Anti-PSMA antibody, complex, and usage instructions

Abstract

For example, methods and compositions are provided for use in treating cancer. [Solution] 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 use in treating, for example, cancer, by administering the compositions provided herein.

Description

[Technical Field]

[0001]

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

[0002]

[0002] The present disclosure relates to anti-PSMA antibodies and antigen-binding fragments thereof, as well as antibody-drug conjugates (ADCs), such as conjugates including STING agonists, and their use in the treatment and diagnosis of cancers that express PSMA and / or are suitable for treatment by modulating STING pathway activity or by administering the compositions disclosed herein. [Background technology]

[0003]

[0003] Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in men. Currently, treatment options for metastatic prostate cancer are limited, and such cases have a poor prognosis, so there is a need to develop more effective treatments.

[0004]

[0004] Prostate-specific membrane antigen (PSMA) is a cell surface antigen highly expressed in prostate cancer. PSMA expression levels increase with the progression of prostate cancer, and high PSMA expression is maintained at metastatic sites. Anti-PSMA antibodies, including modified antibodies with reduced immunogenicity in humans, have been generated. See, for example, U.S. Patent Nos. 7,045,605 and 11,059,903. Examples of antibodies that bind to PSMA include J591 and deimmunized J591 (deJ591). The amino acid sequence of the heavy chain variable domain of the deJ591 antibody is provided herein as SEQ ID NO: 40, and the corresponding light chain variable domain is provided herein as SEQ ID NO: 41. However, clinical trials using this antibody have shown undesirable immunogenic effects, including bone marrow suppression and liver enzyme abnormalities. See, for example, 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]

[0005] Given the high expression of PSMA in prostate cancer, it can be used as a target for tumor antigen-specific drug delivery approaches, such as antibody-mediated approaches. Antibodies conjugated with cytotoxic compounds, such as chemotherapeutic agents, have also been investigated to enhance the cell-killing activity of antibody-based drug delivery to tumor cells. Nevertheless, there remains a need to provide suitable antibodies and / or ADCs that provide a combination of efficient prostate tumor targeting, on-target effect, and / or reduced off-target effect.

[0006]

[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-β (IFN-β), tumor necrosis factor alpha (TNFα), C-X-C motif chemokine ligand 10 (CXCL10), interleukin-6 (IL-6)), which in turn mediate innate immune responses to infection or disease, such as cancer. STING signaling has been shown to have antitumor effects, such as modulating the vasculature and enhancing adaptive immunity. First-generation STING agonists, such as cyclic dinucleotides, often require intratumoral injection and exhibit only modest systemic effects. These STING agonists also have poor membrane permeability, which may limit their ability to engage STING within cells.

[0007]

[0007] While the use of STING agonists to treat infections or diseases has been reported in the art, there remains an unmet need for a delivery system that allows for systemic administration of STING agonists that specifically target tumor sites. Similarly, there remains a need in the art for improved antibodies that bind to PSMA that have superior properties, e.g., with respect to antigen binding and / or the ability to effectively deliver a payload, e.g., a STING agonist, to target cells or tissues that express PSMA. Summary of the Invention

[0008] In various embodiments, the present disclosure provides, in part, novel antibodies and antigen-binding fragments that can specifically bind to PSMA and that can be used alone or linked to one or more additional agents (e.g., as ADCs) 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 mammals and can be useful for treating human cancer patients.

[0009]

[0009] More specifically, the present disclosure relates to antibody and antibody-drug conjugate compounds that, in various embodiments, can bind to and / or kill PSMA-expressing cells. In various embodiments, the compounds can also be internalized into target PSMA-expressing cells after binding. Anti-PSMA-ADC compounds are disclosed that include a linker connecting a STING agonist moiety, such as a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1, to the anti-PSMA antibody moiety. 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, the antibody or antigen-binding fragment having (i) three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising SEQ ID NO:32 (LCDR1), SEQ ID NO:35 (LCDR2), and SEQ ID NO:37 (LCDR3); or (ii) three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (LCDR3), as defined by the Kabat numbering system. , 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); or (iii) three HCDRs comprising the amino acid sequences of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3) as defined by the IMGT numbering system; and three LCDRs comprising SEQ ID NO: 38 (LCDR1), SEQ ID NO: 39 (LCDR2), and SEQ ID NO: 37 (LCDR3).

[0011]

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

[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 IgG1 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 a melting 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 conjugated to at least one linker. In some embodiments, at least one linker is cleavable. In some embodiments, at least one linker is conjugated to a cytotoxic agent or a detectable reagent.

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

[0017] In various embodiments, the present disclosure provides a linker-payload conjugate comprising LD, where L is a linker covalently attached to D, and D has the following formula: [ka] a compound, an isomer thereof, a deuterated derivative of the compound or isomer; or a salt of the compound, isomer or deuterated derivative; wherein, independently for each occurrence: P a and P b are independently selected from (R) and (S) stereochemistry when not racemic; Q a and Q b each of which is independently selected from NH and O; ·V a and V b each of which is independently selected from F and OH; W is selected from H and NH2; X a and X b each of which is independently selected from OH and SH; Y a and Y b are independently selected from O and S; ·Each Z a and Z b is independently selected from CH, O, and NH; and · [ka] indicates that the bond is a single bond ( [ka] ), a double bond in the (E) or (Z) configuration ( [ka] ), or triple bond ( [ka] ) means that (However, Z a and Z b At least one of X is NH, or a and X b at least one of which is SH).

