Anti-PSMA antibodies, conjugates and methods of use

Abstract

Disclosed are antibodies, antigen binding fragments and conjugates thereof (e.g., antibody-drug conjugates) that bind to PSMA, as well as STING agonist linker-drug conjugates and their preparation. The disclosure further relates to methods and compositions for treating, for example, cancer by administering the compositions provided herein.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 487,553, filed February 28, 2023, and U.S. Provisional Application No. 63 / 557,342, filed February 23, 2024, the contents of both of which are incorporated by reference in their entirety.

[0002] The present disclosure relates to anti-PSMA antibodies and antigen-binding fragments thereof, as well as conjugates (such as antibody drug conjugates (ADCs), e.g., those comprising a STING agonist), and their use for treating and diagnosing cancers that express PSMA and / or are amenable to treatment by modulating STING pathway activity or by administration of the compositions disclosed herein.

[0003] Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in men. There are limited treatment options for metastatic prostate cancer and the prognosis for such cases is poor, necessitating the development of more effective treatment methods.

[0004] Prostate-specific membrane antigen (PSMA) is a cell surface antigen that is highly expressed in prostate cancer. The expression level of PSMA increases with the progression of prostate cancer, and high expression of PSMA is maintained at metastatic sites. Anti-PSMA antibodies have been previously generated, including modified antibodies with reduced immunogenicity in humans. See, e.g., U.S. Patent No. 7,045,605 and U.S. Patent No. 11,059,903. Examples of antibodies that bind PSMA are J591 and de-immunized J591 (deJ591). The amino acid sequence of the heavy chain variable domain of the deJ591 antibody is given herein as SEQ ID NO: 40, and the corresponding light chain variable domain is given herein as SEQ ID NO: 41. However, clinical trials using this antibody have shown adverse effects of immunogenicity, including myelosuppression and liver enzyme abnormalities. See, e.g., de Bono et al. (2021) Clin Cancer Res 27(13):3602-3609. There remains a need for improved PSMA antibodies, e.g., those that are fully humanized to minimize immunogenicity while retaining desirable properties such as good target binding affinity, low off-target binding, and good stability.

[0005] Given the high expression of PSMA in prostate cancer, it can be used as a target for tumor antigen-specific drug delivery methods (e.g., antibody-mediated methods). Antibodies conjugated to cytotoxic compounds (such as chemotherapeutics) have also been explored to enhance the cell-killing activity of antibody-based drug delivery to tumor cells. However, there remains a need to provide suitable antibodies and / or ADCs, e.g., those that provide a combination of effective prostate tumor targeting, on-target effects, and / or reduced off-target effects.

[0006] STING (stimulator of interferon genes) is a pattern recognition receptor that senses cyclic dinucleotides in the cytosol and induces the expression of type I interferons and other inflammatory cytokines (e.g., interferon-beta (IFN-b), tumor necrosis factor alpha (TNFa), C-X-C motif chemokine ligand 10 (CXCL10), interleukin-6 (IL-6)), which in turn mediate the innate immune response to infection or disease (e.g., cancer). STING signaling has been shown to have anti-tumor effects, for example, modulating vasculature and enhancing adaptive immunity. First generation STING agonists (e.g., cyclic dinucleotides) generally require intratumoral injection and only show modest systemic efficacy. These STING agonists also have poor membrane permeability, which can limit their ability to engage STING inside the cell.

[0007] While the use of STING agonists for the treatment of infection or disease has been reported in the art, the need for delivery systems that allow for systemic administration of STING agonists that specifically target tumor sites remains unmet. Likewise, there remains a need in the art for improved antibodies that bind PSMA with superior properties, for example, in terms of antigen binding and / or the ability to efficiently deliver a payload, such as a STING agonist, to a target cell or tissue expressing PSMA. SUMMARY

[0008] In various embodiments, the present disclosure provides, in part, novel antibodies and antigen-binding fragments that are capable of specifically binding to PSMA and can be used alone or linked to one or more additional agents (e.g., as an ADC) and administered as part of a pharmaceutical composition. In some embodiments, the antibodies, antigen-binding fragments, and / or ADCs of the present disclosure can be used to slow, inhibit, and / or reverse tumor growth in a mammal, and can be used to treat human cancer patients.

[0009] In various embodiments, the present disclosure is more specifically directed to antibodies and antibody-drug conjugate compounds that are capable of binding to and / or killing cells expressing PSMA. In various embodiments, these compounds are also capable of internalizing into target cells expressing PSMA upon binding. Anti-PSMA-ADC compounds comprising a linker that attaches a STING agonist moiety (e.g., a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1) to an anti-PSMA antibody moiety are disclosed. The anti-PSMA antibody moiety can be a full-length antibody or an antigen-binding fragment.

[0010] In various embodiments, the present disclosure provides a humanized anti-prostate-specific membrane antigen (PSMA) antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds human PSMA, and wherein the antibody or antigen-binding fragment comprises (i) three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or (ii) three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 33 (LCDR1), SEQ ID NO: 36 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or (iii) three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

[0011] In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

[0012] In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0013] In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a human IgGl heavy chain constant region. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

[0014] In some embodiments, the anti-PSMA antigen-binding fragment has an unfolding temperature (Tm) of > 80 °C. In some embodiments, the antigen-binding fragment is a Fab.

[0015] In some embodiments, the anti-PSMA antibody or antigen-binding fragment is attached to at least one linker. In some embodiments, the at least one linker is cleavable. In some embodiments, the at least one linker is conjugated to a cytotoxic agent or a detectable agent.

[0016] In various embodiments, the present disclosure also provides, in part, novel linker-payload conjugates. In various embodiments, the present disclosure is more specifically directed to linker-payload conjugates comprising a linker that attaches a STING agonist moiety (e.g., a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1) to an anti-PSMA antibody moiety.

[0017] In various embodiments, the present disclosure provides a linker-payload conjugate comprising L-D, wherein L is a linker covalently attached to D, wherein D comprises a compound according to one of the following formulae:

[0018]

[0019] an isomer thereof, a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative;

[0020] wherein, independently for each occurrence, is:

[0021] ■P a and P b each, when not racemic, is independently selected from the group consisting of (R)- stereochemistry and (S)-stereochemistry;

[0022] ■Q a and Q b each is independently selected from the group consisting of NH and O;

[0023] ■V a and V b each is independently selected from the group consisting of F and OH;

[0024] ■W is selected from the group consisting of H and NH2;

[0025] ■X a and X b each is independently selected from the group consisting of OH and SH;

[0026] ■Y a and Y b each is independently selected from the group consisting of O and S;

[0027] ■Z a and Z b are each independently selected from the group consisting of CH2, O, and NH; and

[0028] ■ means a bond selected from a single bond (-), a double bond (=) in the (E)- or (Z)- configuration, or a triple bond ;

[0029] provided at least one of Z a and Z b is NH or at least one of X a and X b is SH.

[0030] In some embodiments, P a is in the (S)-configuration and P b is in the (R)-configuration. In some embodiments, P a is in the (R)-configuration and P b is in the (R)-configuration. In some embodiments, Q a and Q b are O. In some embodiments, V a and V b are OH. In some embodiments, V a and V bis F. In some embodiments, W is H. In some embodiments, Z a and Z b is NH. In some embodiments, Z a and Z b is NH. In some embodiments, contains a double bond (=) in the (E)- or (Z)-configuration. In some embodiments, the bridge has the structure In some embodiments, at least one of Y a and Y b is O. In some embodiments, Y a and Y b is O. In some embodiments, at least one of X a and X b is SH. In some embodiments, X a and X b is SH. In some embodiments, D comprises a compound having Formula (III).

[0031] In some embodiments, D comprises a compound having Formula (III) selected from the group consisting of:

[0032]

[0033]

[0034] and salts thereof.

[0035] In some embodiments, D comprises a compound having Formula (III) selected from the group consisting of:

[0036]

[0037]

[0038] and salts thereof.

[0039] In some embodiments, D comprises Compound 1.

[0040] In some embodiments, D comprises Compound 2.

[0041] In some embodiments, at least one of X a and X b is SH and L is attached to D through the sulfur atom at the S-2 sulfur or the S-14 sulfur. In some embodiments, X b is SH and L is attached to D at the S-2 sulfur. In some embodiments, X a is SH and L is attached to D at the S-14 sulfur.

[0042] In some embodiments, Z a and Z b At least one of is NH and L is attached to D through a nitrogen atom at the N-34 nitrogen or the N-39 nitrogen. In some embodiments, Z b is NH and L is attached to D at the N-34 nitrogen. In some embodiments, Z a is NH and L is attached to D at the N-39 nitrogen.

[0043] In some embodiments, L is a cleavable linker. In some embodiments, the cleavable linker comprises a cleavable peptide portion. In some embodiments, the cleavable peptide portion can be cleaved by a protease, optionally wherein the protease is a cathepsin or a cysteine ​​protease (legumain). In some embodiments, the cleavable peptide portion comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Ala, Val-Cit, Val-Lys, Ala-Ala-Asn, Ala-(NMe)Ala-Asn, Asn, Gly-Gly-Phe-Gly, Glu-Val-Ala, or Gly-Val-Ala. In some embodiments, the cleavable linker comprises Val-Cit. In some embodiments, the cleavable linker comprises Val-Ala.

[0044] In some embodiments, the linker comprises a maleimide (Mal) moiety. In some embodiments, the Mal moiety comprises a maleimidocaproyl (MC). In some embodiments, the Mal moiety is attached to the antibody or antigen-binding fragment via a cysteine ​​residue on the antibody or antigen-binding fragment.

[0045] In some embodiments, the linker further comprises at least one spacer unit. In some embodiments, at least one spacer unit comprises at least one polyethylene glycol (PEG) moiety. In some embodiments, at least one PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. In some embodiments, m is an integer from 2 to 8. In some embodiments, m is an integer from 2 to 5. In some embodiments, m is 2. In some embodiments, at least one spacer unit comprises PEG2-Lys(ε-PEG8-OMe)-PEG2.

[0046] In some embodiments, at least one Spacer unit comprises In some embodiments, at least one Spacer unit comprises

[0047] In some embodiments, the linker further comprises at least one self-immolative unit. In some embodiments, the linker comprises a first self-immolative unit. In some embodiments, upon cleavage of the linker by self-immolation of the first self-immolative unit, the linker is capable of being removed from D. In some embodiments, the first self-immolative unit comprises p-aminobenzyl (pAB) optionally substituted with 1-3 substituents selected from methyl, fluoro, chloro, trifluoromethyl, aryl, and heteroaryl. In some embodiments, the first self-immolative unit comprises p-aminobenzyl (pAB). In some embodiments, the linker comprises MC-Val-Ala-pAB.

[0048] In some embodiments, the first self-immolative unit comprises p-aminobenzyloxy carbonyl (pABC).

[0049] In some embodiments, the linker further comprises a second self-immolative unit. In some embodiments, upon cleavage of the linker by self-immolation of the first self-immolative unit and / or self-immolation of the second self-immolative unit, the linker is capable of being removed from D. In some embodiments, upon cleavage of the linker by self-immolation of the first self-immolative unit followed by self-immolation of the second self-immolative unit in a stepwise fashion, the linker is removed from D.

[0050] In some embodiments, the linker comprises a cleavable linker, a first self-immolative unit, and a second self-immolative unit. In some embodiments, the cleavable linker comprises Val-Ala. In some embodiments, the cleavable linker comprises Val-Cit. In some embodiments, the cleavable linker comprises Formula (II).

[0051] In some embodiments, the second self-immolative unit comprises one of the following moieties:

[0052]

[0053]

[0054] or an isomer thereof.

[0055] In some embodiments, the cleavable linker comprises Val-Ala, and wherein the second self-immolative unit comprises one of the following moieties:

[0056]

[0057]

[0058] or an isomer thereof.

[0059] In some embodiments, the second self-immolative unit comprises a Unit 1 (MEC) moiety. In some embodiments, the second self-immolative unit comprises a Unit 8 moiety. In some embodiments, the second self-immolative unit comprises a Unit 11 moiety. In some embodiments, the second self-immolative unit comprises a Unit 9 moiety.

[0060] In some embodiments, the linker comprises a Val-Ala-pABC-MEC moiety. In some embodiments, the linker comprises a MC-Val-Ala-pABC-MEC moiety.

[0061] In some embodiments, L-D comprises LP1:

[0062]

[0063] In some embodiments, the linker comprises a Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises a MC-Val-Cit-pABC-MEC moiety. In some embodiments, MC-Val-Cit-pABC-MEC-Compound 1.

[0064] In some embodiments, the linker comprises a Val-Ala-pABC-Unit 8 moiety. In some embodiments, the linker comprises a MC-Val-Ala-pABC-Unit 8 moiety.

[0065] In some embodiments, L-D comprises LP16:

[0066]

[0067] In some embodiments, the linker comprises a Val-Cit-pABC-Unit 8 moiety. In some embodiments, the linker comprises a MC-Val-Cit-pABC-Unit 8 moiety. In some embodiments, L-D comprises MC-Val-Cit-pABC-Unit 8-Compound 1.

[0068] In some embodiments, the linker comprises a Val-Ala-pABC-Unit 11 moiety. In some embodiments, the linker comprises a MC-Val-Ala-pABC-Unit 11 moiety.

[0069] In some embodiments, L-D comprises LP28:

[0070]

[0071] In some embodiments, the linker comprises a Val-Cit-pABC-unit 11 moiety. In some embodiments, the linker comprises a MC-Val-Cit-pABC-unit 11 moiety. In some embodiments, L-D comprises a MC-Val-Cit-pABC-unit 11-Compound 1.

[0072] In some embodiments, the linker comprises a Val-Ala-pABC-unit 9 moiety. In some embodiments, the linker comprises a MC-Val-Ala-pABC-unit 9 moiety.

[0073] In some embodiments, L-D comprises LP20:

[0074]

[0075] In some embodiments, the linker comprises a Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises a MC-Val-Cit-pABC-unit 9 moiety. In some embodiments, L-D comprises a MC-Val-Cit-pABC-unit 9-Compound 1.

[0076] In some embodiments, the linker comprises a Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises a MC-Val-Cit-pABC-unit 9 moiety. In some embodiments, L-D comprises a MC-Val-Cit-pABC-unit 9-Compound 1.

[0077] In some embodiments, the linker comprises Formula (II)-Val-Ala-pABC. In some embodiments, the linker comprises Formula (II)-Val-Ala-pABC-MEC moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-MEC moiety. In some embodiments, L-D comprises Mal-Formula (II)-Val-Ala-pABC-MEC-Compound 1. In some embodiments, the linker comprises Formula (II)-Val-Ala-pABC-Unit 8 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 8 moiety. In some embodiments, L-D comprises Mal-Formula (II)-Val-Ala-pABC-Unit 8-Compound 1. In some embodiments, the linker comprises Formula (II)-Val-Ala-pABC-Unit 11 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 11 moiety. In some embodiments, L-D comprises Mal-Formula (II)-Val-Ala-pABC-Unit 11-Compound 1. In some embodiments, the linker comprises Formula (II)-Val-Ala-pABC-Unit 9 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 9 moiety. In some embodiments, L-D comprises Mal-Formula (II)-Val-Ala-pABC-Unit 9-Compound 1.

[0078] In some embodiments, the linker comprises Formula (II)-Val-Cit-pAB. In some embodiments, the linker comprises Formula (II)-Val-Cit-pAB-Unit 9 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pAB. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pAB-Unit 9 moiety. In some embodiments, L-D comprises Mal-Formula (II)-Val-Cit-pAB-Unit 9-Compound 1.

[0079] In some embodiments, the linker comprises Formula (II)-Val-Ala-pAB. In some embodiments, the linker comprises Formula (II)-Val-Ala-pAB-Unit 9 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pAB. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pAB-Unit 9 moiety.

[0080] In some embodiments, L-D comprises LP25:

[0081]

[0082] In some embodiments, the linker comprises a moiety of Formula (II)-Val-Cit-pAB-Unit 11. In some embodiments, the linker comprises a moiety of Mal-Formula (II)-Val-Cit-pAB-Unit 11. In some embodiments, L-D comprises Mal-Formula (II)-Val-Cit-pAB-Unit 11-Compound 1.

[0083] In some embodiments, the linker comprises a moiety of Formula (II)-Val-Ala-pAB-Unit 11. In some embodiments, the linker comprises a moiety of Mal-Formula (II)-Val-Ala-pAB-Unit 11.

[0084] In some embodiments, L-D comprises LP26:

[0085]

[0086] In various embodiments, the disclosure provides an antibody-drug conjugate of Formula (I):

[0087] Ab-(L-D) p (I)

[0088] wherein Ab is an anti-PSMA antibody or antigen-binding fragment thereof disclosed herein; L-D is a linker-payload conjugate disclosed herein; and p is an integer from 1 to 20.

[0089] In some embodiments, p is an integer from 1 to 12. In some embodiments, p is an integer from 2 to 8. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 2. In some embodiments, p is 4.

[0090] In some embodiments, the cleavable linker comprises a cleavable moiety positioned such that upon cleavage, the linker or any portion of the antibody or antigen-binding fragment does not remain bound to D.

[0091] In some embodiments, the linker-payload conjugate is attached to the antibody or antigen-binding fragment through a Mal moiety. In some embodiments, the Mal moiety is conjugated to the antibody or antigen-binding fragment through a cysteine residue on the antibody or antigen-binding fragment. In some embodiments, the cysteine residue is on the light chain of the antibody or antigen-binding fragment. In some embodiments, the cysteine residue is on the heavy chain of the antibody or antigen-binding fragment.

[0092] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising the following amino acid sequences: SEQ ID NO: 32 (LCDR1), SEQ ID NO: 34 (LCDR2), and SEQ ID NO: 36 (LCDR3), as defined by the Rabat numbering system.

[0093] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising the following amino acid sequences: SEQ ID NO: 37 (LCDR1), SEQ ID NO: 38 (LCDR2), and SEQ ID NO: 36 (LCDR3), as defined by the IMGT numbering system.

[0094] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0095] In some embodiments, L-D comprises LP16, LP20, LP26, or LP28.

[0096] In some embodiments, L-D comprises LP16:

[0097]

[0098] In some embodiments, L-D comprises LP20:

[0099]

[0100] In some embodiments, L-D comprises LP26:

[0101]

[0102] In some embodiments, L-D comprises LP28:

[0103]

[0104] In various embodiments, the disclosure provides a pharmaceutical formulation comprising an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate as disclosed herein, and a pharmaceutically acceptable carrier.

[0105] In various embodiments, the disclosure provides a composition comprising a plurality of copies of an antibody-drug conjugate of Formula (I):

[0106] Ab-(L-D) p (I)

[0107] wherein

[0108] Ab is an anti-PSMA antibody or antigen-binding fragment as disclosed herein;

[0109] L-D is a linker-payload conjugate as disclosed herein; and

[0110] p is the average number of L-D moieties per Ab, wherein the average p of the antibody-drug conjugates in the composition is about 2 to about 8.

[0111] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and

[0112] the L-D comprises LP16:

[0113]

[0114] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and

[0115] The L-D comprises LP20:

[0116]

[0117] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and

[0118] The L-D comprises LP26:

[0119]

[0120] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and

[0121] The L-D comprises an LP28:

[0122]

[0123] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0124] In various embodiments, the disclosure provides methods of treating a patient having or at risk of having a cancer, comprising administering to the patient a therapeutically effective amount of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate as disclosed herein. In various embodiments, the disclosure provides methods of reducing or inhibiting growth of a cancer, comprising administering a therapeutically effective amount of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate as disclosed herein. In some embodiments, the cancer expresses PSMA. In some embodiments, the cancer is prostate cancer.

[0125] In various embodiments, the disclosure provides use of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate as disclosed herein in the treatment of a cancer. In some embodiments, the cancer expresses PSMA. In some embodiments, the cancer is prostate cancer.

[0126] In various embodiments, the disclosure provides methods of producing an anti-PSMA ADC, the methods comprising reacting an antibody or antigen-binding fragment thereof as disclosed herein with a linker-payload conjugate as disclosed herein. In various embodiments, the disclosure provides methods of producing an antibody-drug conjugate, wherein the method comprises conjugating an antibody or antigen-binding fragment as disclosed herein with a linker-payload conjugate as disclosed herein under conditions suitable for attachment.

[0127] In various embodiments, the disclosure provides methods of producing an L-D conjugate (V):

[0128]

[0129] the method comprising reacting a compound of Formula (III) as disclosed herein:

[0130]

[0131] or a salt thereof with an activated linker comprising a suitable linker having the structure:

[0132]

[0133] to produce the L-D conjugate (V),

[0134] wherein Z b is NH.

[0135] In some embodiments, P b has the (S)-configuration and the activated linker preferentially reacts with Z b In some embodiments, the compound of Formula (III) is Compound 1.

[0136] In various embodiments, the disclosure provides methods of producing an L-D conjugate (VI):

[0137]

[0138] the method comprising reacting a compound of Formula (III) as disclosed herein:

[0139]

[0140] or a salt thereof with an activated linker comprising a suitable linker having the structure:

[0141]

[0142] to produce the L-D conjugate (VI),

[0143] wherein Zb is NH.

[0144] In some embodiments, P b having the (S)-configuration, and the activated linker preferentially reacts with Z b In some embodiments, the compound of Formula (III) is Compound 1.

[0145] In various embodiments, the disclosure provides compositions comprising a linker-payload conjugate as disclosed herein. In some embodiments, the disclosure provides compositions comprising a linker-payload conjugate produced according to the methods disclosed herein. BRIEF DESCRIPTION OF DRAWINGS

[0146] Figure 1 Alignments of J591 VH and VL to human germline sequences are shown. Underlined residues are human-specific residues, and lower case residues are mouse-specific residues.

[0147] Figure 2 Computer models of J591 Fv generated using BioLuminate software are shown. CDR residues are shown as space-fill, framework residues that differ between mouse and HCzu1-Lczu1, which are adjacent to CDRs shown as ball-stick. Residue numbering is according to Kabat.

[0148] Figure 3 Similar PSMA binding of humanized heavy chain (HC) variants 1-10 paired with Lczu1 is shown. Hczu1-10 was paired with LCzu1 and binding to PSMA was analyzed by ELISA.

[0149] Figure 4 Superhumanization of J591 is shown. The resulting PSMA antibodies have strong binding affinity. Binding of humanized J591 variants to PSMA was analyzed by ELISA.

[0150] Figure 5A Thermal stability of deJ591 is shown. Figure 5B Thermal stability of humanized J591 variants HC1-LC1, HC2-LC1, HC3-LC1, HC14-LC1, and HC14-LC5 compared to deJ591 is shown. Figure 5C Thermal stability of HC14-LC5 (H14L5) IgG1 antibody modified to include site-specific conjugation residues compared to deJ591 and J591 is shown.

[0151] Figure 6AImmunogenicity prediction scores for 9mer peptide sequences on the J591 heavy chain variable domain are shown. Figure 6B Immunogenicity prediction scores for 9mer peptide sequences on the deJ591 heavy chain variable domain are shown. Figure 6C Immunogenicity prediction scores for 9mer peptide sequences on the zuJ591-H14 heavy chain variable domain are shown.

[0152] Figure 7A Immunogenicity prediction scores for 9mer peptide sequences on the J591 light chain variable domain are shown. Figure 7B Immunogenicity prediction scores for 9mer peptide sequences on the deJ591 light chain variable domain are shown. Figure 7C Immunogenicity prediction scores for 9mer peptide sequences on the zuJ591-L5 light chain variable domain are shown.

