52 nM and EC50 values for the engineered ENPP3 overexpression cell lines were 1.4 to 2.6 nM. ADC1 also exhibited a dose-dependent binding to the cynomolgus monkey ENPP3-expressing cell lines HepG2 KO – cyENPP3 OE and H1975 cyENPP3 OE with an EC50 value of 2.3 and 2.5 nM, respectively. ADC1 did not exhibit binding to ENPP3-negative cell lines HepG2 ENPP3 KO and H1975 and no binding was observed to any of the cell lines with the isotype control ADC HIVB60- Dola. Table 42: Binding of the ADC1 to ENPP3-expressing tumor cell lines (EC50). Cells EC50 (nM) Example cell line 1 0.34 VMRCRCW (Renal cell carcinoma) 0.27 VMRCRCW huENPP3 High OE 2.3 HepG2 (liver cancer) 0.52 HepG2 ENPP3 KO ND HepG2 KO – huENPP3 OE 1.4 HepG2 KO – cyENPP3 OE 2.3 H1975 (Non-small cell lung cancer) ND H1975 huENPP3 High OE 2.6 H1975 cyENPP3 OE 2.5 cy, cynomolgus monkey; EC50, 50% effective concentration; ENPP3, ectonucleotide pyrophosphatase/phosphodiesterase family member 3; hu, human; KO, knockout; ND, not determined; OE, overexpressing. Duplicate points for each condition were tested for ADC1. EC50 values were ND if the dose-response curve did not satisfy one or both of the following criteria: R2 >0.9 and log (95% confidence interval) difference <1.2. [0577] Next, Binding specificity of ADC1 to ENPP3 compared to other ENPP family members was tested in CHO-K1 cells engineered to express ENPP1, ENPP2, ENPP3. ADC1 exhibited a dose-dependent binding only to the ENPP3-expressing CHO-K1 cell line, with an EC50 value of 0.7 nM, and no binding was observed to CHO-K1 parental cells or CHO-K1 cell lines expressing ENPP1 or ENPP2 (FIG.10). No binding was observed to any cell line with isotype control ADC HIVB60-Dola (Dolasynthen) (FIG. 10). This confirmed ADC1’s specific binding to ENPP3 and not to other ENPP family members. Example 11: Internalization of ADC1 [0578] Internalization of ADC1 (or the parental unconjugated mAb) was evaluated using confocal-microscopy-based high-content imaging in an ENPP3 medium expressing cell line (Example Cell line 1) and VMRCRCW huENPP3 High OE (ENPP3 high overexpression). ADC1 exhibited a dose-dependent internalization over time, with the maximal antibody internalization seen as early as 30 minutes post binding at 4°C. No internalization was seen in either of the cell lines with the isotype control ADC B23B251- Dola (FIG.11). [0579] Higher levels of internalization were observed in cell lines expressing medium and high levels of ENPP3, i.e., Example cell line 1 and VMRCRCW huENPP3 High OE, compared to the ENPP3 low cell line VMRCRCW, suggesting a correlation between internalization and ENPP3 expression. Similar dose and ENPP3-expression-dependent internalization was observed in additional ENPP3-expressing cell lines VMRCRCW (endogenous low), A704, and TUHR4TKB. In addition to internalization, cellular phenotypic changes associated with microtubule inhibition (monomethyl auristatin E [MMAE]-driven phenotype) and tumor cell cytotoxicity (cytotoxic phenotype) were evaluated using high-content imaging in the presence of ADC1 over time (FIG.12A). In both ENPP3-positive cell lines tested (Example cell line 1 and VMRCRCW huENPP3 High OE), ADC1 exhibited a dose- and time-dependent induction of internalization, auristatin (MMAE) and cytotoxic phenotype, with no phenotypic changes were seen with the isotype control ADC B23B251-Dola (FIG.12B). In both cell lines, the MMAE phenotype was observed as early as after ~6 hours post binding at 4°C, followed by the cytotoxic phenotype seen after 24 hours and later. Finally, ≥50% tumor cell cytotoxicity was seen at 24 to 48 hours and later the Example cell line 1and VMRCRCW – huENPP3 High OE cell lines. This data shows that ADC1 undergoes rapid internalization, leading to auristatin (MMAE) and cytotoxic phenotype, eventually resulting in tumor cell cytotoxicity. Example 12: ADC1 induced cytotoxicity in ENPP3 cell lines [0580] ADC1-induced tumor cell cytotoxicity