[0153] Figure 8 Specific binding of anti-PSMA to PSMA-expressing LNCaP cells is shown.

[0154] Figure 9 PSMA-dependent ADCP activity as assessed by flow cytometry is shown. The percentage of macrophages that have engulfed at least one target cell is shown.

[0155] Figure 10 Target cell-dependent internalization of anti-PSMA ADCs as measured by flow cytometry is shown.

[0156] Figure 11 ADCP-dependent IFN production resulting from anti-PSMA ADC treatment is shown.

[0157] Figure 12 ADCP-dependent myeloid cell activation resulting from anti-PSMA ADC treatment is shown.

[0158] Figure 13 In vivo anti-tumor activity of anti-PSMA ADCs in a PSMA-positive LNCaP xenograft model is shown.

[0159] Figure 14A Heatmap of type 1 interferon gene expression as assessed by RNA-seq in LNCaP xenograft models treated with anti-PSMA antibody (PSMA control), anti-PSMA-LP3 ADC, or negative control (anti-SEB-LP3) is shown. Figure 14B Anti-PSMA-LP3 ADC treatment modulates cytokines specific to the STING pathway is shown. Figure 14C Macrophage polarization in the tumor microenvironment shifts from M2 to M1 when treated with anti-PSMA-LP3 ADC is shown.

[0160] Figure 15A Tumor volume (left) and percent body weight change (right) in human prostate cancer 22RV1 xenograft mice (castrated) treated with anti-PSMA antibody or anti-PSMA ADC are shown. Figure 15B Tumor volume (left) and percent body weight change (right) in human prostate cancer 22RV1 xenograft mice (not castrated) treated with anti-PSMA antibody or anti-PSMA ADC are shown. Sp = S phosphothioate linker attachment point on Compound 1; Rp = R phosphothioate linker attachment point on Compound 1.

[0161] Figure 16A A model of in vivo efficacy of anti-PSMA ADC in 22RV1 xenograft model is shown. Figure 16B Concentration of mouse TNFa (left) or IFNp (right) in plasma 6h after injection of anti-PSMA ADC is shown.

[0162] Figure 17 Percent change in DAR of anti-PSMA ADC is shown.

[0163] Figure 18A , 18B and 18C show DAR change over time for S-attached linker.

[0164] Figure 19A , 19B and 19C show free Compound 1 over time for S-attached linker.

[0165] Figure 20A , 20B and 20C show percent monomer over time for S-attached linker.

[0166] Figure 21A , 21B , 21C, 21D, 21E, 21F, and 21G show DAR change over time for N-attached linker.

[0167] Figure 22A , 22B , 22C, 22D, 22E, 22F, and 22G show free Compound 1 over time for N-attached linker.

[0168] Figure 23A , 23B , 23C, 23D, 23E, 23F, and 23G show percent monomer over time for N-attached linker.

[0169] Figure 24A Percent Compound 1 released from anti-PSMA ADC in mouse plasma over time is shown. Figure 24BAverage DAR of anti-PSMA ADCs in mouse plasma over time is shown. Figure 24C Percent change in anti-PSMA ADC relative to starting DAR in mouse plasma is shown. Figure 24D Free Compound 1 in mouse plasma over time is shown.

[0170] Figure 25 Mouse plasma stability of S-linked anti-PSMA Compound 1 ADC is shown.

[0171] Figure 26 Structures of Compound 1 and monophosphate form of Compound 1 are shown.

[0172] Figure 27A Average DAR of anti-PSMA ADC LP3 (random DAR4 and RESPECT-L DAR4) is shown. Figure 27B Metabolism of anti-PSMA ADC LP3 random DAR4 is shown. Figure 27C Metabolism of anti-PSMA ADC LP3 RESPECT-L DAR4 is shown.

[0173] Figure 28A Stability of N-linked anti-PSMA ADC in mouse plasma over a 10-day treatment is shown. Figure 28B Stability of N-linked anti-PSMA ADC in mouse plasma at day 7 is shown.

[0174] Figure 29 DAR of N-linked anti-PSMA Compound 1 ADC in mouse plasma at day 7 / 10 is shown.

[0175] Figure 30 hIFN-β production in C4-2 / THP1 co-cultures when treated with anti-PSMA ADC is shown.

[0176] Figure 31 Average tumor volume and percent body weight loss in xenograft tumors treated with anti-PSMA ADC is shown.

[0177] Figure 32 Anti-tumor activity of anti-PSMA-LP ADC in a 22Rv1 xenograft model (cohort 1) is shown. Average tumor growth and average body weight change are shown.

[0178] Figure 33 Serum cytokine analysis of PSMA-LP ADC in a 22Rv1 xenograft model (cohort 1) is shown. n=3; each point represents a single value. Data is presented as mean ± SEM.

[0179] Figure 34Anti-PSMA-LP ADC antitumor activity in 22Rvl xenograft model is shown (cohort 2). Mean tumor growth and mean body weight change are shown.

[0180] Figure 35 Serum cytokine analysis of PSMA-LP ADC in 22Rvl xenograft model is shown (cohort 2). n=3; each point represents an individual value. Data are presented as mean ± SEM.

[0181] Figure 36 Anti-PSMA-LP ADC antitumor activity in 22Rvl xenograft model is shown (cohort 3). Mean tumor growth and mean body weight change are shown.

[0182] Figure 37 Serum cytokine analysis of PSMA-LP ADC in 22Rvl xenograft model is shown (cohort 3). n=3; each point represents an individual value. Data are presented as mean ± SEM.

[0183] Figure 38 Anti-PSMA-LP ADC antitumor activity in C4-2 xenograft model is shown. Mean tumor growth and mean body weight change are shown.

[0184] Figure 39 Serum cytokine analysis of PSMA-LP ADC in 22Rvl xenograft model is shown (cohort 3). n=3; each point represents an individual value. Data are presented as mean ± SEM.

[0185] Figure 40 Pharmacokinetics of anti-PSMA LP3 ADC (randomized DAR4) at 1 mpk IV dose in normal mice is shown.

[0186] Figure 41 Pharmacokinetics of anti-PSMA LP3 ADC (RESPECT-L DAR2) at 3 and 9 mg / kg IV dose in C4-2 tumor-bearing mice is shown.

[0187] Figure 42 Levels of Compound 1 in plasma from C4-2 tumor-bearing mice dosed with anti-PSMA LP3 ADC (RESPECT-L DAR2) or anti-PSMA LP1 ADC (RESPECT-L DAR4) is shown.

[0188] Figure 43Intratumoral levels of Compound 1 in C4-2 tumor-bearing mice administered anti-PSMA LP3 ADC (RESPECT-L DAR2) or anti-PSMA LP1 ADC (RESPECT-L DAR4) are shown.

[0189] Figure 44 Tumor PK parameters from C4-2 tumor-bearing mice administered anti-PSMA LP3 ADC (RESPECT-L DAR2) and anti-PSMA LP1 ADC (RESPECT-L DAR4) are shown.

[0190] Figure 45 A scheme for a two-step payload release assay is shown. LP2 is used as an example.

[0191] Figure 46 In vitro IFN-β release following treatment with anti-PSMA S attached ADC is shown. Panel labeled A (left column) shows IFN-β release in THP-1 single cultures, while panel labeled B (right column) shows IFN-β release in C4-2 and THP-1 co-cultures.

[0192] Figure 47 In vitro IFN-β release following treatment with anti-PSMA N attached ADC is shown. Panel labeled A (left column) shows IFN-β release in THP-1 single cultures, while panel labeled B (right column) shows IFN-β release in C4-2 and THP-1 co-cultures. DETAILED DESCRIPTION

[0193] The disclosed compositions and methods can be more readily understood by reference to the following detailed description, taken in conjunction with the accompanying drawings, which form a part of this disclosure.

[0194] Throughout this document, the descriptions relate to compositions and methods of using the compositions. When this disclosure describes or claims a feature or embodiment related to a composition, such feature or embodiment equally applies to a method of using the composition. Likewise, when this disclosure describes or claims a feature or embodiment related to a method of using a composition, such feature or embodiment equally applies to the composition.

[0195] When expressing a range of values, it includes embodiments using any particular value within the range. In addition, a recitation of values stated in a range includes each value within that range. All ranges include their endpoints and are combinable. When a value is expressed as an approximation by use of “about” preceding that value, it should be understood that the particular value forms another embodiment. Unless the context clearly indicates otherwise, a recitation of a particular numerical value includes at least that particular value.

[0196] All references cited herein are incorporated by reference for any purpose. In the event of a contradiction between a reference and this specification, the specification shall control.

[0197] It is understood that certain of the disclosed compositions and methods described herein in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods described herein in the context of a single embodiment can also be provided separately or in any sub-combination.

[0198] Definitions

[0199] Various terms related to aspects of the present specification are used throughout. Unless otherwise indicated, these terms are to be given their ordinary meaning in the art. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

[0200] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0201] In the context of numerical values and ranges, the term "about" or "approximately" refers to a value or range that is approximately or nearly the value or range such that the embodiments can function as intended, for example, having the desired amount of nucleic acid or polypeptide in a reaction mixture, as would be apparent to one of skill in the art from the teachings contained herein. In some embodiments, "about" means ±10% of the stated amount.

[0202] The term "agent" is used herein to refer to a compound, a mixture of compounds, a biological macromolecule, or an extract made from biological materials. The term "therapeutic agent," "drug," or "drug moiety" refers to an agent that is capable of modulating a biological process and / or having a biological activity.

[0203] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. In some embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 4 aliphatic carbon atoms.

[0204] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions. The terms "room temperature" and "ambient temperature" mean 15 °C to 30 °C.

[0205] The terms "antibody-drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to a compound or derivative thereof linked to an antibody (e.g., an anti-PSMA antibody) and definable by the general formula: Ab-(L-D)p(Formula I), where Ab = antibody moiety (i.e., an antibody or antigen-binding fragment), L = linker moiety, D = drug moiety, and p = number of drug moieties per antibody moiety. In some embodiments, the linker L can include a cleavable moiety between the antibody or antigen-binding fragment and the therapeutic compound. In some embodiments, the linker L can include a cleavable moiety that can be attached to either or both of the antibody or antigen-binding fragment and the therapeutic compound, e.g., via a spacer unit. Exemplary cleavable linkers are described and exemplified herein.

[0206] The term "antibody" is used in the broadest sense of the term, and refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain (HC) of an antibody is comprised of a heavy chain variable domain (VH) and a heavy chain constant region (CH). The light chain (LC) is comprised of a light chain variable domain (VL) and a light chain constant domain (CL). As used herein, the terms "domain" and "region" are used interchangeably (e.g., the term "variable domain" can be used interchangeably with the term "variable region," and is understood to refer to the same portion of an antibody). For purposes of this application, the mature heavy and light chain variable domains each comprise, from N-terminus to C-terminus, three complementarity determining regions (CDR1, CDR2, and CDR3; also known as "hypervariable regions") within four framework regions (FR1, FR2, FR3, and FR4) arranged in the order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The CDRs can be identified according to the Kabat and / or IMGT numbering system (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991); International ImMunoGeneTics Information System ). An "antibody" can be naturally occurring or man-made, such as a monoclonal antibody produced by conventional hybridoma technology. The term "antibody" includes full-length monoclonal and full-length polyclonal antibodies, as well as antibody fragments such as Fab, Fab', F(ab')2, Fv, and single chain antibodies. An antibody can be of any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses thereof (e.g., IgGl, IgG2, IgG3, IgG4). An antibody of any of the foregoing classes or subclasses can also comprise one of two possible light chain types: Ig kappa (also referred to herein as "Ig kappa" or "kappa") and Ig lambda (also referred to herein as "Ig lambda" or "lambda"). The term "antibody" encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule that contains an antigen recognition site, so long as it exhibits the desired biological activity.

[0207] The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from two or more species. In some instances, the variable regions of both the heavy and light chains correspond to the variable regions of antibodies derived from one species having the desired specificity, affinity, and activity characteristics, while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize immunological response in the latter species.

[0208] The term "human antibody" as used herein refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human.

[0209] The term "humanized antibody" as used herein refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. Typically, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The humanized antibody can be further modified by the substitution of residues either in the Fv framework regions and / or residues within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or activity. The humanized antibody can be further modified by the substitution of residues in the Fc domain to reduce its binding to various cellular receptors such as Fc gamma receptors (FcγRs) and other immune molecules.

[0210] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a variety of antibodies directed against different epitopes or having different specificities. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be made by recombinant DNA methods. See, e.g., U.S. Patent No. 4,816,567. The monoclonal antibodies can also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J. Mol. Biol. 222:581-97, for example.

[0211] The monoclonal antibodies described herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical with or homologous to a corresponding sequence in an antibody which is derived from a particular species or belongs to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0212] The term "antigen-binding fragment" or "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PSMA). The antigen-binding fragment preferably also retains the ability to be internalized into a cell expressing the antigen. In some embodiments, the antigen-binding fragment also retains immunoeffect or activity. It has been shown that fragments of a full-length antibody can perform the antigen-binding function of the full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment, which consists of a single variable domain, such as a VH domain (see, e.g., Ward et al. (1989) Nature 341 :544-6; and Winter et al., WO 90 / 05144); and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)). See, e.g., Bird et al. (1988) Science 242:423-6; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-83. Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody, and are known in the art as an exemplary binding fragment type that is internalized into cells upon binding. See, e.g., Zhu et al. (2010) 9:2131-41; He et al. (2010) J Nucl. Med. 51 :427-32; and Fitting et al. (2015) MAbs 7:390-402. In certain embodiments, scFv molecules can be incorporated into fusion proteins. Other forms of single chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites.See, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-8; and Poljak et al. (1994) Structure 2:1121-3). Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and these binding fragments screen in the same manner, e.g., binding affinity, internalization, as do whole antibodies. Antigen-binding fragments can be produced, for example, by cleavage of the intact protein, e.g., by protease or chemical cleavage.

[0213] The term "anti-PSMA antibody" or "antibody that specifically binds PSMA" refers to any form of antibody or fragment thereof that specifically binds PSMA, and encompasses both monoclonal antibodies, including full-length monoclonal antibodies, polyclonal antibodies and biologically functional antibody fragments so long as they specifically bind PSMA. Preferably, the anti-PSMA antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. As used herein, the terms "specific," "specifically binds" and "binds specifically" refer to the selective binding of an antibody to a target antigen or epitope over alternative antigens or epitopes. Binding specificity of an antibody can be tested by comparing binding to the appropriate antigen with binding to an unrelated antigen or a mixture of antigens under a given set of conditions. An antibody is considered specific if its binding affinity for the appropriate antigen is at least 2-fold greater, or preferably at least 50-fold, at least 100-fold, or at least 1000-fold greater than its binding affinity for an unrelated antigen or antigen mixture, as measured, for example, by surface plasmon resonance, e.g., BIACORE®. Analysis. In one embodiment, the specific antibody is an antibody that binds to a PSMA antigen but does not bind to other antigens (or exhibits minimal binding to other antigens).

[0214] The term "aryl" refers to a group or substituent derived from an aromatic ring, and encompasses monocyclic aromatic rings as well as bicyclic, tricyclic, and fused ring systems (having a total of six to fourteen ring members), wherein at least one ring in the system is aromatic. An aryl group can be optionally substituted with one or more substituents.

[0215] The term "heteroaryl" refers to a cyclic group comprising at least one ring atom that is a heteroatom (e.g., O, N, or S). Heteroaryl groups encompass monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains three to seven ring members.

[0216] The term "at least one" means one or more.

[0217] The term“bridge” refers to a set of atoms in a macrocyclic bridged STING agonist compound that extends from a first nucleic acid base in the macrocyclic bridged STING agonist compound to a second nucleic acid base in the macrocyclic bridged STING agonist compound.

[0218] The term“cancer” refers to a physiological condition in mammals in which a population of cells is characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the bile duct (e.g., cholangiocarcinoma), esophageal cancer, nasopharyngeal cancer, peritoneal cancer, hepatocellular cancer (e.g., hepatocellular carcinoma), gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, osteosarcoma, skin cancer (e.g., melanoma), colon cancer, colorectal cancer, endometrial cancer or uterine cancer, ovarian cancer, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer (e.g., advanced prostate cancer, metastatic castration-resistant prostate cancer), vulvar cancer, thyroid cancer, hepatic carcinoma, bone cancer, and various types of head and neck cancers.

[0219] The terms“cancer cell” and“tumor cell” refer to an individual cell or population of cells derived from a tumor, including non-tumorigenic cells and cancer stem cells. When referring only to those tumor cells that lack the ability of renewal and differentiation, the term“tumor cell” as used herein will be modified by the term“non-tumorigenic” to distinguish those tumor cells from cancer stem cells.

[0220] The terms“tumor” and“neoplasm” refer to any mass of tissue that results from excessive cell growth or proliferation, whether benign or malignant, including pre-cancerous lesions.

[0221] The terms“chemotherapeutic agent” or“anti-cancer agent” are used herein to refer to a compound that is effective in the treatment of cancer, regardless of mechanism of action. Inhibition of metastasis or angiogenesis is often a property of a chemotherapeutic agent. Stimulation of an anti-tumor immune response can also be a property of a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include stimulants, such as STING agonists. In addition, chemotherapeutic agents include antibodies, biological molecules, and small molecules. A chemotherapeutic agent can be a cytotoxic agent or a cytostatic agent.

[0222] The term“cytotoxic agent” refers to a substance that causes the death of cells by interfering with their expression activities and / or functions or by stimulating a response (e.g., an immune response) that results in cell death. Examples of cytotoxic agents include, but are not limited to, STING agonists, such as Compound 1.

[0223] An "effective amount" of an ADC as disclosed herein is an amount sufficient to accomplish a stated purpose (e.g., produce a therapeutic effect, such as reducing the rate of tumor growth or tumor volume, reducing cancer symptoms, or some other indicator of therapeutic efficacy, after administration). An effective amount can be determined in a routine manner in relation to the stated purpose. The term "therapeutically effective amount" refers to an amount of an ADC effective to treat a disease or condition in a subject. In the case of cancer, a therapeutically effective amount of an ADC can reduce the number of cancer cells; reduce tumor size; inhibit (e.g., slow or stop) tumor metastasis; inhibit (e.g., slow or stop) tumor growth; and / or relieve one or more symptoms resulting from the cancer. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary to achieve the desired prophylactic result. Typically, a prophylactically effective amount will be less than a therapeutically effective amount since a prophylactic dose is used before or at an early stage of disease.

[0224] The term "epitope" refers to a portion of an antigen that is recognized and specifically bound by an antibody. When the antigen is a polypeptide, the epitope can be formed by contiguous amino acids or noncontiguous amino acids that are brought into close proximity by tertiary folding of the polypeptide. Epitopes bound by antibodies can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of an antigen-antibody complex, as well as monitoring binding of an antibody to fragments or mutant variants of an antigen, or monitoring solvent accessibility of different parts of an antigen. Exemplary strategies for mapping epitopes of an antibody include, but are not limited to, array-based oligopeptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry. See, e.g., Gershoni et al. (2007) 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev. Proteomics 2:745-56).

[0225] The term "Compound 1" as used herein refers to the structure of Compound 1 as shown below, or a salt thereof:

[0226]

[0227] Compound 1 is a macrocyclic bridged STING agonist (MBSA) with a bioactive U-shaped conformation of a locked cyclic dinucleotide, comprising a macrocyclic bridge across the nucleic acid bases. As used herein, “Compound 1” can include salts of Compound 1, such as diammonium and / or sodium salts of Compound 1. The term “Compound 1 moiety,” “E7766,” “E7766 agonist moiety,” or “E7766 moiety” refers to a component of an ADC that has the structure of Compound 1, and is attached to a linker of the ADC, for example, through the N-34 nitrogen, N-39 nitrogen, S-2 sulfur, or S-14 sulfur of the Compound 1 moiety. WO 2018 / 152450 discloses compositions and methods of inhibiting growth of a patient’s tumor comprising administration of Compound 1, the entire disclosure of which is incorporated herein by reference in its entirety for all Compound 1 structures and methods of synthesizing these structures.

[0228] As referred to herein, atoms in Compound 1 can be numbered as shown below:

[0229]

[0230] The term “Compound 2” as used herein refers to the structure of Compound 2 as shown below, or a salt thereof:

[0231]

[0232] As referred to herein, atoms in Compound 2 can be numbered as shown below:

[0233]

[0234] In various embodiments of the disclosure, “N-34 nitrogen,” “N-39 nitrogen,” “S-2 sulfur,” or “S-14 sulfur” can be used to refer to a nitrogen or sulfur atom in other STING agonists that corresponds to the numbered nitrogen or sulfur atom in Compound 1 or Compound 2, whether or not the atom is otherwise numbered according to nomenclature rules. In some cases, for a compound of Formula (III), Formula (IV), or a compound of Table 14, such as Compound 1 or Compound 2, an L-D conjugate attached at the N-34 nitrogen can be referred to as “R N ” or “RN,” while an L-D conjugate attached at the N-39 nitrogen can be referred to as “S N ” or “SN.”

[0235] “Fc gamma receptor” or “Fc-gamma receptor” or “Fc gamma R” refers to a cell surface protein typically found on various types of immune cells, such as neutrophils. Binding of the Fc region of an antibody to an Fc gamma receptor can induce different effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP).

[0236] As used herein, the term “halogen” or “halo” means F, CI, Br, or I.

[0237] The term “homolog” refers to a molecule that exhibits homology to another molecule by, for example, having identical or similar chemical residues at corresponding positions of the sequence.

[0238] The term “IgG1 Fc,” “IgG1 Fc domain,” or “IgG1 Fc-containing antibody” as used herein refers to an antibody having at least IgG1 CH2 and CH3 domains, as identified by SEQ ID NO: 70 and SEQ ID NO: 71, respectively.

[0239] “Wild-type IgG1 Fc domain” refers to a human IgG1 Fc domain comprising the amino acid sequence of SEQ ID NO: 69 or a fragment thereof.

[0240] The term “inhibit” or “inhibition of” as used herein means to reduce a measurable amount, and can include but does not require complete prevention or inhibition.

[0241] “Internalization” as used herein in reference to an antibody or antigen-binding fragment means that the antibody or antigen-binding fragment is capable of passing through the lipid bilayer membrane of a cell into an internal compartment (i.e., “internalizing”) upon binding to the cell, preferably into a degrading compartment in the cell. For example, an internalizing anti-PSMA antibody is one that is capable of entering a cell upon binding to PSMA on the cell membrane.

[0242] The term “KD” refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. KD is calculated from the ratio of k a / k d The rate can be determined using standard assays such as BIACORE® or ELISA assays.

[0243] The term “k on ” or “k a ” refers to the association rate constant of an antibody associating with an antigen to form an antibody / antigen complex. The rate can be determined using standard assays such as BIACORE® or ELISA assays.

[0244] The term “k off ” or “k d ” refers to the dissociation rate constant of an antibody dissociating from an antibody / antigen complex. The rate can be determined using standard assays such as BIACORE® or ELISA assays.

[0245] ​​​A "linker" or "linker moiety" refers to any chemical moiety that is capable of covalently joining a compound, typically a drug moiety (such as a chemotherapeutic agent), to another moiety (such as an antibody moiety). The linker can be susceptible to or substantially resistant to acid-induced cleavage, peptidase-induced cleavage, light-based cleavage, esterase-induced cleavage, and / or disulfide bond cleavage under conditions in which the compound or antibody remains active. A "cleavable linker" is any linker that comprises a cleavable moiety and can therefore be susceptible to cleavage. The cleavable moiety can be a cleavable peptide moiety. The term "cleavable peptide moiety" refers to any chemically linked amino acids (natural or synthetic amino acid derivatives) that can be cleaved by an agent present in the intracellular environment.

[0246] The use of "or" means "and / or" unless specifically indicated otherwise, or in a case of

[0247] The term "p" or "antibody:drug ratio" or "drug to antibody ratio" or "DAR" refers to the number of drug moieties per antibody moiety, i.e., the drug loading, or the average number of L-D moieties per antibody or antigen binding fragment (Ab) in an ADC having Formula I. In a composition comprising multiple copies of an ADC having Formula I, "p" refers to the average number of L-D moieties per antibody or antigen binding fragment, also referred to as the average drug loading.

[0248] A "pharmaceutical composition" refers to a preparation which is appropriate for administration to a subject and which subsequently provides the intended biological activity of the active ingredient and / or achieves a therapeutic effect, and which is free of additional components which would confer unacceptable toxicity to the subject to which the formulation is administered. The pharmaceutical composition can be sterile.

[0249] A "pharmaceutical excipient" includes materials such as adjuvants, carriers, pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservatives, and the like.

[0250] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0251] As used herein, the term "pi bond" means a covalent bond formed from the p orbitals of adjacent atoms. A pi bond exists when there is a multiple bond (i.e., a double or triple bond) between two atoms. For example, a carbon-carbon double bond consists of one pi bond, while a carbon-carbon triple bond consists of two pi bonds.

[0252] The term “prostate-specific membrane antigen” or “PSMA” as used herein refers to any native form of human PSMA. The term encompasses full-length PSMA (e.g., NCBI Reference Sequence: NP_004467.1; SEQ ID NO: 67), as well as any form of human PSMA that results from cellular processing. The term can also encompass naturally occurring variants of PSMA, including but not limited to splice variants, allelic variants, and isoforms. Antibodies that bind PSMA can not bind all variants, as will be apparent to those skilled in the art. PSMA can be isolated from humans, or can be produced recombinantly or by synthetic methods. The terms “PSMA” and “prostate-specific membrane antigen” are interchangeable with “glutamate carboxypeptidase II (GCPII),” “folate hydrolase 1,” “N-acetylated-alpha-linked acidic dipeptidase I (NAALADase I),” and any other name for the protein encoded by FOLH1 known in the art.

[0253] The term “protecting group” as used herein refers to any chemical group that is introduced into a molecule by chemical modification of a functional group to achieve chemical selectivity in subsequent chemical reactions.

[0254] Methods of adding (generally referred to as “protecting”) and removing (generally referred to as “deprotecting”) protecting groups are well known in the art and can be found, for example, in: P.J. Kocienski, Protecting Groups, 3rdedition (Thieme [Germany], 2005) and Greene and Wuts, Protective Groups in Organic Synthesis, 4thedition (John Wiley & Sons [New York], 2007), both of which are hereby incorporated by reference in their entireties.

[0255] Non-limiting examples of useful protecting groups for amines useful in the present disclosure include monovalent protecting groups such as tert-butoxycarbonyl (Boc), benzyl (Bn), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), and p-toluenesulfonyl (Ts); and divalent protecting groups such as benzylidene, N-phthalimide, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, and N-2,5-dimethylpyrrole.

[0256] Non-limiting examples of useful protecting groups for alcohols useful in the disclosure include, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), beta-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), 4-nitrophenyl carbonate, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS).

[0257] Non-limiting examples of useful protecting groups for carboxylic acids useful in the disclosure include, for example, methyl or ethyl esters, substituted alkyl esters such as 9-fluorenylmethyl, methoxy methyl (MOM), tetrahydropyranyl (THP), tetrahydrofuranyl, beta-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM), acetyl (Ac), benzoylmethyl, substituted benzoylmethyl esters, t-butyl, allyl, phenyl (Ph), silyl esters, benzyl and substituted benzyl esters, 2,6-dialkylphenyl, and pentafluorophenyl (PFP).

[0258] Non-limiting examples of amine bases useful in the disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), lithium bis(trimethylsilyl)amide (LiHMDS), and potassium bis(trimethylsilyl)amide (KHMDS).

[0259] Non-limiting examples of basic carbonate salts useful in the disclosure include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium bicarbonate (NaHCO3), and potassium bicarbonate (KHCO3).

[0260] Non-limiting examples of basic phosphate salts useful in the disclosure include, for example, trisodium phosphate (Na3PO4), tripotassium phosphate (K3PO4), dipotassium hydrogen phosphate (K2HPO4), and potassium dihydrogen phosphate (KH2PO4).

[0261] Non-limiting examples of acids useful in the present disclosure include, for example, acetic acid (AcOH), trifluoroacetic acid (TFA), hydrochloric acid (HC1), camphorsulfonic acid (CSA), methanesulfonic acid (MsOH), formic acid (FA), phosphoric acid (H3PO4), and sulfuric acid (H2SO4).

[0262] Non-limiting examples of peptide coupling reagents include, for example, N,N'- dicyclohexylcarbodiimide (DCC), l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCI), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), l- ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1- hydroxybenzotriazole (HOBT), and N,N,N,N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU).

[0263] For amino acid sequences, sequence identity and / or similarity can be determined by using standard techniques known in the art, or by inspection, including, but not limited to, the following: the local sequence identity algorithm of Smith and Waterman, (1981), Adv. Appl. Math. 2:482, the sequence identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the similarity search method of Pearson and Lipman (1988) Proc. Nat. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wisconsin), the bestfit sequence program described by Devereux et al. (1984) Nucl. Acid Res. 12:387-95 (preferably using default settings). Preferably, percent identity is calculated by FastDB based on the following parameters: mismatch penalty 1; gap penalty 1; gap size penalty 0.33; and join penalty 30. See "Current Methods in Sequence Comparison and Analysis", Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149 (1988), Alan R. Liss, Inc.

[0264] One example of a useful algorithm is PILEUP. PILEUP produces multiple sequence alignments from a set of related sequences using progressive, pairwise alignments. It also plots a tree showing the clustering relationships for the sequences in the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle (1987) J. Mol. Evol. 35:351-60; this method is similar to the method described by Higgins and Sharp (1989) CABIOS 5:151-3. Useful PILEUP parameters include default gap weight 3.00, default gap length weight 0.10, and weighted end gaps.

[0265] Another example of a useful algorithm is the BLAST algorithm. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-10; Altschul et al. (1997) Nucleic Acids Res. 25:3389-402; and Karin et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873-87. A particularly useful BLAST program is the WU-BLAST-2 program available from Altschul et al. (1996) Methods in Enzymology 266:460-80. WU-BLAST-2 uses several search parameters, most of which are set to default values. The adjustable parameters are set as follows: overlap span=l, overlap fraction=0.125, word threshold (T)=l. The HSP S and HSP S2 parameters are dynamic values and are established by the program itself depending on the composition of the particular sequence and the composition of the particular database against which the sequence of interest is searched; however, these values can be adjusted to increase sensitivity.

[0266] An additional useful algorithm is gapped BLAST reported by Altschul et al. (1993) Nucl. Acids Res. 25:3389-402. Gapped BLAST uses the BLOSUM-62 substitution score; the threshold T parameter is set to 9; the two-hit method is used to trigger gapped extension, the charge gap length is k with a cost of 10+k; XU is set to 16, while XG is set to 40 at the database search stage and 67 at the algorithm output stage. Gapped alignments are triggered by scores corresponding to about 22 bits.

[0267] In general, the proteins and variants thereof (e.g., variants that retain the function of the original protein) disclosed herein, including variants of PSMA and variants of antibody variable domains (including individual variant CDRs), have at least 80% amino acid homology, similarity, or identity, and more typically at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and nearly 100% or 100% homology or identity.

[0268] In a similar manner, "percent (%) nucleic acid sequence identity" with respect to a nucleic acid sequence of an antibody and other protein identified herein is defined as the percentage of nucleotide residues in the candidate sequence that are identical with the nucleotide residues in the antigen binding protein coding sequence. A specific method uses the BLASTN module of WU-BLAST-2 with the default parameters set, where the overlap span and overlap fraction are set to 1 and 0.125, respectively.

[0269] The term "stable", as used herein, refers to compounds which are substantially unaltered when subjected to a condition in which they are generated, detected, and preferably recovered, purified, and used for one or more purposes disclosed herein.

[0270] The terms "subject" and "patient" are used interchangeably herein to refer to any animal, such as any mammal, including but not limited to humans, non-human primates, rodents, and the like. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a human.

[0271] The term "target negative" or "target antigen negative" refers to the absence of target antigen expression by a cell or tissue. The term "target positive" or "target antigen positive" refers to the presence of target antigen expression. For example, a cell or cell line that does not express a target antigen can be described as target negative, while a cell or cell line that expresses a target antigen can be described as target positive.

[0272] The term "solvent", as used herein, refers to any liquid in which a product is at least partially soluble (solubility of the product > 1 g / L).

[0273] The term "isomer", as used herein, refers to compounds that contain the same molecular formula but have different spatial arrangements of atoms or bonds. Isomers include stereoisomers, cis- trans isomers, atropisomers, and tautomers.

[0274] The term "stereoisomer", as used herein, refers to both enantiomers and diastereomers.

[0275] It is understood that certain compounds of the present application can exist as single stereoisomers or enantiomers and / or as mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" bond or a "hash" bond indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used herein, a stereogenic atom denoted by (R) or (S) indicates the stereochemical name of that stereogenic atom according to the Cahn-Ingold-Prelog convention. As used in the chemical structures disclosed herein, a "straight" bond indicates that a mixture (e.g., racemate or enrichment) exists. As used herein, two "straight" bonds indicate that the double bond has E / Z stereochemistry as indicated by the figure.

[0276] Certain compounds disclosed herein can exist as tautomers, and both tautomeric forms are contemplated, even if only a single tautomeric structure is depicted.

[0277] The present disclosure also provides methods for preparing salts of the compounds of the present disclosure.

[0278] Salts of the compounds of the present disclosure are formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. Depending on the ratio of the valencies of the basic or acidic groups in the compound to the acid or base, one compound can form a salt with one or more molecular units of the acid / base, or multiple units of the compound can form a salt with one unit of the acid / base. In some embodiments, the salt is a sodium salt. In some embodiments, the salt is a diammonium salt. In some embodiments, the salt is a dialkylammonium salt. In some embodiments, the salt is a bis(triethylammonium) salt.

[0279] The term“stimulator of interferon genes” or“STING” as used herein refers to any native form of human STING. The term encompasses full-length STING (e.g., NCBI Reference Sequence: NP_938023.1; SEQ ID NO: 68), as well as any form of human STING that results from processing by the cell. The term also encompasses naturally occurring variants of STING, including but not limited to splice variants, allelic variants, and isoforms. STING can be isolated from humans, or can be produced recombinantly or by synthetic methods.

[0280] “Treatment” or“therapeutic” and grammatical related terms as used herein refer to any improvement in any outcome of a disease, such as prolonged survival, lower morbidity, and / or lessened side effects from alternative therapeutic modalities. As is readily appreciated by those in the art, complete eradication of the disease is preferred, but not required, for a therapeutic act. “Treatment” or“treat” as used herein refers to the administration of the ADC or antibody to a subject, e.g., a patient. Treatment can be curative, healing, alleviating, relieving, altering, remedying, ameliorating, mitigating, improving or affecting a condition (e.g., cancer), a symptom of a condition, or a predisposition toward a condition.

[0281] The term“unsaturated” as used herein means that the moiety has one or more units of unsaturation.

[0282] Anti-PSMA antibodies and antigen-binding fragments

[0283] The present disclosure provides antibodies that specifically bind PSMA and can be used alone, e.g., formulated as a therapeutic or diagnostic antibody composition, e.g., for use in treating or detecting a cancer that expresses PSMA. These antibodies can be packaged or prepared for therapeutic use as an antibody, antigen-binding fragment thereof, or as part of an ADC.

[0284] The antibodies disclosed herein can bind PSMA with a dissociation constant (KD) of < 1 mM, < 100 nM, or < 10 nM, or any amount therebetween, as measured by, e.g., surface plasmon resonance (SPR) using a Biacore® 2000 or 3000 instrument (Biacore, Inc., Piscataway, NJ) or a ProteOn XPR36 (Bio-Rad, Hercules, CA) or by a KinExa® assay (Igenica Biopharma, Inc., Waltham, MA). The measured dissociation constants were analyzed. In some embodiments, the KD is 500 pM to 1 nM or 1 nM to 10 nM. In some embodiments, the KD is < 10 nM, < 5 nM, < 1 nM, or < 0.5 nM.

[0285] In some embodiments, the antibody is a four-chain antibody (also known as an immunoglobulin) comprising two heavy chains and two light chains. In some embodiments, the antibody is a two-chain half-antibody (one light chain and one heavy chain) or an antigen-binding fragment of an immunoglobulin.

[0286] In some embodiments, the antibody is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody binds to cell surface-expressed PSMA and enters the cell upon or following binding. In some embodiments, the drug moiety of the ADC is released from the antibody portion of the ADC following entry of the ADC and is present in the PSMA-expressing cell (i.e., after the ADC has internalized). In some embodiments, the internalizing antibody binds to cell surface-expressed PSMA of a cell, and the cell is subsequently phagocytosed (e.g., antibody-dependent cellular phagocytosis occurs). In some embodiments, the drug moiety of the ADC is released from the antibody portion of the ADC following entry of the ADC and is present in the phagocytic cell (e.g., macrophage, dendritic cell).

[0287] The antibodies disclosed herein that specifically bind to PSMA protein can comprise three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) having an amino acid sequence selected from the HC CDRs listed in Tables 1 and / or 3 below, as defined by the Kabat numbering system, and three light chain CDRs (LCDR1, LCDR2, and LCDR3) having an amino acid sequence selected from the LC CDRs listed in Tables 1 and / or 3 below, as defined by the Kabat numbering system. In some embodiments, the antibodies comprise three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) having an amino acid sequence selected from the HC CDRs listed in Table 5 below, as defined by the IMGT numbering system, and three light chain CDRs (LCDR1, LCDR2, and LCDR3) having an amino acid sequence selected from the LC CDRs listed in Table 5 below, as defined by the IMGT numbering system.

[0288] In some embodiments, an antibody disclosed herein comprises a VH domain having an amino acid sequence selected from SEQ ID NOs: 1-14 listed in Table 2 and / or 7 below. In some embodiments, an antibody comprises a VL domain having an amino acid sequence selected from SEQ ID NOs: 15-20 listed in Table 2 and / or 7 below.

[0289] In some embodiments, an antigen-binding fragment disclosed herein retains PSMA binding. In some embodiments, an antigen-binding fragment retains PSMA binding by comprising three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) comprising an amino acid sequence selected from the HC CDRs listed in Table 1 and / or 3 below, as defined by the Kabat numbering system, and three light chain CDRs (LCDR1, LCDR2, and LCDR3) comprising an amino acid sequence selected from the LC CDRs listed in Table 1 and / or 3 below, as defined by the Kabat numbering system. In some embodiments, an antigen-binding fragment comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) comprising an amino acid sequence selected from the HC CDRs listed in Table 5 below, as defined by the IMGT numbering system, and three light chain CDRs (LCDR1, LCDR2, and LCDR3) comprising an amino acid sequence selected from the LC CDRs listed in Table 5 below, as defined by the IMGT numbering system. In some embodiments, an antigen-binding fragment disclosed herein can retain PSMA binding by comprising a VH domain comprising an amino acid sequence selected from SEQ ID NOs: 1-14 listed in Table 2 and / or 7 below, and a VL domain comprising an amino acid sequence selected from SEQ ID NOs: 15-20 listed in Table 2 and / or 7 below.

[0290] In some embodiments, an anti-PSMA antibody or antigen-binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 44 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 45 (LCDR1), SEQ ID NO: 46 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system. In some embodiments, an antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 43. In some embodiments, an antibody or antigen-binding fragment comprises an IgGl domain.

[0291] In some embodiments, the anti-PSMA antibody or antigen binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibody or antigen binding fragment comprises an IgGl domain.

[0292] In some embodiments, the anti-PSMA antibodies and antigen binding fragments disclosed herein have advantageous thermal stability. In some embodiments, the anti-PSMA antibodies or antigen binding fragments disclosed herein have a melting temperature (Tm) of > 70 °C, > 75 °C, or > 80 °C. In some embodiments, the anti-PSMA antibodies or antigen binding fragments disclosed herein have a melting temperature (Tm) of > 80 °C. In some embodiments, the anti-PSMA antibodies or antigen binding fragments disclosed herein have a higher melting temperature (Tm) than alternative anti-PSMA antibodies (e.g., J591 and deJ591). See U.S. Patent No. 11,059,903 and U.S. Patent No. 7,045,605.

[0293] Anti-PSMA antibodies or antigen binding fragments can be selected to improve or retain a variety of factors, including retaining target binding affinity, enhancing thermal stability, and / or minimizing immunogenicity. In some embodiments, anti-PSMA antibodies are selected that exhibit superior performance in more than one category. In some embodiments, anti-PSMA antibodies are selected that exhibit improvement in more than one category, even if not necessarily the best antibody in any one category.

[0294] In some embodiments, an anti-PSMA antibody or antigen binding fragment is selected that comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system, that exhibits retained target binding affinity, enhanced thermal stability, and minimally reduced immunogenicity compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). In some embodiments, an anti-PSMA antibody or antigen binding fragment is selected that comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system, that exhibits retained target binding affinity and minimally reduced immunogenicity compared to other anti-PSMA antibodies (e.g., J591, deJ591, and / or an anti-PSMA antibody disclosed herein.

[0295] In some embodiments, an anti-PSMA antibody or antigen-binding fragment comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19 is selected that exhibits retained target binding affinity, enhanced thermal stability, and maximally reduced immunogenicity compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). In some embodiments, an anti-PSMA antibody or antigen-binding fragment comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19 is selected that exhibits retained target binding affinity and maximally reduced immunogenicity compared to other anti-PSMA antibodies (e.g., J591, deJ591, and / or an anti-PSMA antibody disclosed herein).

[0296] In some embodiments, an antibody disclosed herein can comprise an IgG constant domain, e.g., an IgGl domain, or an IgGl domain that has been modified to reduce binding to an Fc receptor, e.g., an Fc gamma receptor (FcγR), compared to an antibody comprising a wild-type constant domain, e.g., comprising wild-type IgGl. Reduction in binding to an Fc receptor, e.g., an FcγR, can be measured by comparison to binding of an antibody without the modification to the same receptor. Reduction in binding can be at least about 10-fold, and preferably at least about 100-fold, compared to an antibody comprising an unmodified constant domain. Reduction in binding can be measured using any assay known in the art. For example, reduction in binding can be measured using a fluorescence resonance energy transfer (FRET) assay.

[0297] In some embodiments, an antibody disclosed herein can comprise an IgG constant domain, e.g., an IgGl domain, or an IgGl domain that has been modified to increase binding to an Fc receptor, e.g., an Fc gamma receptor (FcγR), compared to an antibody comprising a wild-type constant domain, e.g., comprising wild-type IgGl. Increase in binding to an Fc receptor, e.g., an FcγR, can be measured by comparison to binding of an antibody without the modification to the same receptor. Increase in binding can be at least about 5-fold, and preferably at least about 10-fold, compared to an antibody comprising an unmodified constant domain. Increase in binding can be measured using a fluorescence resonance energy transfer (FRET) assay. In some embodiments, the modified IgG constant domain is modified by Fc engineering and / or glycan modification, e.g., afucosylation.

[0298] In some embodiments, an antibody disclosed herein can comprise an IgGl domain comprising mutations L234A, L235A, P238S, H268Q, and / or K274Q according to the EU numbering of Kabat (e.g., comprising all of these mutations). See, e.g., Wang et al. (2017) Protein Cell 9(1):63-73; Vafa et al. (2014) Methods 1;65(1):114-26; and Tam et al. (2017) Antibodies 16(3):12. Without being bound by theory, these mutations can reduce binding of the antibody to Fc gamma receptors (FcγR), which can reduce non-antigen-mediated uptake of the antibody or ADC by immune cells, such as neutrophils, thereby reducing neutropenia. Reduction of neutropenia can be measured using any assay known in the art. For example, reduction of neutropenia can be measured using a flow cytometry assay.

[0299] In some embodiments, an antibody that specifically binds a PSMA protein comprises a heavy chain having an amino acid sequence selected from SEQ ID NOs: 47-60 listed below in Table 8 and / or comprises a set of CDRs and / or a variable domain from an amino acid sequence in Table 8. In some embodiments, an antibody that specifically binds a PSMA protein comprises a light chain having an amino acid sequence selected from SEQ ID NOs: 61-66 listed below in Table 8 and / or comprises a set of CDRs and / or a variable domain from an amino acid sequence in Table 8.

[0300] Amino acid and nucleic acid sequences of exemplary antibodies of the disclosure are listed in Tables 1-9. Monoclonal antibody Kabat CDR and variable region consensus sequences (Tables 1 and 2, respectively) reflect alignment of heavy and light chain variable region sequences represented by SEQ ID NOs: 1-20 Figure 1 ). Residues that differ between clones are represented by “X” in SEQ ID NOs: 42-46. Anti-PSMA antibodies or antigen binding fragments as described herein can be defined by the consensus CDR sequences of Table 1 in combination with the CDR sequences of Table 3, e.g., by selecting the HC CDR2, LC CDR1, and / or LCDR2 sequences of Table 1 and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 of Table 3 to describe the antibody by its three heavy chain and three light chain CDR sequences.

[0301] Table 1. Amino acid sequences of consensus mAb Kabat CDRs

[0302]

[0303] X 1 = A or N; X 2 = E or Q; X 3 = Q or E; X 4 = G or D; X 5 = R or K; X 6 = V or L; X 7 = D or N; and X 8 = S or T

[0304] Table 2. Amino acid sequences of mAb variable regions

[0305]

[0306] X 9 = V or T; X 10 = M or I; X 11 = A or N; X 12 = E or Q; X 13 = Q or E; X 14 = G or D; X 15 = A or V; X 16 = T or K; X 17 = D or S; X 18 = T or A; X 19 = R or K; X 20 = L or V; X 21 = N or D; and X 22 = S or T

[0307] Table 3. Amino acid sequences of mAb Kabat CDRs

[0308]

[0309] Table 4. Nucleic acid sequences encoding mAb Kabat CDRs

[0310]

[0311] Table 5. Amino acid sequences of mAb IMGT CDRs

[0312]

[0313] Table 6. Nucleic acid sequences encoding mAb IMGT CDRs

[0314]

[0315] Table 7. Amino acid sequences of mAb variable regions

[0316]

[0317]

[0318]

[0319]

[0320] Bolded text indicates amino acid positions corresponding to CDR sequences according to the Kabat system; underlined text indicates amino acid positions corresponding to CDR sequences according to the IMGT system. Text that is neither bolded nor underlined corresponds to framework regions.