was evaluated on a panel of ENPP3-positive cell lines as well as ENPP3-negative cell line controls. ADC1 exhibited potent dose- dependent cytotoxicity in example cell lines endogenously expressing ENPP3 at a medium level), with an EC50 value of ~0.3 nM (FIG.13, Table 43). Table 43: EC50 values for tumor cell cytotoxicity in a panel of ENPP3-expressing tumor cell lines. Cell line ADC1 EC50 (nM) auristatin F hydroxypropyl amide (AF-HPA_ EC50 (nM) Day 3 Day 6 Day 3 Day 6 Example cell line 1 0.393 0.276 2.06 1.36 (medium) Example cell line 2 0.645 0.268 1.27 0.7 (medium) TUHR10TKB (Clear cell 37.08 9.949 1.49 1.34 renal cell carcinoma) VMRCRCW (Renal cell ND ND 41.92 37.15 carcinoma) VMRCRCW huENPP3 ND 81.04 38.9 36.17 Med OE VMRCRCW huENPP3 0.046 0.065 36.02 39.41 High OE HepG2 (liver cancer) ND 49.36 4.32 3.97 HepG2 ENPP3 KO ND 40.41 4.7 2.17 HepG2 KO – huENPP3 OE 0.295 0.243 5.56 3.59 HepG2 KO – cyENPP3 OE 13.24 16.14 6.49 4.91 H1975 (non-small cell lung 39.92 16.72 1.23 1.01 cancer) H1975 huENPP3 Med OE 0.950 3.185 1.59 1.22 H1975 huENPP3 High OE 0.045 0.110 1.19 0.85 H1975 cyENPP3 OE 2.51 1.75 1.04 0.77 A704 (kidney ND ND >300 ND adenocarcinoma) A704 huENPP3 OE 0.390 0.41 260.6 ND cy, cynomolgus monkey; EC50, 50% effective concentration; hu, human; KO, knockout; Med, medium; ND, not determined; OE, overexpression. EC50 values were not determined if the dose-response curve did not satisfy one or both of the following criteria: R2 has to be >0.9 and the log (95% confidence interval) difference needs to be <1.2. [0581] ADC1 did not elicit potent cytotoxicity in some solid tumor cell lines with the endogenous ENPP3 levels (HepG2, VMRCRCW and A704). Further these cell lines also exhibited low sensitivity to the payload auristatin F hydroxypropyl amide (AF-HPA) (EC50 >1 nM). To better understand if this resistance to ADC1-mediated cytotoxicity was a function of ENPP3 expression level, human or cynomolgus monkey ENPP3 was overexpressed in HepG2 and VMRCRCW cell lines at different expression levels and evaluated for ADC1 -mediated cytotoxicity. ADC1 exhibited potent dose-dependent cytotoxicity in these ENPP3-overexpression cell lines, i.e., HepG2 KO – huENPP3 OE and VMRCRCW huENPP3 High OE, with EC50 values of 0.2 and 0.065 nM, respectively. [0582] To further evaluate the level of endogenous expressed ENPP3 in cells lines and its sufficiency to lead to ADC1-mediated cytotoxicity, ENPP3 was overexpressed at moderate levels (91,000 receptors/cell) in the ENPP3-negative H1975 lung cell line, with known higher sensitivity to the auristatin class payload. ADC1 exhibited potent dose- dependent cytotoxicity in the H1975 huENPP3 Med OE cell line with an EC50 value of 0.95 nM upon 3 days of treatment. Minimal cytotoxicity (at higher ADC concentrations) was observed with ADC1 in ENPP3-negative cell lines HepG2 ENPP3 KO and H1975. Further, minimal tumor cell cytotoxicity (at the higher ADC concentrations) was observed with the isotype control ADC (HIVB60-Dola) in all the cell lines tested. The payload AF-HPA exhibited dose-dependent cytotoxicity across all cell lines tested, while its membrane-impermeable metabolite auristatin F (AF) exhibited minimal tumor cytotoxicity at the highest doses (Table 43). [0583] ADC1-induced tumor cell cytotoxicity was also evaluated upon shorter drug exposure (i.e., 2 hours), because ADC1 internalization occurs within the first 30 minutes of ADC exposure. Results showed that similar to long-term drug exposure (i.e., 6 days), ADC1 exhibited potent dose-dependent cytotoxicity with the 2-hour ADC exposure in the ENPP3 high HepG2 KO-huENPP3 OE cell line, with a modest decrease in EC50 values compared to longer (ie, 6-day) ADC exposure (FIG.14). While minimal tumor cell cytotoxicity (at the higher ADC1 concentrations) was observed with the isotype control ADC (HIVB60-Dola) upon 6-day drug exposure, no cytotoxicity was observed with the short-term exposure, confirming the specificity