[0321] Table 8. Nucleic acid sequences encoding mAb variable regions

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] Table 9. Amino acid sequences of full-length mAb Ig chains

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] Bolded text indicates amino acid positions corresponding to CDR sequences according to the Kabat system; underlined text indicates amino acid positions corresponding to CDR sequences according to the IMGT system. Text that is neither bolded nor underlined corresponds to framework regions.

[0342] Table 10. Nucleic acid sequences of full-length mAb Ig chains

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] The anti-PSMA antibodies or antigen-binding fragments provided by SEQ ID NOs: 1-39 and 42-46 can provide improved properties compared to other anti-PSMA antibodies, such as J591 and / or deJ591. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments disclosed herein have superior stability compared to other anti-PSMA antibodies, such as J591 and / or deJ591. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments disclosed herein have lower immunogenicity compared to other anti-PSMA antibodies, such as J591 and / or deJ591.

[0371] In some embodiments, the sequences of the heavy chain variable domains, light chain variable domains, full length heavy chains, and full length light chains can be “mixed and matched” to generate variants of the anti-PSMA antibodies. Such “mixed and matched” anti-PSMA antibodies can be tested using binding assays known in the art, such as ELISAs and other assays described in the Examples. In various embodiments, the antibodies disclosed herein can comprise any of the heavy and light chain variable domain combinations, or six CDR sequence combinations, from the heavy and light chain combinations listed in the table above. In some embodiments, the antibodies further comprise human heavy and light chain constant domains or fragments thereof. In various embodiments, the antibodies can comprise any of the full length heavy chain and full length light chain sequence combinations listed in the table above. In some embodiments, the antibodies can comprise a human IgG heavy chain constant domain and a human kappa light chain constant domain. In some embodiments, the antibodies can comprise a human IgGl, IgG2, IgG3, or IgG4 heavy chain constant domain. In various embodiments, the antibodies of the application comprise a human immunoglobulin G subtype 1 (IgGl) heavy chain constant domain and a human Ig kappa light chain constant domain. In some embodiments, the constant domains are modified versions of human constant domains, e.g., comprising one or more of L234A, L235A, P238S, H268Q, and / or K274Q modifications to the human IgGl heavy chain constant domain.

[0372] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 44, wherein SEQ ID NO: 44 comprises NINPNNNGGTTYX 1 X 2 KFX 3 X 4 , as defined by the Kabat numbering system. In some embodiments, in SEQ ID NO: 44, X 1 A or N, X 2 Is E or Q, X 3 is Q or E, and X 4 Is G or D. In some embodiments, in SEQ ID NO: 44, X 1 It's A, X 2 It's E, X 3 is Q, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2 It's E, X 3 is Q, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2 It's Q, X 3 is Q, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2 It's Q, X 3 Is E, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2 It's Q, X 3 Is E, and / or X 4 It’s D.

[0373] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain CDR1 (LCDR1) comprising SEQ ID NO: 45, wherein SEQ ID NO: 45 comprises X 5 ASQDVGTAX 6 X 7 , as defined by the Kabat numbering system. In some embodiments, in SEQ ID NO: 45, X 5 Is R or K, X 6 Is V or L, X 7Is D or N. In some embodiments, in SEQ ID NO: 45, X 5 It's R, X 6 is V, and / or X 7 Is D. In some embodiments, in SEQ ID NO: 45, X 5 It's K, X 6 is V, and / or X 7 Is D. In some embodiments, in SEQ ID NO: 45, X 5 It's R, X 6 Is L, and / or X 7 It's N.

[0374] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain CDR2 (LCDR2) comprising SEQ ID NO: 46, wherein SEQ ID NO: 46 comprises WASTRHX 8 , as defined by the Kabat numbering system. In some embodiments, in SEQ ID NO: 46, X 8 Is S or T. In some embodiments, in SEQ ID NO: 46, X 8 Is S. In some embodiments, in SEQ ID NO: 46, X 8 It’s T.

[0375] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise the following three heavy chain CDRs and three light chain CDRs: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 44, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 45, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 46, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system. In some embodiments, in SEQ ID NO: 44, X 1 It's A, X 2 It's E, X 3 is Q, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2 It's E, X 3 is Q, and / or X 4 Is G. In some embodiments, in SEQ ID NO: 44, X 1 It is N, X 2is Q, X 3 is Q, and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and / or X 4 is D. In some embodiments, in SEQ ID NO: 45, X 5 is R, X 6 is V, and / or X 7 is D. In some embodiments, in SEQ ID NO: 45, X 5 is K, X 6 is V, and / or X 7 is D. In some embodiments, in SEQ ID NO: 45, X 5 is R, X 6 is L, and / or X 7 is N. In some embodiments, in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 46, X 8 is T.

[0376] In some embodiments, in SEQ ID NO: 44, X 1 is A, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is A, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is A, X2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is A, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is A, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is A, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is E, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is Q, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X7 is N; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is G; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is D; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is D; in SEQ ID NO: 45, X 5 is R, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is D; in SEQ ID NO: 45, X 5 is K, X 6 is V, and X 7 is D; and in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is D; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8is S. In some embodiments, in SEQ ID NO: 44, X 1 is N, X 2 is Q, X 3 is E, and X 4 is D; in SEQ ID NO: 45, X 5 is R, X 6 is L, and X 7 is N; and in SEQ ID NO: 46, X 8 is T.

[0377] In some embodiments, an anti-PSMA antibody or antigen binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0378] In some embodiments, an anti-PSMA antibody or antigen binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0379] In some embodiments, an anti-PSMA antibody or antigen binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0380] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0381] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 26, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0382] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Kabat numbering system.

[0383] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0384] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0385] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0386] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 26, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0387] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0388] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0389] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0390] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0391] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 26, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 35, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0392] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0393] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0394] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0395] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0396] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 26, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 34, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0397] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0398] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0399] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0400] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0401] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 26, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 32, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0402] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0403] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 23, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0404] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 24, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0405] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 25, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 33, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 36, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the Rabat numbering system.

[0406] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 28, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 29, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 30; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 38, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 39, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the IMGT numbering system (International Immunogenetics information system ).

[0407] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 28, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 29, a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 31; a light chain CDR1 (LCDR1) comprising SEQ ID NO: 38, a light chain CDR2 (LCDR2) comprising SEQ ID NO: 39, and a light chain CDR3 (LCDR3) comprising SEQ ID NO: 37, as defined by the IMGT numbering system.

[0408] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region of SEQ ID NO: 42, wherein SEQ ID NO: 42 comprises the amino acid sequence:

[0409] EVQLVQSGAEVKKPGATVKISCKX 9 SGYTFTEYTIHWVQQAP GKGLEWX 10 GNINPNNGGTTYX 11 X 12 KFX 13 X 14 RVTITX 15 DX 16 STX 17 TAYMELSSLRSEDTAVYYCAX 18 GWNFDYWGQGTLLTVSS

[0410] wherein X 9 is V or T, X 10 is M or I, X 11 is A or N, X 12 is E or Q, X 13 is Q or E, X 14 is G or D, X 15 is A or V, X 16 is T or K, X 17 is D or S, and X 18 is T or A. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a light chain variable region of SEQ ID NO: 43, wherein SEQ ID NO: 43 comprises the amino acid sequence:

[0411] DIQMTQSPSSLSASVGDRVTITCX 19 ASQDVGTAX 20 X 21WYQQK PGKAPKLLIYWASTRHX 22 GVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYNSYPLTFGQGTKLEIK

[0412] wherein X 19 is R or K, X 20 is L or V, X 21 is N or D, and X 22 is S or T. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain variable region of SEQ ID NO: 42 and a light chain variable region of SEQ ID NO: 43, wherein X 9 is V or T, X 10 is M or I, X 11 is A or N, X 12 is E or Q, X 13 is Q or E, X 14 is G or D, X 15 is A or V, X 16 is T or K, X 17 is D or S, X 18 is T or A, X 19 is R or K, X 20 is L or V, X 21 is N or D, and X 22 is S or T.

[0413] In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and / or X 18 is T. In some embodiments, in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and / or X 22 is S. In some embodiments, in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and / or X 22 is S. In some embodiments, in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and / or X 22 is S.

[0414] In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is A, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X9 is V, X 10 is M, X 11 is N, X 12 is E, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is Q, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X11 It is N, X 12 It's Q, X 13 It's E, X 14 It's G, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 It's K, X 20 It's V, X 21 is D, and X 22 Is T. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's G, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 It's R, X 20 It's V, X 21 is D, and X 22 Is T. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's G, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 It's R, X 20 It's L, X 21 is N, and X 22 Is T. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's G, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is G, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is S, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's D, X 15 It's A, X 16 It's K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 It's R, X 20 It's V, X 21 is D, and X 22 Is T. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's D, X 15 It's A, X 16 It's K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 It's R, X 20 It's L, X 21 is N, and X 22 Is T. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's D, X 15 It's A, X 16 It's K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 It's K, X 20 It's V, X 21 is D, and X 22 Is S. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's D, X 15 It's A, X 16 It's K, X 17 is D, and X 18is A, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is A, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is S, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is K, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is V, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is I, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X19 is K, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is V, X 21 is D, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is R, X 20 is L, X 21 is N, and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X 13 is E, X 14 is D, X 15 is A, X 16 is T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 is K, X 20 is V, X 21 is D, and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V, X 10 is M, X 11 is N, X 12 is Q, X13 It's E, X 14 It's D, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 It's R, X 20 It's V, X 21 is D, and X 22 Is S. In some embodiments, in SEQ ID NO: 42, X 9 It's V, X 10 It's M, X 11 It is N, X 12 It's Q, X 13 It's E, X 14 It's D, X 15 It's A, X 16 It's T, X 17 is D, and X 18 is T, and in SEQ ID NO: 43, X 19 It's R, X 20 It's L, X 21 is N, and X 22 It’s S.

[0415] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 18.In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 20.

[0416] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15.

[0417] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15.

[0418] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0419] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 2. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 3. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 14. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a light chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a light chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 19.

[0420] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 40 (i.e., does not have 100% identity to SEQ ID NO: 40), wherein the anti-PSMA antibody or antigen-binding fragment provides an improved property compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a light chain variable region that is at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 41 (i.e., does not have 100% identity to SEQ ID NO: 41), wherein the anti-PSMA antibody or antigen-binding fragment provides an improved property compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain variable region that is at least 86% identical to SEQ ID NO: 40 and a light chain variable region that is at least 87% identical to SEQ ID NO: 41 (but does not have 100% identity to either variable region), wherein the anti-PSMA antibody or antigen-binding fragment provides an improved property compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). The improved property can include superior stability and / or lower immunogenicity.

[0421] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 40, wherein the anti-PSMA antibody or antigen-binding fragment comprises at least the following amino acid that is different from SEQ ID NO: 40:

[0422] Position relative to SEQ ID NO: 40 Amino acid 9 A 38 Q 67 R 68 V 70 I 111 V

[0423] wherein the anti-PSMA antibody or antigen binding fragment provides an improved property compared to other anti-PSMA antibodies, such as J591 and / or deJ591. The improved property can include superior stability and / or lower immunogenicity. The position relative to SEQ ID NO: 40 is determined by aligning the heavy chain variable region of the anti-PSMA antibody or antigen binding fragment with SEQ ID NO: 40, optionally using the BLAST algorithm, and then counting amino acid positions starting from the N-terminus of the aligned sequences.

[0424] In some embodiments, the anti-PSMA antibody or antigen binding fragment thereof provided herein comprises a light chain variable region that is at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 41, wherein the anti-PSMA antibody or antigen binding fragment comprises at least the following amino acid that differs from SEQ ID NO: 41:

[0425] Position relative to SEQ ID NO: 41 Amino acid 13 A 21 I 42 K 43 A 58 V 85 T 100 Q 104 L 105 E

[0426] wherein the anti-PSMA antibody or antigen binding fragment provides an improved property compared to other anti-PSMA antibodies, such as J591 and / or deJ591. The improved property can include superior stability and / or lower immunogenicity. The position relative to SEQ ID NO: 41 is determined by aligning the heavy chain variable region of the anti-PSMA antibody or antigen binding fragment with SEQ ID NO: 41, optionally using the BLAST algorithm, and then counting amino acid positions starting from the N-terminus of the aligned sequences.

[0427] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 42, wherein the anti-PSMA antibody or antigen-binding fragment provides an improved property compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof provided herein comprises a light chain variable region that is at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 43, wherein the anti-PSMA antibody or antigen-binding fragment provides an improved property compared to other anti-PSMA antibodies (e.g., J591 and / or deJ591). The anti-PSMA antibody or antigen-binding fragment does not comprise a heavy chain variable region that is 100% identical to SEQ ID NO: 40 and a light chain variable region that is 100% identical to SEQ ID NO: 41. The improved property can include superior stability and / or lower immunogenicity.

[0428] In various embodiments, any of the anti-PSMA antibodies disclosed herein can comprise a human IgGl Fc domain. In some embodiments, the anti-PSMA antibody comprises a human IgGl Fc domain that is modified to reduce binding to FcyR compared to an IgGl Fc-containing antibody having a wild-type IgGl Fc domain. In some embodiments, the anti-PSMA antibody comprises a mutated human IgGl Fc domain comprising one or more (e.g., all) of L234A, L235A, P238S, H268Q, and K274Q modifications to the human IgGl heavy chain constant domain.

[0429] In various embodiments, the anti-PSMA antibody comprises a human Ig kappa light chain constant region. In various embodiments, the anti-PSMA antibody comprises a human Ig lambda light chain constant region.

[0430] In some embodiments, the anti-PSMA antibody provided herein comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 47-60 and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-66.

[0431] In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 65.In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 50 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 51 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 64.In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 52 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 53 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 54 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 63.In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 55 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 56 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 62.In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 58 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 63. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 66.

[0432] In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 48 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 49 and a light chain amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 61.

[0433] In some embodiments, the anti-PSMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 60 and a light chain amino acid sequence of SEQ ID NO: 65.

[0434] In any of the antibodies discussed above, the heavy chain amino acid sequence can lack the C-terminal lysine.

[0435] In various embodiments, amino acid substitutions can be made while retaining the binding affinity and / or specificity of the antibodies disclosed herein and / or providing one or more additional beneficial properties, such as by making one or more changes in the framework, constant domain, and / or CDR sequences. In some embodiments, the substitutions are single residue substitutions. For example, in some embodiments, the anti-PSMA antibody comprises a human IgGl Fc domain comprising amino acid substitutions to reduce binding to FcyR compared to an IgGl Fc-containing antibody having a wild-type IgGl Fc domain. In some embodiments, the anti-PSMA antibody comprises a mutated human IgGl Fc domain comprising substitutions L234A, L235A, P238S, H268Q, and K274Q. Insertions are typically of the order of about 1 to about 20 amino acid residues, but significantly larger insertions can be tolerated as long as the biological function (e.g., binding to PSMA) is retained. Deletions are typically in the range of about 1 to about 20 amino acid residues, but in some cases deletions can be much larger. Substitutions, deletions, insertions or any combination thereof can be used to arrive at the final derivative or variant. Generally these changes are made in

[0436] Table 11.

[0437] Original residue Exemplary substitution Ala Ser Arg Lys Asn Gln, His Asp Glu Cys Ser Gln Asn Glu Asp Gly Pro His Asn, Gln Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe Met, Leu, Tyr Ser Thr Thr Ser Trp Tyr Tyr Trp, Phe Val Ile, Leu

[0438] In various embodiments in which a variant antibody sequence is used in an ADC, the variant can exhibit the same qualitative biological activity and elicit the same immune response, although variants can also be selected to modify the characteristics of the antigen binding protein as desired. For example, the anti-PSMA antibodies provided herein can comprise a human IgGl Fc domain that is mutated to reduce binding to FcyRs compared to an IgGl Fc-containing antibody having a wild-type IgGl Fc domain. Alternatively, the variant can be designed such that the biological activity of the antigen binding protein is altered.

[0439] Any of the anti-PSMA antibodies and antigen binding fragments disclosed herein can be used as, for example, conjugates with a detectable agent and / or another therapeutic agent. In some embodiments, the anti-PSMA antibodies or antigen binding fragments can be used in an antibody-drug conjugate (ADC), such as any of the ADCs disclosed herein, preferably to target the drug in the ADC to cancer cells. As shown below, surprisingly, the linkers-toxins in the ADCs disclosed herein are effective with the anti-PSMA antibodies also disclosed herein. These antibodies can be used with the linkers and toxins (e.g., Compound 1) disclosed herein.

[0440] Linker

[0441] In various embodiments, the anti-PSMA antibodies and antigen binding fragments disclosed herein can be conjugated to a drug moiety (e.g., a cytotoxic payload, such as Compound 1) through a linker to produce an antibody-drug conjugate (ADC).

[0442] In some embodiments, the linker in the ADC has extracellular stability in a manner sufficient to have a therapeutically effective. In some embodiments, the linker is stable extracellularly such that the ADC remains intact when present in extracellular conditions (e.g., prior to transport or delivery into a cell). The term “intact” as used in the context of an ADC means that the antibody portion remains attached to the drug moiety (e.g., Compound 1). As used herein, “stable” in the context of a linker or an ADC comprising the linker means that no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 3%, or no more than about 1% (or any percentage therebetween) of the linkers in a sample of the ADC are cleaved (or in the case of the overall ADC is otherwise not intact) when the ADC is present in extracellular conditions when assessed over a set period of time. In some embodiments, the linkers in the ADCs disclosed herein are selected to remain stable for more than about 48 hours, more than about 60 hours, more than about 72 hours, more than about 84 hours, or more than about 96 hours.

[0443] Extracellular stability of the linker can be determined, for example, by including the ADC in plasma for a pre-determined period of time (e.g., 2, 4, 6, 8, 16, or 24 hours), and then quantifying the amount of free drug moiety present in the plasma. Stability can allow the ADC time to localize to the target tumor cell and prevent premature release of the drug, which can decrease the therapeutic index of the ADC by indiscriminately damaging both normal and tumor tissue. In some embodiments, the linker is stable outside of the target cell and releases the drug moiety from the ADC once inside the cell, such that the drug moiety can bind its target (e.g., bind STING). Thus, an effective linker will: (i) maintain the specific binding properties of the antibody moiety; (ii) allow for delivery (e.g., intracellular delivery) of the drug moiety by stable attachment to the antibody moiety; (iii) remain stable and intact until the ADC has been transported or delivered to its target site; and (iv) allow for the therapeutic effect of the drug moiety, e.g., a cytotoxic effect, after cleavage.

[0444] The linker can affect the physical-chemical properties of the ADC. Since many cytotoxic agents are inherently hydrophobic, attaching them to an antibody with an additional hydrophobic moiety can cause aggregation. ADC aggregates are insoluble and generally limit the drug loading that can be achieved on the antibody, which can adversely affect the potency of the ADC. In general, protein aggregates of biologic products are also associated with increased immunogenicity. As shown below, the linkers disclosed herein enable ADCs with low levels of aggregation and desirable levels of drug loading. In various embodiments, the linker is conjugated to the antibody or antigen binding fragment through a cysteine. In various embodiments, the linker is conjugated to the antibody or antigen binding fragment through a lysine. Suitable methods for conjugating the linkers of the disclosure to an antibody include techniques for direct attachment to lysines on the antibody heavy chain, cysteines on the antibody heavy chain, and cysteines on the antibody light chain, e.g., as disclosed in PCT applications WO 2017 / 213267, WO 2017 / 106643, and WO 2016 / 205618, and Junutula et al. (2008) Journal of Immunological Methods 332:41-52, all of which are incorporated by reference herein in their entirety. In some embodiments, the linker is conjugated to the antibody or antigen binding fragment on the light chain, e.g., at a cysteine on the light chain, e.g., at cysteine 80 on the light chain. In some embodiments, the linker is conjugated to the antibody or antigen binding fragment on the heavy chain, e.g., at a cysteine on the heavy chain, e.g., at cysteine 118 on the heavy chain.

[0445] A linker used herein can be "cleavable" or "non-cleavable" (Ducry and Stump, Bioconjugate Chem. (2010) 21 :5-13). Cleavable linkers are designed to release the drug when subjected to certain environmental factors (e.g., when internalized into a target cell), while non-cleavable linkers typically rely on degradation of the antibody moiety itself.

[0446] In some embodiments, the linker is a non-cleavable linker. In some embodiments, the drug moiety of the ADC is released by degradation of the antibody moiety.

[0447] In some embodiments, the linker is cleavable. Cleavable linkers are designed to release the drug when subjected to certain environmental factors (e.g., when internalized into a target cell). A cleavable linker refers to any linker that comprises a cleavable moiety. As used herein, the term "cleavable moiety" refers to any chemical bond that can be cleaved. Suitable cleavable chemical bonds are known in the art and include, but are not limited to, acid-labile bonds, protease / peptidase-labile bonds, photo-labile bonds, disulfide bonds, and esterase-labile bonds. A linker comprising a cleavable moiety can allow release of the drug moiety from the ADC by cleavage at a particular site in the linker.

[0448] In some embodiments, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the drug moiety from the antibody moiety sufficiently in the intracellular environment to activate the drug and / or make the drug therapeutically effective. In some embodiments, the drug moiety is not cleaved from the antibody moiety until the ADC enters a cell expressing an antigen to which the antibody moiety of the ADC is specific, but rather the drug moiety is cleaved from the antibody moiety upon entry into the cell. In some embodiments, the linker comprises a cleavable moiety that is positioned such that upon cleavage, the linker or any portion of the antibody moiety does not remain bound to the drug moiety. Exemplary cleavable linkers include acid-labile linkers, protease / peptidase-sensitive linkers, photo-labile linkers, dimethyl-containing linkers, disulfide-containing linkers, or sulfonamide-containing linkers.

[0449] In some embodiments, the linker can be cleaved by a cleavage agent (e.g., an enzyme) present in the intracellular environment (e.g., a lysosome, an endosome, or a pit). The linker can be, for example, a peptide linker that is cleaved by an intracellular peptidase or protease (including but not limited to a lysosomal or endosomal protease). In some embodiments, the linker is a cleavable peptide linker. As used herein, a cleavable peptide linker refers to any linker comprising a cleavable peptide portion. The term "cleavable peptide portion" refers to any chemically bonded amino acids (natural or synthetic amino acid derivatives) that can be cleaved by an agent present in the intracellular environment. In some embodiments, the cleavable peptide linker is more stably conjugated to the antibody disclosed herein than an acid-labile linker.

[0450] In some embodiments, the linker is an enzyme-cleavable linker, and the cleavable peptide portion in the linker can be cleaved by an enzyme. In some embodiments, the cleavable peptide portion can be cleaved by a lysosomal enzyme, such as a cathepsin or a cysteine ​​protease (also known as an asparaginyl endopeptidase or vacuolar processing enzyme). In some embodiments, the linker is a cathepsin-cleavable linker. In some embodiments, the linker is a cysteine ​​protease-cleavable linker. In some embodiments, the cleavable peptide portion in the linker can be cleaved by a lysosomal cysteine ​​cathepsin (such as cathepsin B, C, F, H, K, L, O, S, V, X or W). In some embodiments, the cleavable peptide portion can be cleaved by cathepsin B. An exemplary dipeptide that can be cleaved by cathepsin B is valine-citrulline (Val-Cit). See, for example, Dubowchik et al. (2002) Bioconjugate Chem. [Biological conjugate chemistry] 13: 855-69. Another exemplary dipeptide that can be cleaved by cathepsin B is valine-alanine (Val-Ala). See, eg, Fu and Ho (2002) Antib. Ther. 1(2):33-43.

[0451] In some embodiments, the cleavable peptide portion of the linker can be cleaved by lysosomal cysteine ​​endopeptidases (such as cysteine ​​proteases). An exemplary single peptide that can be cleaved by cysteine ​​proteases is asparagine (Asn). Another exemplary single peptide that can be cleaved by cysteine ​​proteases is aspartic acid (Asp).

[0452] In some embodiments, the cleavable peptide moiety in the linker or linker comprises an amino acid unit. In some embodiments, the amino acid unit allows for protease cleavage of the linker, thereby facilitating release of the drug moiety from the ADC upon exposure to one or more intracellular proteases, such as one or more lysosomal enzymes. See, e.g., Doronina et al. (2003) Nat. Biotechnol. 21 :778-84; and Dubowchik and Walker (1999) Pharm. Therapeutics 83:67-123. Exemplary amino acid units include, but are not limited to, monopeptides, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary monopeptides include, but are not limited to, asparagine (Asn) and aspartic acid (Asp). Exemplary dipeptides include, but are not limited to, valine-citrulline (Val-Cit), alanine-asparagine (Ala-Asn), alanine-phenylalanine (Ala-Phe), phenylalanine-lysine (Phe-Lys), alanine-lysine (Ala-Lys), alanine-valine (Ala-Val), valine-alanine (Val-Ala), valine-lysine (Val-Lys), lysine-lysine (Lys-Lys), phenylalanine-citrulline (Phe-Cit), leucine-citrulline (Leu-Cit), isoleucine-citrulline (Ile-Cit), tryptophan-citrulline (Trp-Cit), and phenylalanine-alanine (Phe-Ala). Exemplary tripeptides include, but are not limited to, alanine-alanine-asparagine (Ala-Ala-Asn), glycine-valine-citrulline (Gly-Val-Cit), glutamic acid-valine-citrulline, glycine-glycine-glycine (Gly-Gly-Gly), phenylalanine-phenylalanine-lysine (Phe-Phe-Lys), alanine-phenylalanine-lysine (Ala-Phe-Lys), glycine-valine-alanine (Gly-Val-Ala), and glycine-phenylalanine-lysine (Gly-Phe-Lys). An exemplary tetrapeptide includes, but is not limited to, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly). Other exemplary amino acid units include, but are not limited to, Gly-Phe-Leu-Gly, Ala-Leu-Ala-Leu, Phe-N9-tosyl-Arg, and Phe-N9-nitro-Arg, as described in, e.g., U.S. Patent No. 6,214,345. In some embodiments, the amino acid unit can comprise an amino acid residue comprising at least one methyl group, e.g., a monomethyl or dimethyl group.Exemplary amino acid units comprising an amino acid residue comprising at least one methyl group include, but are not limited to, N-methylated alanine ((NMe)Ala), methylated aspartate (Asp(OMe)), and dimethylated lysine (Val-Lys(Me)2). In some embodiments, the amino acid unit in the linker comprises Val-Ala. In some embodiments, the amino acid unit in the linker comprises Val-Cit. The amino acid unit can comprise naturally occurring amino acid residues and / or secondary amino acids and / or non-naturally occurring amino acid analogs (such as citrulline). The amino acid unit can be designed and optimized for enzymatic cleavage by a particular enzyme, such as a tumor-associated protease, a lysosomal protease (such as a cysteine protease or cathepsin B, C, D, or S).

[0453] In some embodiments, the linker in the ADCs disclosed herein can comprise an antibody attachment moiety. The antibody attachment moiety can be used, for example, to connect the antibody moiety to the linker, which in turn can be indirectly connected to the drug moiety, for example, through a cleavable moiety (such as a cleavable peptide).

[0454] In some embodiments, the linker comprises an antibody attachment moiety comprising a maleimide moiety (Mal). The term “maleimide moiety” as used herein means a compound comprising a maleimide group and is reactive with a sulfhydryl group (such as the sulfhydryl group of a cysteine residue on an antibody moiety). Other functional groups that are reactive with sulfhydryl groups (thiols) and thus can be used in place of Mal include, but are not limited to, iodoacetamide, bromoacetamide, vinylpyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate.

[0455] In some embodiments, the linker is attached to the antibody or antigen binding fragment through the Mal moiety. In some embodiments, the Mal moiety is reactive with a cysteine residue on the antibody or antigen binding fragment. In some embodiments, the Mal moiety is conjugated to the antibody or antigen binding fragment through the cysteine residue.

[0456] In some embodiments, the Mal moiety is a maleimidocaproyl (MC) moiety. In some embodiments, the linker is attached to the antibody or antigen binding fragment through the MC moiety. In some embodiments, the MC moiety is reactive with a cysteine residue on the antibody or antigen binding fragment. In some embodiments, the MC moiety is conjugated to the antibody or antigen binding fragment through the cysteine residue.

[0457] In some embodiments, the linker comprises a Mal moiety and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the Mal moiety attaches the antibody moiety to the cleavable peptide moiety in the linker. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the linker comprises Mal-Val-Cit. In some embodiments, the linker comprises Mal-Val-Ala.

[0458] In some embodiments, the linker comprises a MC moiety and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the MC moiety attaches the antibody moiety to the cleavable peptide moiety in the linker. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the linker comprises MC-Val-Cit. In some embodiments, the linker comprises MC-Val-Ala.

[0459] In some embodiments, any of the linkers in the ADCs disclosed herein can comprise at least one spacer unit that joins the antibody moiety to the drug moiety. In some embodiments, the spacer unit joins a cleavage site (e.g., a cleavable peptide moiety) in the linker to the antibody moiety. In some embodiments, the spacer unit joins a cleavage site (e.g., a cleavable peptide moiety) in the linker to the drug moiety. In some embodiments, the linker and / or the spacer unit in the linker is substantially hydrophilic. In some embodiments, the linker comprises one or more polyethylene glycol (PEG) moieties, e.g., 1, 2, 3, or 4 PEG moieties. In some embodiments, the linker comprises one or more alkyl moieties, e.g., 1, 2, 3, 4, or 5 alkyl moieties.

[0460] In some embodiments, the spacer unit in the linker comprises one or more PEG moieties. In some embodiments, the spacer unit comprises -(PEG) mand m is an integer from 1 to 10. In some embodiments, m is in the range of 1 to 4; or in the range of 2 to 4. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, the spacer unit comprises (PEG)2, (PEG)3, or (PEG)4. In some embodiments, the spacer unit comprises PEG2-Lys(e-PEG8-OMe)-PEG2.

[0461] In some embodiments, the spacer unit in the linker comprises an alkyl moiety. In some embodiments, the spacer unit comprises -(CH2) n and n is an integer from 1 to 10 (i.e., n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, n is 3, 4, or 5. In some embodiments, the spacer unit comprises (CH2)3 or (CH2)4 or (CH2)5. In some embodiments, the spacer unit comprises CH2-CH2.

[0462] In some embodiments, the spacer unit comprises In some embodiments, the spacer unit comprises and (PEG)2. In some embodiments, the spacer unit comprises In some embodiments, the spacer unit comprises

[0463] In some embodiments, the linkers disclosed herein can be used in L-D constructs with other D moieties. In some embodiments, the use of a linker comprising a spacer unit comprising Formula (II) can provide benefits to various D moieties, including, for example, improved conjugation stability, improved plasma stability, and / or anti-tumor activity in vivo as compared to other linkers comprising alternative spacer units. In some embodiments, without being bound by theory, the use of a linker comprising Formula (II) with the STING agonists disclosed herein, e.g., a compound of Formula (III), Formula (IV), or a compound of Table 14, e.g., Compound 1, can include improved conjugation stability, improved plasma stability, and / or anti-tumor activity in vivo. In some embodiments, a linker comprising Formula (II) and a payload comprising a STING agonist disclosed herein, e.g., a compound of Formula (III), Formula (IV), or a compound of Table 14, exhibit superior properties when conjugated to an anti-PSMA antibody disclosed herein. Exemplary evidence of superior benefits of such L-D and antibody-drug conjugates is shown in Examples 4, 9, 12, and 15.

[0464] For example, a spacer unit can be used to directly or indirectly link an antibody moiety to a drug moiety. In some embodiments, a spacer unit directly links an antibody moiety to a drug moiety. In some embodiments, an antibody moiety and a drug moiety are attached by a spacer unit comprising one or more alkyl moieties (e.g., (CH2)3 or (CH2)4 or (CH2)5). In some embodiments, an antibody moiety and a drug moiety are attached by a spacer unit comprising one or more PEG moieties (e.g., (PEG)2 or (PEG)3 or (PEG)4). In some embodiments, an antibody moiety and a drug moiety are attached by a spacer unit comprising Formula (II). In some embodiments, a spacer unit indirectly links an antibody moiety to a drug moiety. In some embodiments, a spacer unit indirectly links an antibody moiety to a drug moiety by a cleavable moiety (e.g., a cleavable peptide) and / or an antibody attachment moiety (e.g., a maleimide moiety or a benzyloxycarbonyl-L-glutaminyl-glycine moiety) for joining the spacer unit to the antibody moiety.

[0465] In some embodiments, a spacer unit is attached to an antibody moiety (i.e., an antibody or antigen binding fragment) by a maleimide moiety (Mal). A spacer unit attached to an antibody or antigen binding fragment by a Mal is referred to herein as a “Mal-spacer unit.” In some embodiments, a Mal-spacer unit is reactive with a cysteine residue on an antibody or antigen binding fragment. In some embodiments, a Mal-spacer unit is joined to an antibody or antigen binding fragment by a cysteine residue. In some embodiments, a Mal-spacer unit comprises a PEG moiety. In some embodiments, a Mal-spacer unit comprises an alkyl moiety. In some embodiments, a Mal-spacer unit comprises Formula (II). In some embodiments, a spacer unit is attached to an antibody moiety (i.e., an antibody or antigen binding fragment) by a maleimidocaproyl moiety (MC). A spacer unit attached to an antibody or antigen binding fragment by a MC is referred to herein as a “MC-spacer unit.” In some embodiments, a MC-spacer unit is reactive with a cysteine residue on an antibody or antigen binding fragment. In some embodiments, a MC-spacer unit is joined to an antibody or antigen binding fragment by a cysteine residue. In some embodiments, a MC-spacer unit comprises a PEG moiety. In some embodiments, a MC-spacer unit comprises an alkyl moiety. In some embodiments, a MC-spacer unit comprises Formula (II).

[0466] In some embodiments, the linker comprises a Mal-spacer unit or MC-spacer unit and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the linker comprises a Mal-spacer unit or MC-spacer unit and an amino acid unit. In some embodiments, the linker comprises Mal-(CH2) n and an amino acid unit, where n is 3 to 5, or 3, 4, or 5. In some embodiments, the linker comprises MC-(CH2) n and an amino acid unit, where n is 3 to 5, or 3, 4, or 5.

[0467] In some embodiments, the linker comprises Mal-(PEG) m and an amino acid unit, where m is 2 to 4, or 2, 3, or 4. In some embodiments, the linker comprises MC-(PEG) m and an amino acid unit, where m is 2 to 4, or 2, 3, or 4. In some embodiments, the linker further comprises a cleavable dipeptide, such as Val-Cit or Val-Ala. In some embodiments, the linker comprises Mal-(PEG) n -Val-Cit, where n is any number between 1 and 10. In some embodiments, the linker comprises Mal-(PEG) n -Val-Ala, where n is any number between 1 and 10. In some embodiments, the linker comprises MC-(PEG) n -Val-Cit, where n is any number between 1 and 10. In some embodiments, the linker comprises MC-(PEG) n -Val-Ala, where n is any number between 1 and 10.

[0468] In some embodiments, the linker comprises a Mal-formula (II) and an amino acid unit. In some embodiments, the linker comprises a cleavable dipeptide, such as Val-Cit or Val-Ala. In some embodiments, the linker comprises Mal-formula (II)-Val-Cit. In some embodiments, the linker comprises Mal-formula (II)-Val-Ala.

[0469] In some embodiments, the Mal-spacer unit or MC-spacer unit attaches the antibody moiety (i.e., antibody or antigen binding fragment) to the cleavable moiety in the linker. In some embodiments, the Mal-spacer unit or MC-spacer unit attaches the antibody or antigen binding fragment to the cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises a Mal-spacer unit-amino acid unit. In some embodiments, the Mal-spacer unit comprises a PEG moiety. In some embodiments, the Mal-spacer unit comprises an alkyl moiety. In some embodiments, the Mal-spacer unit comprises Formula (II). In some embodiments, the linker comprises a MC-spacer unit-amino acid unit. In some embodiments, the MC-spacer unit comprises a PEG moiety. In some embodiments, the MC-spacer unit comprises an alkyl moiety.

[0470] In various embodiments, the cleavable moiety in the linker is directly conjugated to the drug moiety and / or antibody moiety. In other embodiments, a spacer unit is used to attach the cleavable moiety in the linker to the drug moiety and / or antibody moiety. In various embodiments, the drug moiety can be any STING agonist drug moiety disclosed herein, e.g., a compound of Formula (III), Formula (IV), or a compound disclosed in Table 14 below. In various embodiments, the drug moiety is attached to the cleavable moiety in the linker via a spacer unit. In various embodiments, the drug moiety is Compound 1. In various embodiments, the Compound 1 moiety is attached to the cleavable moiety in the linker via a spacer unit. In some embodiments, the drug moiety, e.g., Compound 1, is attached to the cleavable moiety in the linker via a self-immolization unit. In some embodiments, the drug moiety, e.g., Compound 1, is attached to the cleavable moiety in the linker via a self-immolization unit, the cleavable moiety comprises an amino acid unit, and an additional spacer unit (e.g., comprising one or more alkyl or PEG moieties or Formula (II)) conjugates the cleavable moiety to the antibody moiety. In some embodiments, the drug moiety, e.g., Compound 1, is conjugated to an anti-PSMA antibody via a Mal-spacer unit in the linker that is conjugated to a cleavable peptide moiety and a pAB or pABC self-immolization unit. In some embodiments, the drug moiety, e.g., Compound 1, is conjugated to an anti-PSMA antibody via a MC-spacer unit in the linker that is conjugated to a cleavable peptide moiety and a pAB or pABC self-immolization unit.

[0471] Spacer units can be "self-immolative" or "non-self-immolative." A "non-self- immolative" spacer unit is one in which cleavage of part or all of the linker from the spacer unit still has the drug moiety bound. Examples of non-self-immolative units include, but are not limited to, glycine spacer units and glycine-glycine spacer units. Non-self- immolative units can eventually degrade over time, but do not readily completely release the attached native drug under cellular conditions. A "self-immolative" unit comprises any structure that allows for release of the native drug moiety under, e.g., intracellular conditions, upon administration to a subject. A "native drug" is one that does not retain part of the spacer unit or other chemical modification after cleavage / degradation of the spacer unit.

[0472] Self-immolative chemistry is known in the art and can be readily selected for the disclosed ADCs. In various embodiments, the spacer unit that attaches the cleavable portion in the linker to the drug moiety (e.g., Compound 1) is self-immolative and undergoes self-immolation at or shortly before / after cleavage of the cleavable portion under intracellular conditions.

[0473] In various embodiments, the linkers disclosed herein can comprise at least one self-immolative unit. Any of the linkers disclosed herein can comprise a first self- immolative unit. The phrase "first self-immolative unit" can mean a linker comprising one self-immolative unit or a linker comprising one or more self-immolative units. In some embodiments, the linkers disclosed herein comprise a first self-immolative unit and a second self-immolative unit.

[0474] In certain embodiments, at least one self-immolative unit in the linker comprises a p-aminobenzyl unit. In some embodiments, a p-aminobenzyl alcohol (pABOH) is attached to an amino acid unit or other cleavable portion in the linker via an amide bond and forms a carbamate, methylcarbamate, or carbonate between the pABOH and the drug moiety. See, e.g., Hamann et al. (2005) Expert Opin. Ther. Patents 15: 1087-103. In some embodiments, at least one self-immolative unit is or comprises a p-aminobenzyl (pAB). In some embodiments, at least one self-immolative unit is or comprises a p-aminobenzyloxy carbonyl (pABC). Without being bound by theory, it is believed that self-immolation of pAB or pABC involves a spontaneous 1,6-elimination reaction. See, e.g., Jain et al. (2015) Pharm Res 32:3526-40.

[0475] In various embodiments, the structure of the p-aminobenzyl (pAB) used in the disclosed ADCs is as follows:

[0476]

[0477] In various embodiments, the structure of the p-aminobenzyloxycarbonyl (pABC) group used in the disclosed ADCs is shown below:

[0478]

[0479] The structure of pAB or pABC in the self-immolative unit can be substituted.

[0480] In some embodiments, pAB is selected from methyl, fluoro, chloro, trifluoromethyl, C6-C 10 Aryl and C5-C 12 substituted with 1-3 substituents of the heteroaryl group. Exemplary substituted pAB units are disclosed in Table 12. In some embodiments, the linkers disclosed herein may comprise a self-immolative unit selected from the self-immolative units disclosed in Table 12 below.

[0481] Table 12. Exemplary substituted pAB segments

[0482]

[0483]

[0484]

[0485] The linker moiety can be modified to achieve desired properties of the ADC, such as stability, tolerability, and / or efficacy. For example, a linker comprising a modified pAB or pABC moiety can increase ADC stability and / or in vivo ADC tolerability (as determined, for example, by percent weight loss) while minimizing ADC efficacy reduction compared to a linker comprising pAB or pABC. Certain additional modifications to the linker-drug structure, such as the spacer unit or the modified drug moiety attachment point, may be required to achieve one or more (e.g., all) of these properties. For example, certain modifications or combinations of modifications may be required to enhance ADC stability while avoiding efficacy loss. For example, in some embodiments, an ADC comprising LP1, LP2, LP16, LP20, LP26, or LP28 can achieve desired ADC properties, such as stability, tolerability, and / or efficacy, compared to other anti-PSMA ADCs.

[0486] In some embodiments, any of the linkers disclosed herein can comprise an additional self-immolative unit. In some embodiments, the additional self-immolative unit attaches the first self-immolative unit to the drug moiety (e.g., Compound 1). The addition of one or more additional self-immolative units to the linker-payload conjugate as disclosed herein can provide superior technical benefits, e.g., superior stability and / or improved activity, compared to other linker-payload conjugates comprising any of the payload compounds disclosed herein. Any of the linkers disclosed herein can comprise a second self-immolative unit.

[0487] Exemplary additional self-immolative units are disclosed in Table 13. In some embodiments, the linker-payload conjugate comprises a second self-immolative unit listed in Table 13 below. In some embodiments, the linker-payload conjugate comprises Val-Ala-pAB and a second self-immolative unit selected from Table 13. In some embodiments, the linker-payload conjugate comprises Val-Ala-pABC and a second self-immolative unit selected from Table 13. In some embodiments, the linker-payload conjugate comprises Val-Cit-pAB and a second self-immolative unit selected from Table 13. In some embodiments, the linker-payload conjugate comprises Val-Cit-pABC and a second self-immolative unit selected from Table 13.

[0488] Table 13. Exemplary self-immolative units

[0489]

[0490]

[0491] Units 2 and 9-13 include all stereoisomers.

[0492] In some embodiments, the additional self-immolative unit comprises a Unit 1 (MEC) moiety. In some embodiments, the MEC moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-MEC moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 2 moiety. In some embodiments, the Unit 2 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 2 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 3 moiety. In some embodiments, the Unit 3 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 3 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 4 moiety. In some embodiments, the Unit 4 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 4 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 5 moiety. In some embodiments, the Unit 5 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 5 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 6 moiety. In some embodiments, the Unit 6 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 6 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 7 moiety. In some embodiments, the Unit 7 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 7 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 8 moiety. In some embodiments, the Unit 8 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 8 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 9 moiety. In some embodiments, the Unit 9 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 9 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 10 moiety. In some embodiments, the Unit 10 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 10 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 11 moiety. In some embodiments, the Unit 11 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 11 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 12 moiety. In some embodiments, the Unit 12 moiety attaches the first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 12 moiety”). In some embodiments, the additional self-immolative unit comprises a Unit 13 moiety.In some embodiments, the Unit 13 moiety attaches a first self-immolative unit to a drug moiety (e.g., Compound 1) (“self-immolative unit-Unit 13 moiety”).

[0493] In various embodiments, the cleavable moiety in the linker is directly or indirectly attached to the sulfur in the drug moiety. The drug moiety can be any suitable drug moiety disclosed herein, e.g., a compound of Formula (III), Formula (IV), or disclosed in Table 14 below. In some embodiments, the drug moiety is or comprises Compound 1. In some embodiments, the cleavable moiety in the linker is directly or indirectly attached to the S-14 sulfur in a STING agonist drug moiety disclosed herein (e.g., Compound 1). In some embodiments, the one or more self-immolative units comprise pAB. In some embodiments, the pAB attaches the cleavable moiety in the linker to the S-14 sulfur in a STING agonist drug moiety disclosed herein (e.g., Compound 1). In some embodiments, the pAB undergoes self-immolation upon cleavage of the cleavable moiety, and the STING agonist drug moiety (e.g., Compound 1) is released from the ADC in its native active form. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit-pAB. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pAB. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pAB.

[0494] In various embodiments, the cleavable moiety in the linker is attached directly or indirectly to a nitrogen in the drug moiety. The drug moiety can be a STING agonist drug moiety disclosed herein, e.g., a compound of Formula (III), Formula (IV), or a compound disclosed in Table 14 below. In some embodiments, the drug moiety is or comprises Compound 1. In some embodiments, the nitrogen in the STING agonist drug moiety (e.g., Compound 1) is the N-34 nitrogen. In some embodiments, the nitrogen in the STING agonist drug moiety (e.g., Compound 1) is the N-39 nitrogen. In some embodiments, the one or more self-immolative units comprise a pAB. In some embodiments, the one or more self-immolative units comprise a pABC. In some embodiments, the one or more self-immolative units comprise a MEC moiety. In some embodiments, the one or more self-immolative units comprise a pABC-MEC moiety. In some embodiments, the carboxylate moiety of the pABC binds to the n-methyl moiety of the MEC to form an N-methyl carbamate moiety. In some embodiments, the one or more self-immolative units comprise a Unit 8 moiety. In some embodiments, the one or more self-immolative units comprise a pABC-Unit 8 moiety. In some embodiments, the one or more self-immolative units comprise a Unit 9 moiety. In some embodiments, the one or more self-immolative units comprise a pABC-Unit 9 moiety. In some embodiments, the one or more self-immolative units comprise a Unit 11 moiety. In some embodiments, the one or more self-immolative units comprise a pABC-Unit 11 moiety.

[0495] In some embodiments, the linker comprises a third spacer unit between the first and second spacer units. In some embodiments, the second and / or third spacer unit is selected from the moieties of Table 13 above. In some embodiments, the linker comprises a third spacer unit between the pABC spacer unit and the MEC spacer unit. In some embodiments, the linker comprises a third spacer unit between the pABC spacer unit and the Unit 8 spacer unit. In some embodiments, the linker comprises a third spacer unit between the pABC spacer unit and the Unit 9 spacer unit. In some embodiments, the linker comprises a third spacer unit between the pABC spacer unit and the Unit 11 spacer unit. In some embodiments, the pABC attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1.