of ADC1-induced cytotoxicity and the incubation-time-dependent non-specific isotype control cytotoxicity. [0584] Thus, ADC1 exhibited potent and dose-dependent cytotoxicity in vitro in tumor cell lines expressing ENPP3, and the potency was dependent on the cell line sensitivity to payload and ENPP3 expression levels. Example 13: ADC1 -mediated bystander effect [0585] ADC1-induced bystander effect was evaluated using a coculture of ENPP3-positive and ENPP3-negative cell lines, wherein the cytotoxicity to the ENPP3-negative cell line would be derived from payload bystander activity. This assay was performed using a pair of cell lines fluorescently labeled with different fluorochromes: (i) HepG2 ENPP3 KO (ENPP3 negative, green) and HepG2 KO – huENPP3 OE (ENPP3 positive, red). ADC1 exhibited potent dose-dependent cytotoxicity against the ENPP3-positive cell line HepG2 KO – huENPP3 OE (red), while no tumor cytotoxicity was seen in the ENPP3-negative cell line HepG2 ENPP3 KO (green), when cultured alone. (FIG.15A-B) [0586] When cocultured, ENPP3-negative cell lines were efficiently killed by ADC1 in a dose-dependent manner, demonstrating payload bystander effect. No significant tumor cell cytotoxicity was observed with isotype control ADC HIVB60-Dola against all cell lines and conditions tested, nor with vcMMAF-conjugated ENPP3 antibody (vcMMAF is non-cell permeable and hence absence of bystander effect can be expected) against ENPP3-negative cell line under coculture condition (FIG.15C). This data suggested that ADC1 exhibited ENPP3-specific bystander cytotoxicity of ENPP3-negative cells in the presence of ENPP3-positive tumor cells. Example 14: ADC1 efficacy in mouse xenograft models Renal Cell Carcinoma (RCC) PDX [0587] Female NSG (i.e., non-obese diabetic [NOD] severe combined immunodeficiency [scid] gamma mice bearing SC RCC PDX (310,000 receptors/cell), were dosed once IV with ADC1 at increasing amounts of A, B, C, and D or Isotype-ADC (B23B251-Dola) at an amount D (i.e., the highest amount given for ADC1). Significant antitumor efficacy was observed with ADC1 treatment at increasing amounts of A, B, C and D resulting in ΔTGI of 103%, 106%, 110%, and 111%, respectively (p<0.001; FIG.16A) as compared to Isotype-ADC on Day 38 post tumor implantation. ADC1 treatment at B resulted in 8 of 12 partial tumor regressions (PRs) and 2 of 12 CRs, C treatment resulted in 11 of 12 PRs and 1 of 12 CRs, while the D dose resulted in 11 of 12 PRs and 1 of 12 CRs. [0588] Female NSG mice bearing a second (SC) RCC PDX (410,000 receptors/cell), were dosed once IV with ADC1 at increasing amounts of A, B, and C or Isotype-ADC at an amount D (i.e., the highest amount given for ADC1). Significant antitumor efficacy was observed with the ADC1 increasing amounts of A, B, C, and D resulting in ΔTGI of 71%, 85%, and 100%, respectively (p<0.001; FIG.16B) as compared to Isotype-ADC on Day 45 post tumor implantation. ADC1 at amount C dose resulted in 3 of 11 PRs, while the D dose resulted in 7 of 11 PRs on Day 45. Non-small cell lung cancer (NSLC) PDX [0589] Female NMRI nude mice bearing SC NSLC PDX (200,000 receptors/cell), were dosed once IV with ADC1 at increasing amounts of A, B, C, and D or Isotype-ADC at an amount D (i.e., the highest amount given for ADC1). Significant antitumor efficacy was observed with ADC1 treatment at C and D resulting in ΔTGI of 74% and 100%, respectively (p<0.001; FIG.17) as compared to Isotype-ADC-treated control on Day 31 post tumor implantation. ADC1 at C resulted in 2 of 12 PRs and D dose resulted in 9 of 12 PRs on Day 31. Treatment with ADC1 at A and B resulted in 24% and 39% ΔTGI, respectively, as compared to Isotype-ADC-treated control. Statistically significant (p<0.05) data at B with ADC1 did not result in biologically significant efficacy. Conclusion [0590] ADC1 treatment induced in vivo antitumor efficacy in CDX and PDX tumors, in an ENPP3 expression level dependent manner.