[0496] In some embodiments, the pABC-MEC moiety attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-MEC moiety attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1. In some embodiments, the pABC or pABC-MEC moiety undergoes self-immolation upon cleavage of the cleavable moiety and Compound 1 is released from the ADC in its native active form. In some embodiments, the release of Compound 1 from the antibody and linker occurs in a stepwise fashion, where the cleavable moiety in the linker is first cleaved, then the pABC moiety undergoes self-immolation, then the MEC moiety undergoes self-immolation. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit-pABC. In some embodiments, the linker comprises an amino acid unit-pABC-MEC moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pABC. In some embodiments, the linker comprises Val-Cit-pABC-MEC moiety. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Val-Ala-pABC-MEC moiety.

[0497] In some embodiments, the pABC-unit 8 moiety attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 8 moiety attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1. In some embodiments, the pABC or pABC-unit 8 moiety undergoes self-immolation upon cleavage of the cleavable moiety and Compound 1 is released from the ADC in its native active form. In some embodiments, the release of Compound 1 from the antibody and linker occurs in a stepwise fashion, where the cleavable moiety in the linker is first cleaved, then the pABC moiety undergoes self-immolation, then the unit 8 moiety undergoes self-immolation. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit-pABC. In some embodiments, the linker comprises an amino acid unit-pABC-unit 8 moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pABC. In some embodiments, the linker comprises Val-Cit-pABC-unit 8 moiety. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Val-Ala-pABC-unit 8 moiety.

[0498] In some embodiments, the pABC-unit 9 moiety attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 9 moiety attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1. In some embodiments, the pABC or pABC-unit 9 moiety undergoes self-immolation upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native active form. In some embodiments, the release of Compound 1 from the antibody and linker occurs in a stepwise fashion, where the cleavable moiety in the linker is first cleaved, then the pABC moiety undergoes self-immolation, then the unit 9 moiety undergoes self-immolation. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit-pABC. In some embodiments, the linker comprises an amino acid unit-pABC-unit 9 moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pABC. In some embodiments, the linker comprises Val-Cit-pABC-unit 9 moiety. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Val-Ala-pABC-unit 9 moiety.

[0499] In some embodiments, the pABC-unit 11 moiety attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 11 moiety attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1. In some embodiments, the pABC or pABC-unit 11 moiety undergoes self-immolation upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native active form. In some embodiments, the release of Compound 1 from the antibody and linker occurs in a stepwise fashion, where the cleavable moiety in the linker is first cleaved, then the pABC moiety undergoes self-immolation, then the unit 11 moiety undergoes self-immolation. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit-pABC. In some embodiments, the linker comprises an amino acid unit-pABC-unit 11 moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pABC. In some embodiments, the linker comprises Val-Cit-pABC-unit 11 moiety. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Val-Ala-pABC-unit 11 moiety.

[0500] In some embodiments, the at least one self-immolysis unit (e.g., pAB, pABC, pABC-MEC moiety, pABC-Unit 8 moiety, pABC-Unit 9 moiety, or pABC-Unit 11 moiety) undergoes self-immolysis upon cleavage of the cleavable peptide moiety in the linker. In some embodiments, the self-immolysis of the at least one self-immolysis unit (e.g., pAB, pABC, pABC-MEC moiety, pABC-Unit 8 moiety, pABC-Unit 9 moiety, or pABC-Unit 11 moiety) occurs in a stepwise manner upon cleavage of the cleavable peptide moiety in the linker, starting with the self-immolysis moiety closest to the cleavable peptide moiety. In some embodiments, the at least one self-immolysis unit (e.g., pAB, pABC, pABC-MEC moiety, pABC-Unit 8 moiety, pABC-Unit 9 moiety, or pABC-Unit 11 moiety) undergoes self-immolysis in a stepwise manner upon cleavage of the cleavable peptide moiety in the linker, where a first self-immolysis unit (e.g., pABC or pAB) undergoes self-immolysis before a second self-immolysis unit (e.g., MEC moiety, Unit 8 moiety, Unit 9 moiety, Unit 11 moiety) undergoes self-immolysis. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises an amino acid unit - pAB. In some embodiments, the linker comprises an amino acid unit - pABC. In some embodiments, the linker comprises an amino acid unit - pABC-MEC moiety. In some embodiments, the linker comprises an amino acid unit - pABC-Unit 8 moiety. In some embodiments, the linker comprises an amino acid unit - pABC-Unit 9 moiety. In some embodiments, the linker comprises an amino acid unit - pABC-Unit 11 moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pAB. In some embodiments, the linker comprises Val-Cit-pABC. In some embodiments, the linker comprises Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises Val-Cit-pABC-Unit 8 moiety. In some embodiments, the linker comprises Val-Cit-pABC-Unit 9 moiety. In some embodiments, the linker comprises Val-Cit-pABC-Unit 11 moiety. In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises Val-Ala-pAB. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Val-Ala-pABC-MEC moiety. In some embodiments, the linker comprises Val-Ala-pABC-Unit 8 moiety. In some embodiments, the linker comprises Val-Ala-pABC-Unit 9 moiety. In some embodiments, the linker comprises Val-Ala-pABC-Unit 11 moiety.

[0501] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC-spacer unit, a cleavable amino acid unit, and a pABC. In some embodiments, the linker comprises MC-Val-Cit-pABC. In some embodiments, the linker comprises MC-Val-Ala-pABC.

[0502] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC-spacer unit, a cleavable amino acid unit, and a pABC. In some embodiments, the linker comprises MC-Val-Cit-pABC. In some embodiments, the linker comprises MC-Val-Ala-pABC.

[0503] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, a pABC, and a MEC moiety. In some embodiments, the linker comprises MC-Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises MC-Val-Ala-pABC-MEC moiety.

[0504] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, a pABC, and a Unit 8 moiety. In some embodiments, the linker comprises MC-Val-Cit-pABC-Unit 8 moiety. In some embodiments, the linker comprises MC-Val-Ala-pABC-Unit 8 moiety.

[0505] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, a pABC, and a Unit 9 moiety. In some embodiments, the linker comprises MC-Val-Cit-pABC-Unit 9 moiety. In some embodiments, the linker comprises MC-Val-Ala-pABC-Unit 9 moiety.

[0506] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, a pABC, and a Unit 11 moiety. In some embodiments, the linker comprises MC-Val-Cit-pABC-Unit 11 moiety. In some embodiments, the linker comprises MC-Val-Ala-pABC-Unit 11 moiety.

[0507] In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC) and an amino acid. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, and a pAB. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, and a pABC. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, a pABC, and a MEC moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, a pABC, and a Unit 8 moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, a pABC, and a Unit 9 moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety by a linker comprising a maleimidocaproyl moiety (MC), an amino acid, a pABC, and a Unit 11 moiety.

[0508] In various aspects, the antibody moiety of the ADC is conjugated to the drug moiety by a linker, wherein the linker comprises a Mal-spacer unit, a cleavable amino acid unit, and a pAB. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pAB. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pAB. In various aspects, the antibody moiety of the ADC is conjugated to the drug moiety by a linker, wherein the linker comprises a Mal-spacer unit, a cleavable amino acid unit, and a pABC. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pABC. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC.

[0509] In various aspects, the antibody moiety of the ADC is conjugated to the drug moiety by a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, a pABC, and a MEC moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-MEC moiety.

[0510] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and Unit 8 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pABC-Unit 8 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 8 moiety.

[0511] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and Unit 9 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pABC-Unit 9 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 9 moiety.

[0512] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety through a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and Unit 11 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Cit-pABC-Unit 11 moiety. In some embodiments, the linker comprises Mal-Formula (II)-Val-Ala-pABC-Unit 11 moiety.

[0513] In some embodiments, the drug moiety is Compound 1.

[0514] In some embodiments, the drug moiety is Compound 2.

[0515] Drug moiety

[0516] The drug moiety (D) of the linker-drug conjugates and ADCs disclosed herein can be any chemotherapeutic agent. In some embodiments, the drug moiety is a STING agonist. Exemplary STING agonists are known in the art and include cyclic dinucleotides, e.g., macrocyclic bridged STING agonists, non-cyclic dinucleotides. In some embodiments, the drug moiety is a non-cyclic dinucleotide. In some embodiments, the drug moiety is a macrocyclic bridged STING agonist.

[0517] The drug moiety of the linker-drug conjugates and ADCs disclosed herein comprises a compound according to one of the following formulae:

[0518]

[0519] isomers thereof, deuterated derivatives of the compound or isomer; or salts of the compound, isomer, or deuterated derivative;

[0520] wherein, independently for each occurrence, is:

[0521] ■P a and P b each, when not racemic, is independently selected from the group consisting of the (R)-configuration and the (S)-configuration;

[0522] ■Q a and Q b each is independently selected from the group consisting of NH and O;

[0523] ■V a and V b each is independently selected from the group consisting of F and OH;

[0524] ■W is selected from the group consisting of H and NH2;

[0525] ■X a and X b each is independently selected from the group consisting of OH and SH;

[0526] ■Y a and Y b each is independently selected from the group consisting of O and S;

[0527] ■Z a and Z b are each independently selected from the group consisting of CH2, O and NH; and

[0528] ■ means a bond selected from a single bond (-), a double bond (=) in the (E)- or (Z)-configuration, or a triple bond

[0529] provided that at least one of Z a and Z b is NH or X a and X b is SH.

[0530] As referred to herein, the atoms in formula (III) and (IV) can be numbered as follows:

[0531]

[0532] In some embodiments, each of P a and P b is racemic. In some embodiments, P a is racemic and P b is selected from the group consisting of the (R)-configuration and the (S)-configuration. In some embodiments, P a is selected from the group consisting of the (R)-configuration and the (S)-configuration and P b is racemic. In some embodiments, P a and P beach of R and S is selected from the (R)-configuration and the (S)-configuration.

[0533] In some embodiments, P a is the (R)-configuration and P b is the (R)-configuration. In some embodiments, P a is the (R)-configuration and P b is the (S)-configuration. In some embodiments, P a is the (S)-configuration and P b is the (R)-configuration. In some embodiments, P a is the (S)-configuration and P b is the (S)-configuration.

[0534] In some embodiments, Q a is O and Q b is O. In some embodiments, Q a is NH and Q b is O. In some embodiments, Q a is O and Q b is NH. In some embodiments, Q a is NH and Q b is NH.

[0535] In some embodiments, V a is OH and V b is OH. In some embodiments, V a is F and V b is OH. In some embodiments, V a is OH and V b is F. In some embodiments, V a is F and V b is F.

[0536] In some embodiments, W is H. In some embodiments, W is NH2.

[0537] In some embodiments, X a is OH and X b is OH. In some embodiments, X a is SH and X b is OH. In some embodiments, X a is OH and X b is SH. In some embodiments, X a is SH and X b is SH.

[0538] In some embodiments, Y a is O and Y b is O. In some embodiments, Y a is S and Yb is O. In some embodiments, Y a is O and Y b is S. In some embodiments, Y a is S and Y b is S.

[0539] In some embodiments, Z a is NH and Z b is selected from CH2, O, and NH. In some embodiments, Z a is NH and Z b is CH2. In some embodiments, Z a is NH and Z b is O. In some embodiments, Z a is NH and Z b is NH.

[0540] In some embodiments, Z a is O and Z b is selected from CH2, O, and NH. In some embodiments, Z a is O and Z b is CH2. In some embodiments, Z a is O and Z b is O. In some embodiments, Z a is O and Z b is NH.

[0541] In some embodiments, Z a is CH2and Z b is selected from CH2, O, and NH. In some embodiments, Z a is CH2and Z b is CH2. In some embodiments, Z a is CH2and Z b is O. In some embodiments, Z a is CH2and Z b is NH.

[0542] In some embodiments, is a single bond. In some embodiments, is a double bond in the (E)-configuration. In some embodiments, is a double bond in the (Z)-configuration. In some embodiments, is a triple bond.

[0543] In some embodiments, X a and at least one of X b is SH and Z a and each of Z b is independently selected from CH2, O, and NH. In some embodiments, Xa is SH and Z a and Z b Each of X is independently selected from CH2, O and NH. In some embodiments, X b is SH and Z a and Z b Each of X is independently selected from CH2, O and NH. In some embodiments, X a and X b Each of them is SH and Z a and Z b Each of the R-H-H groups is independently selected from CH2, O, and NH.

[0544] In some embodiments, Z a and Z b At least one of them is NH and X a and X b In some embodiments, Z a is NH and X a and X b In some embodiments, Z b is NH and X a and X b In some embodiments, Z a and Z b Each of them is NH and X a and X b Selected from OH and SH.

[0545] In some embodiments, the bridge of the drug moiety is an aliphatic group wherein at least one CH2 unit is replaced by an NH group. In some embodiments, the aliphatic group is fully saturated. In some embodiments, the aliphatic group contains at least one unsaturated unit. In some embodiments, the bridge is an aliphatic group wherein one CH2 unit is replaced by an NH group. In some embodiments, the bridge is an aliphatic group wherein two CH2 units are replaced by NH groups. In some embodiments, the bridge atoms comprise In some embodiments, the bridge atom comprises In some embodiments, the bridge atom comprises

[0546] In some embodiments, D comprises a compound having formula (III) and X a In some embodiments, D comprises a compound having formula (III) and X b In some embodiments, D comprises a compound having formula (IV) and X a In some embodiments, D comprises a compound having formula (IV) and X b It’s SH.

[0547] In some embodiments, D comprises a compound of Formula (III) selected from:

[0548]

[0549]

[0550]

[0551] and salts thereof.

[0552] In some embodiments, the compound of Formula (III) is selected from:

[0553]

[0554] and salts thereof.

[0555] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0556] In some embodiments, D comprises a compound of Formula (IV) selected from:

[0557]

[0558] and salts thereof.

[0559] In some embodiments, D comprises a compound of Formula (IV) selected from:

[0560]

[0561] and salts thereof.

[0562] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0563] In some embodiments, D comprises a compound selected from:

[0564]

[0565] and salts thereof.

[0566] In some embodiments, the STING agonist is Compound 1. The structure of Compound 1 is shown below:

[0567]

[0568] As described above, the term Compound 1 also encompasses salts of the structure shown above, unless the context indicates otherwise. In some embodiments, the drug moiety is Compound 1. In some embodiments, a linker, e.g., a linker of an ADC, is attached to Compound 1 through the S-14 sulfur on Compound 1. In some embodiments, a linker, e.g., a linker of an ADC, is attached to Compound 1 through the N-34 nitrogen on Compound 1. In some embodiments, a linker, e.g., a linker of an ADC, is attached to Compound 1 through the N-39 nitrogen on Compound 1. In some embodiments, a linker of an ADC is covalently attached to the S-14 sulfur on Compound 1 through a pAB. In some embodiments, the pAB is an analog of a pAB as disclosed above. In some embodiments, a linker of an ADC is covalently attached to the N-34 nitrogen on Compound 1 through a pABC. In some embodiments, a linker of an ADC is covalently attached to the N-39 nitrogen on Compound 1 through a pABC. In some embodiments, a linker of an ADC is covalently attached to the N-34 nitrogen on Compound 1 through a second self-immolative unit as disclosed below. In some embodiments, a linker of an ADC is covalently attached to the N-39 nitrogen on Compound 1 through a second self-immolative unit as disclosed below.

[0569] In some embodiments, the STING agonist is Compound 2. The structure of Compound 2 is shown below:

[0570]

[0571]

[0572] Unless otherwise noted, the term Compound 2 also encompasses salts of the structure shown above. In some embodiments, the drug moiety is Compound 2. In some embodiments, the linker, e.g., of an ADC, is attached to Compound 1 through the S-14 sulfur on Compound 2. In some embodiments, the linker, e.g., of an ADC, is attached to Compound 1 through the N-34 nitrogen on Compound 2. In some embodiments, the linker, e.g., of an ADC, is attached to Compound 1 through the N-39 nitrogen on Compound 2. In some embodiments, the linker of an ADC is covalently attached to the S-14 sulfur on Compound 2 through a pAB. In some embodiments, the pAB is an analog of a pAB as disclosed above. In some embodiments, the linker of an ADC is covalently attached to the N-34 nitrogen on Compound 2 through a pABC. In some embodiments, the linker of an ADC is covalently attached to the N-39 nitrogen on Compound 2 through a pABC. In some embodiments, the linker of an ADC is covalently attached to the N-34 nitrogen on Compound 2 through a second self-immolative unit as disclosed below. In some embodiments, the linker of an ADC is covalently attached to the N-39 nitrogen on Compound 2 through a second self-immolative unit as disclosed below. In some embodiments, the STING agonist is selected from the compounds of Table 14 below.

[0573] Table 14. Exemplary STING agonist compounds

[0574]

[0575]

[0576]

[0577] Further disclosed are isomers of the compounds of Table 14, deuterated derivatives of the compounds and isomers; and salts of the compounds, isomers, and deuterated derivatives.

[0578] In certain embodiments, an intermediate, e.g., a precursor of a linker as disclosed above, is reacted with a drug moiety under appropriate conditions. In certain embodiments, reactive groups are used on the drug and / or the intermediate or linker. The reaction product between the drug and the intermediate or derivatized drug is then reacted with an antibody or antigen binding fragment under appropriate conditions, e.g., according to the methods discussed below. Alternatively, the linker or intermediate can first be reacted with an antibody or derivatized antibody, and then reacted with a drug or derivatized drug.

[0579] A number of different reactions can be used for the covalent attachment of a drug and / or linker to an antibody moiety. This is typically accomplished by reaction of one or more amino acid residues of the antibody molecule, including the amine group of lysine, the free carboxylic acid group of glutamic acid and aspartic acid, the sulfhydryl group of cysteine, and various moieties of aromatic amino acids. For example, non-specific covalent attachment can be carried out using a carbodiimide reaction to link a carboxyl (or amino) group on the compound to an amino (or carboxyl) group on the antibody moiety. Additionally, a bifunctional reagent such as a dialdehyde or imidoester can also be used to link an amino group on the compound to an amino group on the antibody moiety. A Schiff base reaction can also be used to attach a drug to a binding agent. This method involves periodate oxidation of a drug containing diol or hydroxyl groups, thereby forming an aldehyde, which is then reacted with the binding agent. Attachment occurs by formation of a Schiff base with an amino group of the binding agent. Isothiocyanate can also be used as a coupling agent for covalent attachment of a drug to a binding agent. Other techniques are known to the skilled artisan and are within the scope of the present disclosure.

[0580] Linker-drug conjugates

[0581] The present disclosure provides linker-drug conjugates comprising L-D, wherein L is a cleavable linker covalently attached to D. The terms “linker-drug conjugate” and “linker- payload conjugate” are used interchangeably herein. The linker-drug conjugates disclosed herein are suitable for conjugation to a variety of antibodies, including the anti-PSMA antibodies disclosed herein. In the context of L-D, D is a compound that forms a covalent bond with L, which results in the loss of at least one hydrogen radical. In the context of L-D, D can be any suitable compound that can benefit from the disclosed linker. In some embodiments, D is selected from any of the compounds disclosed herein. In the context of L-D, L can be selected from any of the linkers disclosed herein. D comprises a compound according to one of the following formulae:

[0582]

[0583] an isomer thereof, a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative;

[0584] wherein, independently for each occurrence, is:

[0585] ■P a and P b each of which, when not racemic, is independently selected from the (R)-configuration and the (S)-configuration;

[0586] ■Q a and Q b each of which is independently selected from NH and O;

[0587] ■V a and V b each independently is selected from F and OH;

[0588] ■W is selected from H and NH2;

[0589] ■X a and X b each independently is selected from OH and SH;

[0590] ■Y a and Y b each independently is selected from O and S;

[0591] ■Z a and Z b each independently is selected from CH2, O and NH; and

[0592] ■ means a bond selected from a single bond (-), a double bond (=) in (E)- or (Z)- configuration, or a triple bond

[0593] provided that at least one of Z a and Z b is NH or X a and X b is SH.

[0594] In some embodiments, each of P a and P b is racemic. In some embodiments, P a is racemic and P b is selected from (R)-configuration and (S)-configuration. In some embodiments, P a is selected from (R)-configuration and (S)-configuration and P b is racemic. In some embodiments, each of P a and P b is selected from (R)-configuration and (S)-configuration.

[0595] In some embodiments, P a is (R)-configuration and P b is (R)-configuration. In some embodiments, P a is (R)-configuration and P b is (S)-configuration. In some embodiments, P a is (S)-configuration and P b is (R)-configuration. In some embodiments, P a is (S)-configuration and P b is (S)-configuration.

[0596] In some embodiments, Q a is O and Q b is O. In some embodiments, Q a is NH and Q b is O. In some embodiments, Q a is O and Q b is NH. In some embodiments, Q a is NH and Q b is NH.

[0597] In some embodiments, V a is OH and V b is OH. In some embodiments, V a is F and V b is OH. In some embodiments, V a is OH and V b is F. In some embodiments, V a is F and V b is F.

[0598] In some embodiments, W is H. In some embodiments, W is NH2.

[0599] In some embodiments, X a is OH and X b is OH. In some embodiments, X a is SH and X b is OH. In some embodiments, X a is OH and X b is SH. In some embodiments, X a is SH and X b is SH.

[0600] In some embodiments, Y a is O and Y b is O. In some embodiments, Y a is S and Y b is O. In some embodiments, Y a is O and Y b is S. In some embodiments, Y a is S and Y b is S.

[0601] In some embodiments, Z a is NH and Z b is selected from CH2, O, and NH. In some embodiments, Z a is NH and Z b is CH2. In some embodiments, Z a is NH and Z b is O. In some embodiments, Za is NH and Z b is NH.

[0602] In some embodiments, Z a is O and Z b is selected from CH2, O, and NH. In some embodiments, Z a is O and Z b is CH2. In some embodiments, Z a is O and Z b is O. In some embodiments, Z a is O and Z b is NH.

[0603] In some embodiments, Z a is CH2and Z b is selected from CH2, O, and NH. In some embodiments, Z a is CH2and Z b is CH2. In some embodiments, Z a is CH2and Z b is O. In some embodiments, Z a is CH2and Z b is NH.

[0604] In some embodiments, is a single bond. In some embodiments, is a double bond in the (E)-configuration. In some embodiments, is a double bond in the (Z)-configuration. In some embodiments, is a triple bond.

[0605] In some embodiments, X a and X b is SH and Z a and Z b are each independently selected from CH2, O, and NH. In some embodiments, X a is SH and Z a and Z b are each independently selected from CH2, O, and NH. In some embodiments, X b is SH and Z a and Z b are each independently selected from CH2, O, and NH. In some embodiments, X a and X b is SH and Z a and Z b are each independently selected from CH2, O, and NH.

[0606] In some embodiments, Z a and Zb at least one of Z and Z is NH and X a and X b is selected from OH and SH. In some embodiments, Z a is NH and X a and X b is selected from OH and SH. In some embodiments, Z b is NH and X a and X b is selected from OH and SH. In some embodiments, Z a and Z b each of Z and Z is NH and X a and X b is selected from OH and SH.

[0607] In some embodiments, D comprises a compound of Formula (III) and X a is SH. In some embodiments, D comprises a compound of Formula (III) and X b is SH. In some embodiments, D comprises a compound of Formula (IV) and X a is SH. In some embodiments, D comprises a compound of Formula (IV) and X b is SH.