Claims

CLAIMS 1. An antibody drug conjugate having the structure Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3, L is a linker covalently bound to Ab and LA, LA is a divalent moiety connecting L and D, D is a drug; n is 1, 2 or 3; and m is 1, 2 or 3, wherein the antibody comprises: a CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of SEQ ID NO:7 or 22- 26 and a CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8 or 27- 31. 2. An antibody drug conjugate having the structure Ab-(L-(LA-D)n)m wherein Ab is an antibody or antigen binding fragment thereof that binds to ENPP3; L is a linker covalently bound to Ab and LA; LA is a divalent moiety connecting L and D; D is an auristatin; n is 1, 2 or 3; and m is 1, 2 or 3. 3. The antibody drug conjugate of claim 1 or 2, wherein n is 2 or 3. 4. The antibody drug conjugate of any one of claims 1-3, wherein m is 1 or 2. 5. The antibody drug conjugate of any one of claims 1-4, wherein n is 3 and m is 2. The antibody drug conjugate of any one of claims 1-5, wherein the antibody drug conjugate has a DAR that is 6. The antibody drug conjugate of any one of claims 1-6, wherein the antibody or antigen binding fragment thereof comprises; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. 8. The antibody drug conjugate of any one of claims 1-7, wherein the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. 9. The antibody drug conjugate of any one of claims 1-8, wherein the antibody or antigen binding fragment thereof comprises a VH comprising at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and a VL comprising at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8, or 27-31. 10. The antibody drug conjugate of claim 9, wherein, the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or the VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. 11. The antibody drug conjugate of any one of claims 1-10, wherein the antibody or antigen binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and the VL comprising the amino acid sequence set forth in SEQ ID NO: 8. 12. The antibody drug conjugate of any one of claims 1-11, wherein the antibody or antigen binding fragment thereof comprises a heavy chain (HC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:9 or 12-16, and a light chain (LC) that has at least 90%, 95% or 99% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:10 or 17-21. 13. The antibody drug conjugate of claim 12, wherein, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. 14. The antibody drug conjugate of claim 12, wherein the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. 15. The antibody drug conjugate of any one of claims 1-14, wherein each L is attached to a heavy chain of the antibody or antigen binding fragment thereof at an asparagine residue at position 297 when numbered in accordance with EU numbering. 16. The antibody drug conjugate of any one of claims 1-15, wherein the L is attached to the antibody or antigen binding fragment thereof through an N-linked glycan. 17. The antibody drug conjugate of any one of claims 1-16, wherein the antibody or antigen binding fragment thereof comprises an Fc region. 18. The antibody drug conjugate of any one of claims 1-17, wherein the antibody or antigen binding fragment thereof is a full length antibody. 19. The antibody drug conjugate of any one of claims 1-18, wherein the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for a Fcγ receptor. 20. The antibody drug conjugate of any one of claims 1-19, wherein the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering. 21. The antibody drug conjugate of any one of claims 1-20, wherein the antibody or antigen binding fragment thereof is human, chimeric, or humanized. 22. The antibody drug conjugate of any one of claims 1-21, wherein the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3. 23. The antibody drug conjugate of any one of claims 1-22, wherein the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3.