[0608] In some embodiments, the bridge of the linker-drug conjugate is an aliphatic group, wherein at least one CH2unit is replaced by an NH group. In some embodiments, the aliphatic group is fully saturated. In some embodiments, the aliphatic group contains at least one unsaturated unit. In some embodiments, the bridge is an aliphatic group, wherein one CH2unit is replaced by an NH group. In some embodiments, the bridge is an aliphatic group, wherein two CH2units are replaced by an NH group. In some embodiments, the bridge atoms comprise In some embodiments, the bridge atoms comprise In some embodiments, the bridge atoms comprise In some embodiments, L is attached to D through a sulfur atom. In some embodiments, L is attached to D at the S-2 sulfur or the S-14 sulfur. In some embodiments, L is attached to D at the S-2 sulfur. In some embodiments, L is attached to D at the S-14 sulfur.

[0609] In some embodiments, D comprises a compound of Formula (III) and Z a is NH. In some embodiments, D comprises a compound of Formula (III) and Z b is NH. In some embodiments, D comprises a compound of Formula (IV) and Z a is NH. In some embodiments, D comprises a compound of Formula (IV) and Z b is NH.

[0610] In some embodiments, L is attached to D through a bridging nitrogen atom. In some embodiments, L is attached to D at the N-34 nitrogen or the N-39 nitrogen. In some embodiments, L is attached to D at the N-34 nitrogen. In some embodiments, L is attached to D at the N-39 nitrogen.

[0611] In some embodiments, D comprises a compound of formula (III). Exemplary compounds of formula (III) are shown below. In some embodiments, D comprises a compound of formula (III) selected from the following:

[0612]

[0613]

[0614] and its salts.

[0615] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0616] In some embodiments, D comprises a compound of formula (IV) selected from:

[0617]

[0618] and its salts.

[0619] In some embodiments, D comprises a compound of formula (IV) selected from:

[0620]

[0621] and its salts.

[0622] In some embodiments, X a or X b is SH and L is attached to D through the sulfur atom at the S-2 sulfur or the S-14 sulfur. In some embodiments, Z a or Z b is NH and L is attached to D through the nitrogen atom at the N-34 nitrogen or the N-39 nitrogen.

[0623] In some embodiments, D comprises a compound having formula (III), X a is SH and L is attached to D at the S-2 sulfur. In some embodiments, D comprises a compound having formula (III), X b is SH and L is attached to D at the S-14 sulfur. In some embodiments, D comprises a compound having formula (III), Z a is NH and L is attached to D at the N-34 nitrogen. In some embodiments, D comprises a compound having formula (III), Zb is NH and L is attached to D at the N-39 nitrogen.

[0624] In some embodiments, D comprises a compound of Formula (IV) and L is attached to D at the S-2 sulfur. In some embodiments, D comprises a compound of Formula (IV) and L is attached to D at the S-14 sulfur. In some embodiments, D comprises a compound of Formula (IV) and L is attached to D at the N-34 nitrogen. In some embodiments, D comprises a compound of Formula (IV) and L is attached to D at the N-39 nitrogen.

[0625] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0626] The present disclosure provides linker-payload conjugates comprising L-D, wherein L is a cleavable linker covalently attached to D, wherein D comprises a compound selected from:

[0627]

[0628] and salts thereof.

[0629] In some embodiments, L is attached to D through a sulfur atom at the S-2 sulfur or the S-14 sulfur. In some embodiments, L is attached to D at the S-2 sulfur. In some embodiments, L is attached to D at the S-14 sulfur.

[0630] In some embodiments, L is attached to D through a nitrogen atom at the N-34 nitrogen or the N-39 nitrogen. In some embodiments, L is attached to D at the N-34 nitrogen. In some embodiments, L is attached to D at the N-39 nitrogen.

[0631] In some embodiments of the linker-payload conjugate comprising L-D, L is any linker disclosed herein. In some embodiments of the linker-payload conjugate comprising L-D, D is any drug moiety disclosed herein.

[0632] In some embodiments of the linker-payload conjugate comprising L-D, wherein L is a cleavable linker covalently attached to D, the cleavable linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety is cleavable by a protease. In some embodiments, the protease is a cysteine protease or cathepsin. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Ala, Val-Cit, Val-Lys, Ala-Ala-Asn, Ala-(NMe)Ala-Asn, Asn, Gly-Gly-Phe-Gly, or Gly-Val-Ala. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the amino acid unit comprises Val-Cit.

[0633] In some embodiments, the linker-payload conjugate comprises Val-Ala, and D is selected from the compounds of Table 14. In some embodiments, the linker-payload conjugate comprises Val-Cit, and D is selected from the compounds of Table 14.

[0634] In some embodiments, the linker-payload conjugate comprises Formula (II), and D is selected from the compounds of Table 14.

[0635] In some embodiments, the linker-payload conjugate comprises Formula (II)-Val-Ala, and D is selected from the compounds of Table 14. In some embodiments, the linker-payload conjugate comprises Formula (II)-Val-Cit, and D is selected from the compounds of Table 14.

[0636] In some embodiments, the linker-drug conjugate comprises MC-Val-Cit-pABC-MEC-Compound 1. In some embodiments, the linker-drug conjugate comprises MC-Val-Ala-pABC-MEC-Compound 1 (e.g., LP1 or LP2). In some embodiments, the linker-drug conjugate comprises MC-Val-Cit-pABC-Unit 8-Compound 1. In some embodiments, the linker-drug conjugate comprises MC-Val-Ala-pABC-Unit 8-Compound 1 (e.g., LP16). In some embodiments, the linker-drug conjugate comprises MC-Val-Cit-pABC-Unit 9-Compound 1. In some embodiments, the linker-drug conjugate comprises MC-Val-Ala-pABC-Unit 9-Compound 1 (e.g., LP20). In some embodiments, the linker-drug conjugate comprises MC-Val-Cit-pABC-Unit 11-Compound 1. In some embodiments, the linker-drug conjugate comprises MC-Val-Ala-pABC-Unit 11-Compound 1 (e.g., LP28).

[0637] In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pABC-MEC-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pABC-Unit 8-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pABC-Unit 9-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pABC-Unit 11-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pABC-MEC-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pABC-Unit 8-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pABC-Unit 9-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pABC-Unit 11-Compound 1.

[0638] In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pAB-Unit 9-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pAB-Unit 9-Compound 1. In some embodiments, the linker-drug conjugate comprises LP25.

[0639] In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Cit-pAB-Unit 11-Compound 1. In some embodiments, the linker-drug conjugate comprises Mal-form (II)-Val-Ala-pAB-Unit 11-Compound 1. In some embodiments, the linker-drug conjugate comprises LP26.

[0640] Exemplary linker-drug conjugates of the present application are disclosed below in Tables 15 and 16. In various embodiments, the linker-drug conjugate is selected from the linker-drug conjugates shown in Tables 15 and 16.

[0641] Table 15. Exemplary S-attached linker-drug conjugates

[0642]

[0643]

[0644]

[0645] Table 16. Exemplary N-attached Linker-Drug Conjugates

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, can be referred to as "LP3" and has the structure of LP3 as shown below:

[0655]

[0656] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, can be referred to as "LP1" and has the structure of LP1 as shown below:

[0657]

[0658] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, can be referred to as "LP2" and has the structure of LP2 as shown below:

[0659]

[0660] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, has the structure of LP16 as shown below:

[0661]

[0662] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, has the structure of LP20 as shown below:

[0663]

[0664] In some embodiments, an exemplary linker-drug conjugate, or salt thereof, has the structure of LP26 as shown below:

[0665]

[0666] In some embodiments, an exemplary Linker-Drug Conjugate, or salt thereof, has the structure of LP28 as shown below:

[0667]

[0668] In some embodiments, the Linker-Payloads disclosed herein, such as LP1, LP2, LP16, LP20, LP26, LP28, or LP3, have improved properties compared to existing Linker-STING Agonist Conjugates. In some embodiments, the Linker-Payloads disclosed herein, such as LP1, LP2, LP3, LP16, LP20, LP26, or LP28, have improved plasma stability over prior art Linker-STING Agonist Conjugates. In some embodiments, the Linker-Payloads disclosed herein, such as LP1, LP2, LP3, LP16, LP20, LP26, or LP28, have improved in vivo anti-tumor activity over prior art Linker-STING Agonist Conjugates. In some embodiments, the Linker-Payloads disclosed herein, such as LP1, LP2, LP3, LP16, LP20, LP26, or LP28, have improved in vivo tolerability over prior art Linker-STING Agonist Conjugates.

[0669] In some embodiments of the Linker-Payload Conjugates disclosed herein, wherein D is a STING Agonist, such as a compound of Formula (III), Formula (IV), or a compound of Table 14, e.g., Compound 1, and L is conjugated to D at the N-34 nitrogen or the N-39 nitrogen (e.g., LP16, LP20, LP26, or LP28), the Linker-Payload Conjugate exhibits superior properties (e.g., plasma stability, in vitro immune response, in vivo anti-tumor activity, tolerability, stimulation of anti-immune response in the tumor microenvironment) compared to other Linker-Payload Conjugates comprising a compound of Formula (III), Formula (IV), or a compound of Table 14 that are conjugated to D at an alternative attachment point, such as at a sulfur (e.g., S-2 or S-14). Exemplary evidence of the superior benefits of such Linker-Payload Conjugates is shown in Examples 4, 9, 12, 14, and 15.

[0670] In some embodiments of the linker-payload conjugates disclosed herein, wherein L comprises a spacer unit comprising Formula (II), the linker-payload conjugates exhibit superior properties (e.g., improved conjugation stability, improved plasma stability, in vivo anti-tumor activity) compared to other linker-payload conjugates comprising alternative spacer units. In some embodiments, without being bound by theory, the use of linkers comprising Formula (II) with the STING agonists disclosed herein, e.g., compounds having Formula (III), Formula (IV), or a compound of Table 14, e.g., Compound 1, can include improved conjugation stability, improved plasma stability, and in vivo anti-tumor activity. In some embodiments, linker-payload conjugates comprising a linker comprising Formula (II) and a payload comprising a STING agonist disclosed herein, e.g., a compound having Formula (III), Formula (IV), or a compound of Table 14, exhibit superior properties when conjugated to an anti-PSMA antibody disclosed herein. Exemplary evidence of superior benefits of such linker-payload conjugates, e.g., benefits that can be provided when conjugated to a variety of different antibodies, is shown in Examples 4, 9, 12, and 15.

[0671] In some embodiments, the ADC disclosed herein comprises a cleavable linker and an internalizing anti-PSMA antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 33 (LCDR1), SEQ ID NO: 36 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

[0672] In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0673] In some embodiments, p is 1 to 12 or 2 to 11. In some embodiments, p is 1 to 8. In some embodiments, p is 4 to 11. In some embodiments, p is 4 to 8. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is 7. In some embodiments, p is 11.

[0674] The present disclosure includes methods of producing the described linker-drug conjugates. The linker-drug conjugates comprise a linker and a drug moiety and can be prepared using linkers having reactive functionality for covalently attaching the linker to the drug moiety. In some embodiments, the method of producing a linker-drug conjugate comprises reacting a drug or a salt thereof with an activated linker.

[0675] In some embodiments, the drug reacted with the activated linker is a compound disclosed in Table 14; an isomer of the compound; a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative. In some embodiments, the drug is a sodium salt of a compound disclosed in Table 14. In some embodiments, the drug is a diammonium salt of a compound disclosed in Table 14. In some embodiments, the drug is a dialkylammonium salt of a compound disclosed in Table 14. In some embodiments, the drug is a bis(triethylammonium) salt of a compound disclosed in Table 14.

[0676] In some embodiments, the activated linker that reacts with a compound disclosed in Table 14; an isomer of the compound; a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative is In some embodiments, the activated linker that reacts with a compound disclosed in Table 14; an isomer of the compound; a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative is In some embodiments, the linker portion of the activated linker comprises a linker of the disclosure, e.g., a linker disclosed above, e.g., as disclosed in this section.

[0677] In some embodiments, the method of producing a linker-drug conjugate comprises reacting a compound disclosed in Table 14; an isomer of the compound; a deuterated derivative of the compound or isomer; or a salt of the compound, isomer, or deuterated derivative with an activated linker of the disclosure. In some embodiments, the reaction of the compound, isomer, deuterated derivative, or salt is performed in the presence of an organic metal base. In some embodiments, the organic metal base is selected from LDA, NaHMDS, LiHMDS, and KHMDS. In some embodiments, the organic metal base is LiHMDS.

[0678] In some embodiments, the method of producing an activated linker comprises reacting a linker of the disclosure with 4-nitrophenyl chloroformate. In some embodiments, the reaction of the linker with 4-nitrophenyl chloroformate is performed in the presence of a base. In some embodiments, the base is pyridine.

[0679] In some embodiments, the method of producing an activated linker comprises reacting a linker of the disclosure with pentafluorophenol. In some embodiments, the reaction of the linker with pentafluorophenol is performed in the presence of a peptide coupling reagent. In some embodiments, the peptide coupling reagent is DCC.

[0680] In some embodiments, the activated linker is used in a method of producing an L-D conjugate (V):

[0681]

[0682] In some embodiments, the method of producing an L-D conjugate (V) comprises reacting a compound of Formula (III) or a salt thereof with an activated linker In some embodiments, Z b is NH. In some embodiments, P b has the (S)-configuration, and the activated linker preferentially reacts with Z breaction. As used herein, "preferentially" (unless context dictates otherwise) means more than 70% of the reaction, e.g., 70% of the activated linker reacts with Z b nitrogen rather than with Z a nitrogen.

[0683] In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 95%, more than 90%, more than 85%, more than 80%, more than 75%, or more than 70% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 95% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 90% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 85% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 80% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 75% of the reaction with Z a nitrogen. In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 70% of the reaction with Z a nitrogen.

[0684] In some embodiments, the activated linker is used in a method of producing L-D conjugate (VI):

[0685]

[0686] In some embodiments, the method of producing L-D conjugate (VI) comprises reacting a compound of formula (III) or salt thereof: with an activated linker. In some embodiments, Z b is NH. In some embodiments, P b has the (S)-configuration and the activated linker preferentially reacts with Z b .

[0687] In some embodiments, the activated linker preferentially reacts with Z b nitrogen more than 95%, more than 90%, more than 85%, more than 80%, more than 75%, or more than 70% of the reaction with Z a95%, more than 90%, more than 85%, more than 80%, more than 75%, or more than 70% as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 95% with the Zb nitrogen as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 90% with the Zb nitrogen as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 85% with the Zb nitrogen as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 80% with the Zb nitrogen as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 75% with the Zb nitrogen as compared to the Za nitrogen. In some embodiments, the activated linker reacts more than 70% with the Zb nitrogen as compared to the Za nitrogen.

[0688] Antibody-drug conjugates

[0689] In various embodiments, an anti-PSMA antibody moiety or antigen-binding fragment thereof as disclosed herein can be conjugated (i.e., covalently attached, e.g., via a linker) to a drug moiety, wherein the drug moiety has cytotoxic or cytostatic effects when not conjugated to the antibody moiety. In some embodiments, the drug moiety exhibits reduced cytotoxicity or no cytotoxicity when bound in the conjugate, but reverts to cytotoxicity upon cleavage from the linker and antibody moiety.

[0690] Development and production of ADCs for use as human therapeutics (e.g., as oncology agents) can require more than just identification of an antibody that is capable of binding one or more desired targets and attaching to a drug used alone to treat cancer. Linking the antibody to the drug can have significant and unpredictable effects on the activity of one or both of the antibody and the drug, which will vary depending on the type of linker and / or drug selected. Thus, in some embodiments, the components of the ADC are selected to (i) preserve one or more therapeutic properties exhibited by the antibody and drug moieties alone; (ii) maintain the specific binding properties of the antibody moiety; (iii) optimize drug loading and drug-to-antibody ratio; (iv) allow for targeted tumor cell delivery (e.g., intracellular delivery) of the drug moiety by stable attachment to the antibody moiety; (v) reduce toxicity compared to non-targeted and / or systemic delivery of the drug moiety; (vi) preserve stability of the ADC as an intact conjugate until transport or delivery to the target site; (vii) minimize aggregation of the ADC before and after administration; (viii) exhibit in vivo anti-cancer treatment efficacy comparable to or superior to the antibody and drug moieties alone; (ix) minimize off-target killing by the drug moiety; (x) exhibit desirable pharmacokinetic and pharmacodynamic properties, formulatability, and toxicological / immunological profiles; (xi) maintain stimulation of anti-immune responses in the tumor microenvironment; and / or (xii) increase phagocytosis of PSMA-expressing cells by bone marrow cells (e.g., macrophages or dendritic cells). Each of these properties can need to be screened to identify improved ADCs for therapeutic use. See, e.g., Ab et al. (2015) Mol. Cancer Ther. 14: 1605-13.

[0691] In some embodiments, the ADC compounds of the disclosure have superior stability as intact conjugates before transport or delivery to the target site compared to ADC compounds comprising other antibodies (e.g., J591 or deJ591) and / or other linkers. In some embodiments, the ADC compounds of the disclosure have lower immunogenicity compared to ADC compounds comprising other antibodies (e.g., J591 or deJ591) and / or other linkers.

[0692] The ADC compounds of the present disclosure can selectively deliver an effective dose of a cytotoxic or cytostatic agent to cancer cells or tumor tissue. It has been found that the disclosed ADCs have potent cytotoxic and / or cytostatic activity against cells expressing PSMA. In some embodiments, the cytotoxic and / or cytostatic activity of the ADCs is dependent on the level of PSMA expression in the cell. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells expressing high levels of PSMA as compared to cancer cells expressing low levels of the same antigen. In some embodiments, the disclosed ADCs are particularly effective at killing cancers expressing high levels of PSMA, such as prostate cancer. In some embodiments, the targeted killing of PSMA-expressing cancer cells is improved by the presence or recruitment of myeloid cells (e.g., macrophages and / or dendritic cells).

[0693] In some embodiments, the ADCs disclosed herein demonstrate PSMA-specific binding to cells expressing PSMA (e.g., in a PSMA-expressing cancer). In some embodiments, once bound to PSMA, the disclosed ADCs are internalized. In some embodiments, release of the drug moiety (e.g., Compound 1) results in STING pathway activation and release of proinflammatory cytokines (e.g., IFN ). In some embodiments, release of proinflammatory cytokines promotes myeloid cell activation. In some embodiments, release of proinflammatory cytokines stimulates type I IFN-dependent anti-tumor activity.

[0694] In some embodiments, the disclosed ADCs activate myeloid cells, such as macrophages or dendritic cells. Without being bound by theory, myeloid cell activation can be a result of phagocytosis of PSMA-expressing cancer cells bound by the disclosed ADCs. In some embodiments, the disclosed ADCs activate macrophages. In some embodiments, the activated macrophages are proinflammatory (M1) macrophages. In some embodiments, tumor-associated macrophages or M2 macrophages undergo proinflammatory activation upon administration of the disclosed ADCs. In some embodiments, the activated macrophages release proinflammatory cytokines and chemokines (e.g., TNF, CXCL10, IL-6, IFN, and / or IL-1 ). In some embodiments, the activated macrophages further promote myeloid cell activation. In some embodiments, the activated macrophages promote the generation of cytotoxic T cells. In some embodiments, the activated macrophages exhibit increased phagocytosis of cancer cells. In some embodiments, administration of the disclosed ADCs stimulate type I IFN-dependent anti-tumor activity. As used herein, “activated macrophages” is synonymous with “polarized macrophages.”

[0695] Provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab) that targets a tumor cell, a drug moiety (D), and a linker moiety (L) that covalently attaches the Ab to D. In certain aspects, the antibody or antigen-binding fragment is capable of binding a tumor-associated antigen (e.g., PSMA) with high specificity and high affinity. In certain embodiments, the antibody or antigen-binding fragment is internalized into the target cell upon binding, e.g., into a degradative compartment in the cell. In some embodiments, the ADC is internalized upon binding to the target cell, undergoes degradation, and releases the drug moiety. The drug moiety can be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0696] In some embodiments, the target cell to which the ADC binds is phagocytosed by a myeloid cell, e.g., a macrophage or a dendritic cell. In some embodiments, upon phagocytosis occurs, the ADC undergoes degradation and releases the drug moiety. In some embodiments, the drug moiety is released in the phagolysosome of the myeloid cell, e.g., macrophage or dendritic cell. The drug moiety can be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0697] Exemplary ADCs have the formula I:

[0698] Ab-(L-D)p(I)

[0699] wherein Ab = antibody moiety (i.e., antibody or antigen-binding fragment), L = linker moiety, D = drug moiety, and p = number of drug moieties per antibody moiety.

[0700] In some embodiments, the antibody-drug conjugates disclosed herein comprise an anti-PSMA antibody or antigen-binding fragment. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a heavy chain having an amino acid sequence selected from SEQ ID NOs: 47-60 listed in Table 8 above and / or comprising a set of CDRs and / or a variable domain from an amino acid sequence in Table 8. In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises a light chain having an amino acid sequence selected from SEQ ID NOs: 61-66 listed in Table 8 below and / or comprising a set of CDRs and / or a variable domain from an amino acid sequence in Table 8.

[0701] In some embodiments, the anti-PSMA antibody or antigen binding fragment comprises one or more of the consensus CDR sequences of Table 1 in combination with one or more of the CDR sequences of Table 3, e.g., by selecting the HC CDR2, LC CDR1, and / or LCDR2 sequences of Table 1 and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 of Table 3 to describe the antibody by its three heavy chain and three light chain CDR sequences.

[0702] In some embodiments, the anti-PSMA antibody or antigen binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system. In some embodiments, the anti-PSMA antibody or antigen binding fragment comprises three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

[0703] In some embodiments, the anti-PSMA antibody or antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0704] To accomplish site-specific conjugation of the linker and / or drug moiety to the antibody or antigen binding fragment thereof, in some embodiments, a linker comprising a thiol-reactive group is used to generate the conjugated antibody or antigen binding fragment, e.g., by reacting with the antibody or antigen binding fragment at a cysteine residue. In some embodiments, the cysteine residue is at amino acid position 80 on the light chain. In some embodiments, the cysteine residue is at amino acid position 118 on the heavy chain. Methods to accomplish site-specific conjugation of the linker and / or drug moiety to the antibody or antigen binding fragment to generate an ADC are known in the art and disclosed in PCT Application WO 2016 / 205618, which is incorporated by reference herein in its entirety.

[0705] Drug loading

[0706] Drug loading is represented by p, and is also referred to herein as drug to antibody ratio (DAR). In certain embodiments, the range of drug loading can be 1 to 20 (i.e., 1 to 20 copies of the linker-drug attached to each antibody portion), for example 1 to 12 drug portions / antibody portions. In certain embodiments, p is an integer from 1 to 12. In certain embodiments, p is an integer from 1 to 8. In certain embodiments, p is an integer from 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2. In certain embodiments, p is an integer from 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 or 2 to 3. In certain embodiments, p is an integer from 2 to 11. In certain embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In certain embodiments, p is 2. In certain embodiments, p is 4. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 11. In some embodiments, the drug loading can be expressed as the average loading in the antibody population, e.g., an average loading of about 1-12, e.g., about 2-11. In some embodiments, the average drug loading in the antibody population is about 2 to about 8. In some embodiments, the average drug loading in the antibody population is about 2, about 4, or about 8.