24. The antibody drug conjugate of any one of claims 1-23, wherein the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at the amino acids set forth in SEQ ID NO: 231 and SEQ ID NO: 232. 25. The antibody drug conjugate of any one of claims 1-24, wherein the drug is an auristatin. 26. The antibody drug conjugate of claim 25, wherein the auristatin is selected from the group consisting of auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin. 27. The antibody drug conjugate of any of claims 25-26, wherein the auristatin is auristatin F hydroxypropylamide (AF HPA) comprising, . 28. The antibody drug conjugate of any of claims 1-27, wherein L covalently bonds to Ab via a glycan on a Fc constant region of the Ab. 29. The antibody drug conjugate of any of claims 1-28, wherein L comprises wherein the wavy line denotes attachment to the remainder of L and * denotes attachment to LA. 30. The antibody drug conjugate of any of claims 1-29, wherein LA is , wherein p is an integer from 1 to 25; q is an integer from 1 to 25; wherein the LD-D moiety comprises at least one cleavable bond such that when the bond is broken, D is released in an active form for its intended therapeutic effect; and * denotes attachment to L. 31. The antibody drug conjugate of claim 30, wherein p is 4. 32. The antibody drug conjugate of any of claims 30 or 31, wherein q is 8.
3. The antibody drug conjugate of any of claims 2-32, wherein LA-D is 34. The antibody drug conjugate of any of claims 1-33, wherein the antibody drug conjugate is of Formula (I):
wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; 35. An antibody drug conjugate having the
Formula (I): wherein d13 is about 2; and the drug is attached to the antibody at position 297 when numbered in accordance with EU numbering via a linker moiety; is GlcNAc; is Fuc; and is GalNAc, wherein the antibody comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; 36. The antibody drug conjugate of any of claims 1-35, wherein the antibody drug conjugate is produced by a method comprising i) processing a glycan at position N297 according to EU numbering by incubating an antibody that binds to ENPP3 with an endoglycosidase, ii) attaching an azido modified N-acetylglucosamine to position N297 according to EU numbering by providing glucosyl transferase, and iii) attaching the linker and drug to the azido-modified N-acetyl glucosamine using a coper-free click chemistry. 37. A composition comprising the antibody drug conjugate of any of claims 1-36. 38. An isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising a. CDRH1, a CDRH2, and a CDRH3 of a variable heavy chain domain (VH) comprising the amino acid sequence set forth in any one of claims SEQ ID NO:7 or 22-26; and b. CDRL1, a CDRL2, and a CDRL3 of a variable light chain domain (VL) comprising the amino acid sequence set forth in any one of SEQ ID NO:8, or 27- 31. 39. The isolated antibody or antigen binding fragment thereof of claim 38, comprising; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 37; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 39, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 43; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 45, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 49; a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 50, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 51, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 53, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 55; or a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 56, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 57, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 58, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 61. 40. The isolated antibody or antigen binding fragment thereof of claim 39, comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6. 41. The isolated antibody or antigen binding fragment thereof of any one of claims 38-40, wherein the VH has at least 90%, 95% or 99% sequence identity the amino acid sequence set forth in any one of SEQ ID NO:7 or 22-26 and the VL has at least 90%, 95% or 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NO: 8 or 27-31. 42. The isolated antibody or antigen binding fragment thereof of claim 41, wherein. the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8; the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 27; the VH comprises the amino acid sequence set forth in SEQ ID NO:23 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 28; the VH comprises the amino acid sequence set forth in SEQ ID NO: 24 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 29; the VH comprises the amino acid sequence set forth in SEQ ID NO:25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; or the VH comprises the amino acid sequence set forth in SEQ ID NO:26 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 31. 43. The isolated antibody or antigen binding fragment thereof of any one of claims 38-42, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:7 and the VL comprises the amino acid sequence identity the amino acid sequence set forth in SEQ ID NO: 8. 44. The isolated antibody or antigen binding fragment thereof any one of claims 38-43, wherein the antibody or antigen binding fragment thereof comprises a modified glycan at position N297 according to EU numbering. 45. The isolated antibody or antigen binding fragment thereof any one of claims 38-44, wherein the antibody or antigen binding fragment thereof comprises an Fc region. 46. The isolated antibody or antigen binding fragment of any one of claims 38-45, wherein the antibody or antigen binding fragment thereof is a full length antibody.
47. The isolated antibody or antigen binding fragment thereof of any one of claims 44-46, wherein the HC comprises the amino acid sequence set forth in any one of SEQ ID NO:9, or 12-16 and the LC comprises the amino acid sequence set forth in any one of SEQ ID NO: 10 or 17-21. 48. The isolated antibody or antigen fragment thereof of claim 47, wherein, the HC comprises the amino acid set forth in SEQ ID NO:9 and the LC comprises the amino acid set forth in SEQ ID NO: 10; the HC comprises the amino acid set forth in SEQ ID NO: 12 and the LC comprises the amino acid set forth in SEQ ID NO: 17; the HC comprises the amino acid set forth in SEQ ID NO:13 and the LC comprises the amino acid set forth in SEQ ID NO: 18; the HC comprises the amino acid set forth in SEQ ID NO:14 and the LC comprises the amino acid set forth in SEQ ID NO: 19; the HC comprises the amino acid set forth in SEQ ID NO:15 and the LC comprises the amino acid set forth in SEQ ID NO: 20; or the HC comprises the amino acid set forth in SEQ ID NO:16 and the LC comprises the amino acid set forth in SEQ ID NO: 21. 49. The antibody or antibody fragment thereof of any of claims 44-48, wherein the antibody or antigen binding fragment thereof comprises a HC comprising the amino acid sequence set forth in SEQ ID NO:9 and a LC comprising the amino acid sequence set forth in SEQ ID NO: 10. 50. The isolated antibody or antigen binding fragment of any one of claims 38-49, wherein the antibody or antigen binding fragment thereof comprises one or more amino acid substitutions that reduce affinity for an Fcγ receptor. 51. The isolated antibody or antigen binding fragment of any one of claims 38-50, wherein the antibody or antigen binding fragment thereof comprises the amino acid substitutions L234A, L235A, and/or D265S, according to EU numbering.
52. The isolated antibody or antigen binding fragment of any one of claims 38-51, wherein the antibody or antigen binding fragment thereof is human, chimeric, or humanized. 53. The isolated antibody or antigen binding fragment conjugate of any one of claims 38- 52, wherein the antibody or antigen binding fragment thereof binds to human ENPP3 and cynomolgus monkey ENPP3. 54. The isolated antibody or antigen binding fragment of any one of claims 38-53, wherein the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3. 55. The isolated antibody or antigen binding fragment of any one of claims 38-54, wherein the antibody or antigen binding fragment thereof binds to the extracellular region of ENPP3 at residues 671-681 (VPPSESQKCSF (SEQ ID NO: 231)) and 762- 780 (PDEITKHLANTDVPIPTHY (SEQ ID NO: 232)) 56. An antibody drug conjugate comprising the antibody or antigen binding fragment of any one of claims 38-55 covalently bound to one or more drug molecules. 57. Nucleic acid encoding the isolated antibody of any one of claims 38-55. 58. Nucleic acid encoding a light chain, a heavy chain, or a light chain and heavy chain encoding the isolated antibody of any one of claims 38-55. 59. A vector comprising the nucleic acid of any one of claims claim 57-58. 60. A host cell comprising the vector of claim 59. 61. A method of producing an isolated antibody or antigen binding fragment thereof that binds to ENPP3 comprising culturing the host cell of claim 60 under conditions suitable for expressing the antibody or antigen binding fragment thereof. 62. A pharmaceutical composition comprising the antibody drug conjugate of any one of claims 1-37 or the isolated antibody of any one of claims 38-61 and a pharmaceutically acceptable carrier.
63. A method of treating a solid tumor selected from the group consisting of kidney cancer of clear cell or papillary histologies, a lung adenocarcinoma, an endometrioid uterine cancer, ovarian cancers, or colorectal cancer (CRC) comprising administering the antibody-drug conjugate of any one of claims 1-37 to the individual. 64. The method of claim 63, wherein treating a solid tumor comprises a change in tumor growth inhibition. 65. The method of any of claims 63-64, wherein the tumor volume and/or the rate of tumor volume growth is decreased. 66. A method of killing a tumor cell in an individual comprising administering the antibody drug conjugate of any one of claims 1-37 to the individual. 67. The method of claim 66, wherein the tumor cell expresses ENPP3. 68. The method of claim 66 or 67, wherein the tumor cell is killed through a bystander effect. 69. A method of delivering auristatin F to a tumor cell in an individual comprising administering the antibody drug conjugate of any one of claims 1-37 to the individual. 70. The method of claim 69, wherein the tumor cell expresses ENPP3. 71. The method of claim 69 or 70, wherein the antibody binds to ENPP3 expressed on the surface of the tumor cell. 72. The method of any one of claims 69-71, wherein the antibody drug conjugate is internalized in the tumor cell. 73. The method of claim 72, wherein following internalization, the drug is released from the antibody.
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