[0707] Drug loading may be limited by the number of attachment sites on the antibody portion. In certain embodiments, the connexon portion (L) of ADC is attached to the antibody portion by the chemically active groups on one or more amino acid residues on the antibody portion. For example, connexon can be attached to the antibody portion (for example, with N-terminal or C-terminal, with the epsilon amino group of one or more lysine residues, with the free carboxylic acid groups of one or more glutamic acid or aspartic acid residues or with the sulfhydryl groups of one or more cysteine ​​residues) by free amino groups, imino groups, hydroxyl groups, thiol groups or carboxyl groups. The site attached to the connexon can be the natural residue in the amino acid sequence of the antibody portion, or it can be introduced into the antibody portion b...

Claims

1. A humanized anti-prostate-specific membrane antigen (PSMA) antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment specifically binds to human PSMA, and wherein the antibody or antigen-binding fragment comprises (i) three HCDRs comprising the amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or (ii) three HCDRs comprising the amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 33 (LCDR1), SEQ ID NO: 36 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or (iii) three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2) and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2) and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

2. The anti-PSMA antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises (i) three HCDRs comprising the amino acid sequences: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or (ii) three HCDRs comprising the following amino acid sequences: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2) and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2) and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

3. The anti-PSMA antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15; or (ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15; or (iii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15; or (iv) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15; or (v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

19.

4. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 3, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

19.

5. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 4, wherein the antibody or antigen-binding fragment comprises a human IgG heavy chain constant region.

6. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 5, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

7. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 6, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

8. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 4, wherein the antigen-binding fragment has a melting temperature (Tm) > 80°C, wherein optionally the antigen-binding fragment is a Fab.

9. The anti-PSMA antibody or antigen-binding fragment of any one of claims 1 to 8, wherein the antibody or antigen-binding fragment is attached to at least one linker, wherein optionally the at least one linker is cleavable.

10. The anti-PSMA antibody or antigen-binding fragment of claim 9, wherein the at least one linker is conjugated to a cytotoxic agent or a detectable agent.

11. A linker-payload conjugate comprising LD, wherein L is a linker covalently attached to D, wherein D comprises a compound according to one of the following formulae: Isomers thereof, deuterated derivatives of said compounds or isomers; or salts of said compounds, isomers or deuterated derivatives; in, For each occurrence independently it is: ■P a and P b each of , when not racemic, is independently selected from (R)-stereochemistry and (S)-stereochemistry; ■Q a and Q b Each of is independently selected from NH and O; ■V a and V b Each of is independently selected from F and OH; ■W is selected from H and NH2; ■X a and X b Each of is independently selected from OH and SH; ■Y a and Y b Each of is independently selected from O and S; ■Z a and Z b are each independently selected from CH2, O and NH; and ■ means that the bond is selected from a single bond (-), a double bond (=) in (E)- or (Z)-configuration, or a triple bond (≡); The condition is Z a and Z b At least one of them is NH or X a and X b At least one of them is SH.

12. The linker-payload conjugate of claim 11, wherein P a is (S)-configuration and P b It is (R)-configuration.

13. The linker-payload conjugate of claim 11, wherein P a is (R)-configuration and P b It is (R)-configuration.

14. The linker-payload conjugate of any one of claims 11 to 13, wherein Q a and Q b It's O.

15. The linker-payload conjugate of any one of claims 11 to 14, wherein V a and V b It's OH.

16. The linker-payload conjugate of any one of claims 11 to 14, wherein V a and V b It's F.

17. The linker-payload conjugate of any one of claims 11 to 16, wherein W is H.

18. The linker-payload conjugate of any one of claims 11 to 17, wherein Z a and Z b At least one of them is NH.

19. The linker-payload conjugate of any one of claims 11 to 18, wherein Z a and Z b It's NH.

20. The linker-payload conjugate of any one of claims 11 to 19, wherein Contains a double bond (=) in the (E)- or (Z)-configuration.

21. The linker-payload conjugate of any one of claims 11 to 19, wherein the bridge With structure 22. The linker-payload conjugate of any one of claims 11 to 21, wherein Y a and Y b At least one of them is O.

23. The linker-payload conjugate of any one of claims 11 to 22, wherein Y a and Y b It's O.

24. The linker-payload conjugate of any one of claims 11 to 23, wherein X a and X b At least one of them is SH.

25. The linker-payload conjugate of any one of claims 11 to 24, wherein X a and X b It’s SH.

26. The linker-payload conjugate of any one of claims 11 to 25, wherein D comprises a compound having formula (III).

27. The linker-payload conjugate of claim 11, wherein D comprises a compound having formula (III) selected from the group consisting of: and its salts.

28. The linker-payload conjugate of claim 11 or claim 27, wherein D comprises a compound having formula (III) selected from: and its salts.

29. The linker-payload conjugate of claim 27 or claim 28, wherein D comprises Compound 1.

30. The linker-payload conjugate of claim 27 or claim 28, wherein D comprises Compound 2.

31. The linker-payload conjugate of any one of claims 11 to 30, wherein X a and X b At least one of is SH and L is attached to D through the sulfur atom at the S-2 sulfur or the S-14 sulfur.

32. The linker-payload conjugate of claim 31, wherein X b is SH and L is attached to D at the S-2 sulfur.

33. The linker-payload conjugate of claim 31, wherein X a is SH and L is attached to D at the S-14 sulfur.

34. The linker-payload conjugate of any one of claims 11 to 30, wherein Z a and Z b At least one of is NH and L is attached to D through a nitrogen atom at the N-34 nitrogen or the N-39 nitrogen.

35. The linker-payload conjugate of claim 34, wherein Z b is NH and L is attached to D at the N-34 nitrogen.

36. The linker-payload conjugate of claim 34, wherein Z a is NH and L is attached to D at the N-39 nitrogen.

37. The linker-payload conjugate of any one of claims 11 to 36, wherein L is a cleavable linker.

38. The linker-payload conjugate of claim 37, wherein the cleavable linker comprises a cleavable peptide moiety.

39. The linker-payload conjugate of claim 38, wherein the cleavable peptide moiety is cleavable by a protease, optionally wherein the protease is a cathepsin or a cysteine ​​protease.

40. The linker-payload conjugate of claim 38 or claim 39, wherein the cleavable peptide moiety comprises amino acid units.

41. The linker-payload conjugate of claim 40, wherein the Amino Acid unit comprises Val-Ala, Val-Cit, Val-Lys, Ala-Ala-Asn, Ala-(NMe)Ala-Asn, Asn, Gly-Gly-Phe-Gly, Glu-Val-Ala, or Gly-Val-Ala.

42. The linker-payload conjugate of any one of claims 37 to 41, wherein the cleavable linker comprises Val-Ala.

43. The linker-payload conjugate of any one of claims 11 to 42, wherein the linker comprises a maleimide (Mal) moiety.

44. The linker-payload conjugate of claim 43, wherein the Mal moiety comprises a maleimidocaproyl group (MC).

45. The linker-payload conjugate of claim 43 or claim 44, wherein the MaI moiety is joined to the antibody or antigen-binding fragment via a cysteine ​​residue on the antibody or antigen-binding fragment.

46. ​​The linker-payload conjugate of any one of claims 11 to 45, wherein the linker further comprises at least one spacer unit.

47. The linker-payload conjugate of claim 46, wherein the at least one spacer unit comprises at least one polyethylene glycol (PEG) moiety.

48. The linker-payload conjugate of claim 47, wherein the at least one PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10.

49. The linker-payload conjugate of claim 48, wherein m is an integer from 2 to 8.

50. The linker-payload conjugate of claim 48 or claim 49, wherein m is an integer from 2 to 5.

51. The linker-payload conjugate of any one of claims 48 to 50, wherein m is 2.

52. The linker-payload conjugate of claim 46 or claim 47, wherein the at least one spacer unit comprises PEG2-Lys(ε-PEG8-OMe)-PEG2.

53. The linker-payload conjugate of claim 46, wherein the at least one spacer unit comprises 54. The linker-payload conjugate of claim 46 or claim 53, wherein the at least one spacer unit comprises 55. The linker-payload conjugate of any one of claims 11 to 54, wherein the linker further comprises at least one self-immolative unit.

56. The linker-payload conjugate of claim 55, wherein the linker comprises a first self-immolative unit.

57. The linker-payload conjugate of claim 56, wherein the linker is removable from D following cleavage of the linker by self-immolative cleavage of the first self-immolative unit.

58. The linker-payload conjugate of claim 56 or claim 57, wherein the first self-immolative unit comprises p-aminobenzyl (pAB) optionally substituted with 1-3 substituents selected from methyl, fluoro, chloro, trifluoromethyl, aryl, and heteroaryl.

59. The linker-payload conjugate of claim 58, wherein the first self-immolative unit comprises a p-aminobenzyl group (pAB).

60. The linker-payload conjugate of any one of claims 55 to 59, wherein the linker comprises MC-Val-Ala-pAB.

61. The linker-payload conjugate of any one of claims 56 to 59, wherein the first self-immolative unit comprises a p-aminobenzyloxycarbonyl group (pABC).

62. The linker-payload conjugate of any one of claims 56 to 61, wherein the linker further comprises a second self-immolative unit.

63. The linker-payload conjugate of claim 62, wherein the linker is removable from D after cleavage of the linker by self-immolative unit and / or self-immolative unit.

64. The linker-payload conjugate of claim 62 or claim 63, wherein the linker is removed from D following cleavage of the linker in a stepwise manner by self-immolative action of the first self-immolative unit followed by self-immolative action of the second self-immolative unit.

65. The linker-payload conjugate of any one of claims 11 to 41 and 43 to 64, wherein the linker comprises a cleavable linker, a first self-immolative unit, and a second self-immolative unit.

66. The linker-payload conjugate of claim 65, wherein the cleavable linker comprises Val-Ala.

67. The linker-payload conjugate of claim 65, wherein the cleavable linker comprises Val-Cit.

68. The linker-payload conjugate of any one of claims 65 to 67, wherein the cleavable linker comprises formula (II).

69. The linker-payload conjugate of claim 65, wherein the second self-immolative unit comprises one of the following moieties: or its isomers.

70. The linker-payload conjugate of claim 65, wherein the cleavable linker comprises Val-Ala, and wherein the second self-immolative unit comprises one of the following moieties: or its isomers.

71. The linker-payload conjugate of any one of claims 62 to 70, wherein the second self-immolative unit comprises a Unit 1 (MEC) portion.

72. The linker-payload conjugate of any one of claims 62 to 70, wherein the second self-immolative unit comprises a Unit 8 portion.

73. The linker-payload conjugate of any one of claims 62 to 70, wherein the second self-immolative unit comprises a unit II portion.

74. The linker-payload conjugate of any one of claims 62 to 70, wherein the second self-immolative unit comprises a Unit 9 portion.

75. The linker-payload conjugate of claim 70, wherein the linker comprises a Val-Ala-pABC-MEC moiety.

76. The linker-payload conjugate of claim 70, wherein the linker comprises a MC-Val-Ala-pABC-MEC moiety.

77. The linker-payload conjugate of claim 11, wherein the LD comprises LP1:

78. The linker-payload conjugate of claim 69, wherein the linker comprises a Val-Cit-pABC-MEC moiety.

79. The linker-payload conjugate of claim 69, wherein the linker comprises a MC-Val-Cit-pABC-MEC moiety.

80. The linker-payload conjugate of claim 69, wherein the LD comprises MC-Val-Cit-pABC-MEC-Compound 1.

81. The linker-payload conjugate of claim 70, wherein the linker comprises a Val-Ala-pABC-unit 8 portion.

82. The linker-payload conjugate of claim 70, wherein the linker comprises a MC-Val-Ala-pABC-unit 8 portion.

83. The linker-payload conjugate of claim 11, wherein the LD comprises LP16:

84. The linker-payload conjugate of claim 69, wherein the linker comprises a Val-Cit-pABC-unit 8 portion.

85. The linker-payload conjugate of claim 69, wherein the linker comprises a MC-Val-Cit-pABC-unit 8 portion.

86. The linker-payload conjugate of claim 69, wherein the LD comprises MC-Val-Cit-pABC-unit 8-Compound 1.

87. The linker-payload conjugate of claim 70, wherein the linker comprises a Val-Ala-pABC-unit 11 portion.

88. The linker-payload conjugate of claim 70, wherein the linker comprises a MC-Val-Ala-pABC-unit 11 portion.

89. The linker-payload conjugate of claim 11, wherein the LD comprises LP28:

90. The linker-payload conjugate of claim 69, wherein the linker comprises a Val-Cit-pABC-unit 11 portion.

91. The linker-payload conjugate of claim 69, wherein the linker comprises a MC-Val-Cit-pABC-unit 11 portion.

92. The linker-payload conjugate of claim 69, wherein the LD comprises MC-Val-Cit-pABC-unit 11-Compound 1.

93. The linker-payload conjugate of claim 70, wherein the linker comprises a Val-Ala-pABC-unit 9 portion.

94. The linker-payload conjugate of claim 70, wherein the linker comprises a MC-Val-Ala-pABC-unit 9 portion.

95. The linker-payload conjugate of claim 11, wherein the LD comprises LP20:

96. The linker-payload conjugate of claim 69, wherein the linker comprises a Val-Cit-pABC-unit 9 portion.

97. The linker-payload conjugate of claim 69, wherein the linker comprises a MC-Val-Cit-pABC-unit 9 portion.

98. The linker-payload conjugate of claim 69, wherein the LD comprises MC-Val-Cit-pABC-unit 9-Compound 1.

99. The linker-payload conjugate of claim 69, wherein the linker comprises formula (II)-Val-Cit-pABC.

100. The linker-payload conjugate of claim 69, wherein the linker comprises a moiety of formula (II)-Val-Cit-pABC-MEC.

101. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pABC-MEC moiety.

102. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pABC-MEC-Compound 1.

103. The linker-payload conjugate of claim 69, wherein the linker comprises a portion of formula (II)-Val-Cit-pABC-unit 8.

104. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 8 moiety.

105. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pABC-Unit 8-Compound 1.

106. The linker-payload conjugate of claim 69, wherein the linker comprises a moiety of formula (II)-Val-Cit-pABC-unit 11.

107. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit moiety.

108. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pABC-Unit 11-Compound 1.

109. The linker-payload conjugate of claim 69, wherein the linker comprises a portion of formula (II)-Val-Cit-pABC-unit 9.

110. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 9 moiety.

111. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pABC-Unit 9-Compound 1.

112. The linker-payload conjugate of claim 70, wherein the linker comprises formula (II)-Val-Ala-pABC.

113. The linker-payload conjugate of claim 70, wherein the linker comprises a moiety of formula (II)-Val-Ala-pABC-MEC.

114. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pABC-MEC moiety.

115. The linker-payload conjugate of claim 70, wherein the LD comprises Mal-Formula (II)-Val-Ala-pABC-MEC-Compound 1.

116. The linker-payload conjugate of claim 70, wherein the linker comprises a portion of a unit of formula (II) -Val-Ala-pABC-8.

117. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 8 moiety.

118. The linker-payload conjugate of claim 70, wherein the LD comprises Mal-Formula (II)-Val-Ala-pABC-Unit 8-Compound 1.

119. The linker-payload conjugate of claim 70, wherein the linker comprises a moiety of formula (II) -Val-Ala-pABC-unit 11.

120. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit moiety.

121. The linker-payload conjugate of claim 70, wherein the LD comprises Mal-Formula (II)-Val-Ala-pABC-Unit 11-Compound 1.

122. The linker-payload conjugate of claim 70, wherein the linker comprises a moiety of formula (II) -Val-Ala-pABC-unit 9.

123. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 9 moiety.

124. The linker-payload conjugate of claim 70, wherein the LD comprises Mal-Formula (II)-Val-Ala-pABC-Unit 9-Compound 1.

125. The linker-payload conjugate of claim 69, wherein the linker comprises Formula (II)-Val-Cit-pAB.

126. The linker-payload conjugate of claim 69, wherein the linker comprises a portion of formula (II)-Val-Cit-pAB-unit 9.

127. The linker-payload conjugate of claim 69, wherein the linker comprises Mal-Formula (II)-Val-Cit-pAB.

128. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pAB-unit 9 portion.

129. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pAB-unit 9-Compound 1.

130. The linker-payload conjugate of claim 70, wherein the linker comprises formula (II)-Val-Ala-pAB.

131. The linker-payload conjugate of claim 70, wherein the linker comprises a portion of a unit of formula (II) -Val-Ala-pAB-9.

132. The linker-payload conjugate of claim 70, wherein the linker comprises Mal-Formula (II)-Val-Ala-pAB.

133. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pAB-unit 9 portion.

134. The linker-payload conjugate of claim 11, wherein the LD comprises LP25:

135. The linker-payload conjugate of claim 69, wherein the linker comprises a portion of formula (II)-Val-Cit-pAB-unit 11.

136. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pAB-unit moiety.

137. The linker-payload conjugate of claim 69, wherein the LD comprises Mal-Formula (II)-Val-Cit-pAB-unit 11-Compound 1.

138. The linker-payload conjugate of claim 70, wherein the linker comprises a moiety of formula (II)-Val-Ala-pAB-unit 11.

139. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pAB-unit moiety.

140. The linker-payload conjugate of claim 11, wherein the LD comprises LP26:

141. An antibody-drug conjugate having formula (I): Ab-(L-D) p (I) wherein Ab is an anti-PSMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 8; LD is a linker-payload conjugate according to any one of claims 11 to 140; and p is an integer from 1 to 20.

142. The antibody-drug conjugate of claim 141, wherein p is an integer from 1 to 12, preferably wherein p is an integer from 2 to 8.

143. The antibody-drug conjugate of claim 141 or claim 142, wherein p is an integer from 2 to 4.

144. The antibody-drug conjugate of any one of claims 141 to 143, wherein the linker comprises a cleavable portion positioned such that upon cleavage, the linker or any portion of the antibody or antigen-binding fragment does not remain bound to D.

145. The antibody-drug conjugate of any one of claims 141 to 144, wherein the linker-payload conjugate is attached to the antibody or antigen-binding fragment via a MaI moiety, wherein the MaI moiety is joined to the antibody or antigen-binding fragment via a cysteine ​​residue on the antibody or antigen-binding fragment.

146. The antibody-drug conjugate of claim 145, wherein the cysteine ​​residue is located on the light chain of the antibody or antigen-binding fragment.

147. The antibody-drug conjugate of claim 145, wherein the cysteine ​​residue is located on the heavy chain of the antibody or antigen-binding fragment.

148. The antibody-drug conjugate of any one of claims 141 to 147, wherein the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence: SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising the amino acid sequence: SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system.

149. The antibody-drug conjugate of any one of claims 141 to 147, wherein the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising the amino acid sequence: SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system.

150. The antibody-drug conjugate of claim 148 or claim 149, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

19.

151. The antibody-drug conjugate of any one of claims 141 to 150, wherein LD comprises LP16, LP20, LP26, or LP28.

152. The antibody-drug conjugate of any one of claims 141 to 151, wherein the LD comprises LP16:

153. The antibody-drug conjugate of any one of claims 141 to 151, wherein the LD comprises LP20:

154. The antibody-drug conjugate of any one of claims 141 to 151, wherein the LD comprises LP26:

155. The antibody-drug conjugate of any one of claims 141 to 151, wherein the LD comprises LP28:

156. A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of claims 1 to 10, the linker-payload conjugate of any one of claims 11-140, or the antibody-drug conjugate of any one of claims 141-155, and a pharmaceutically acceptable carrier.

157. A composition comprising multiple copies of an antibody-drug conjugate having formula (I): Ab-(L-D) p (I) in Ab is an anti-PSMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 8; LD is a linker-payload conjugate according to any one of claims 11 to 140; and p is the average number of LD moieties per Ab, wherein the average p of the antibody-drug conjugates in the composition is about 2 to about 8.

158. The composition of claim 157, wherein The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the amino acid sequence of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and The LD comprises LP16:

159. The composition of claim 157, wherein The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the amino acid sequence of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and The LD comprises LP20:

160. The composition of claim 157, wherein The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the amino acid sequence of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and The LD comprises LP26:

161. The composition of claim 157, wherein The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequence of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3); and three LCDRs comprising SEQ ID NO: 32 (LCDR1), SEQ ID NO: 35 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising the amino acid sequence of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3); and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3), as defined by the IMGT numbering system; and The LD comprises LP28:

162. The composition of any one of claims 157 to 161, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

19.

163. A method of treating a patient having or at risk of developing cancer, the method comprising administering to the patient a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 10, the linker-payload conjugate of any one of claims 11 to 140, the antibody-drug conjugate of any one of claims 141 to 155, the pharmaceutical composition of claim 156, or the composition of any one of claims 157 to 162.

164. A method of reducing or inhibiting cancer growth, the method comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 10, the linker-payload conjugate of any one of claims 11 to 140, the antibody-drug conjugate of any one of claims 141 to 155, the pharmaceutical composition of claim 156, or the composition of any one of claims 157 to 162.

165. Use of the antibody or antigen-binding fragment of any one of claims 1 to 10, the linker-payload conjugate of any one of claims 11 to 140, the antibody-drug conjugate of any one of claims 141 to 155, the pharmaceutical composition of claim 156, or the composition of any one of claims 157 to 162 in the manufacture of a medicament for treating cancer.

166. Use of the antibody or antigen-binding fragment of any one of claims 1 to 10, the linker-payload conjugate of any one of claims 11 to 140, the antibody-drug conjugate of any one of claims 141 to 155, the pharmaceutical composition of claim 156, or the composition of any one of claims 157 to 162 in the treatment of cancer.

167. The method of claim 163 or claim 164, or the use of claim 165 or claim 166, wherein the cancer expresses PSMA.

168. The method of claim 163 or claim 164, or the use of claim 165 or claim 166, wherein the cancer is prostate cancer.

169. A method of producing the antibody-drug conjugate of any one of claims 141 to 155 or the composition of any one of claims 157 to 162, the method comprising reacting the antibody or antigen-binding fragment of any one of claims 1 to 8 with the linker-payload conjugate of any one of claims 11 to 140.

170. An antibody-drug conjugate produced according to the method of claim 169.

171. A method for producing an LD conjugate (V): The method comprises making the compound of claim 11 having the formula (III): or a salt thereof is reacted with an activated linker comprising a suitable linker having the structure: To produce the LD conjugate (V), where Z b It's NH.

172. The method of claim 171, wherein P b has an (S)-configuration, and the activation linker preferentially binds to Z b reaction.

173. A method for producing LD conjugate (VI): The method comprises making the compound of claim 11 having the formula (III): or a salt thereof is reacted with an activated linker comprising a suitable linker having the structure: To produce the LD conjugate (VI), where Z b It's NH.

174. The method of claim 173, wherein P b has an (S)-configuration, and the activation linker preferentially binds to Z b reaction.

175. The method of any one of claims 171 to 174, wherein the compound of formula (III) is Compound 1.

176. A linker-drug conjugate produced by the method of any one of claims 171 to 175.

177. A method of producing an antibody-drug conjugate, wherein the method comprises conjugating the antibody or antigen-binding fragment of any one of claims 1 to 8 to the LD conjugate of any one of claims 11 to 140 under conditions suitable for attachment.

178. A composition comprising the linker-payload conjugate of any one of claims 11 to 140.

179. A composition comprising a linker-payload conjugate produced according to the method of any one of claims 171 to 175.

180. The linker-payload conjugate of claim 11, wherein the linker-payload conjugate is selected from the following linker-payload conjugates: and its salts.

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