[0018] 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 is O. In some embodiments, V a and V bis OH. In some embodiments, V a and V b In some embodiments, W is H. In some embodiments, Z a and Z b In some embodiments, at least one of Z a and Z b is NH. In some embodiments, [ka] is a double bond in the (E) or (Z) configuration ( [ka] In some embodiments, the crosslinked [ka] is the structure [ka] In some embodiments, Y a and Y b At least one of Y is O. In some embodiments, Y a and Y b is O. In some embodiments, X a and X b In some embodiments, at least one of X is SH. a and X b is SH. In some embodiments, D comprises a compound of formula (III).

[0019] In some embodiments, D comprises a compound of formula (III) selected from: [ka] [ka] and salts thereof.

[0020] In some embodiments, D comprises a compound of formula (III) selected from: [ka] and salts thereof.

[0021] In some embodiments, D comprises Compound 1.

[0022] In some embodiments, D comprises compound 2.

[0023] In some embodiments, X a and X b At least one of X is SH, and L is attached to D through a sulfur atom at S-2 sulfur or S-14 sulfur. b is SH and L is attached to D at the S-2 sulfur. a is SH, and L is attached to D at the S-14 sulfur.

[0024] In some embodiments, Z a and Z b and L is attached to D through the nitrogen atom at the N-34 nitrogen or the N-39 nitrogen. b is NH and L is attached to D at the N-34 nitrogen. a is NH, and L is attached to D at the N-39 nitrogen.

[0025] In some embodiments, L is a cleavable linker. In some embodiments, the cleavable linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety is cleavable by a protease, and optionally the protease is a cathepsin or legumain. 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 (SEQ ID NO: 141), Glu-Val-Ala, or Gly-Val-Ala.

[0026] In some embodiments, the cleavable linker comprises Val-Cit. In some embodiments, the cleavable linker comprises Val-Ala. In some embodiments, the linker comprises a maleimide (Mal) moiety. In some embodiments, the Mal moiety comprises 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.

[0027] In some embodiments, the linker further comprises at least one spacer unit. In some embodiments, the at least one spacer unit comprises at least one polyethylene glycol (PEG) moiety. In some embodiments, the at least one PEG moiety is -(PEG) m -, wherein 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.

[0028] In some embodiments, at least one spacer unit is [ka] In some embodiments, at least one spacer unit comprises: [ka] Contains formula (II).

[0029] 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, the linker can be removed from D after cleavage of the linker by self-immolation of the first self-immolative unit. In some embodiments, the first self-immolative unit comprises p-aminobenzyl (pAB) optionally substituted with 1 to 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.

[0030] In some embodiments, the first self-immolative unit comprises p-aminobenzyloxycarbonyl (pABC).

[0031] In some embodiments, the linker further comprises a second self-immolative unit. In some embodiments, the linker can be removed from D after being cleaved by the self-immolation of the first self-immolative unit and / or the self-immolation of the second self-immolative unit. In some embodiments, the linker is removed from D after being cleaved stepwise by the self-immolation of the first self-immolative unit and then the self-immolation of the second self-immolative unit. In some embodiments, the linker comprises a cleavable linker, a first self-immolative unit, and a second self-immolative unit.

[0032] 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).

[0033] In some embodiments, the second self-immolative unit comprises one of the following moieties or an isomer thereof:

[0034] [Table 1]

[0035] [Table 2]

[0036] In some embodiments, the cleavable linker comprises Val-Ala and the second self-immolative unit comprises one of the following moieties or an isomer thereof:

[0037] [Table 3]

[0038] [Table 4]

[0039] In some embodiments, the second self-immolative unit comprises a unit 1 (MEC) portion. In some embodiments, the second self-immolative unit comprises a unit 8 portion. In some embodiments, the second self-immolative unit comprises a unit 11 portion. In some embodiments, the second self-immolative unit comprises a unit 9 portion.

[0040] 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.

[0041] In some embodiments, the LD is LP1: [ka] Includes:

[0042] In some embodiments, the linker comprises a Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises a MC-Val-pABC-MEC moiety. In some embodiments, MC-Val-Cit-pABC-MEC-Compound 1.

[0043] 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.

[0044] In some embodiments, the LD is LP16: [ka] Includes:

[0045] 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, LD comprises MC-Val-Cit-pABC-unit 8-compound 1.

[0046] 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.

[0047] In some embodiments, the LD is LP28: [ka] Includes:

[0048] 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, LD comprises MC-Val-Cit-pABC-unit 11-compound 1.

[0049] In some embodiments, the linker comprises a Val-Ala-pABC-unit moiety. In some embodiments, the linker comprises a MC-Val-Ala-pABC-unit 9 moiety.

[0050] In some embodiments, the LD is LP20: [ka] Includes:

[0051] 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, LD comprises MC-Val-Cit-pABC-unit 9-compound 1.

[0052] In some embodiments, the linker comprises a Formula (II)-Val-Cit-pABC. In some embodiments, the linker comprises a Formula (II)-Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-MEC moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Cit-pABC-MEC-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Cit-pABC-unit 8 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 8 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Cit-pABC-unit 8-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Cit-pABC-unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 11 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Cit-pABC-unit 11-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 9 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Cit-pABC-unit 9 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Cit-pABC-unit 9-compound 1.

[0053] In some embodiments, the linker comprises a Formula (II)-Val-Ala-pABC. In some embodiments, the linker comprises a Formula (II)-Val-Ala-pABC-MEC moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-MEC moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Ala-pABC-MEC-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Ala-pABC-unit 8 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 8 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Ala-pABC-unit 8-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Ala-pABC-unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 11 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Ala-pABC-unit 11-compound 1. In some embodiments, the linker comprises a Formula (II)-Val-Ala-pABC-unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 9 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Ala-pABC-unit 9 moiety. In some embodiments, LD comprises a Mal-Formula (II)-Val-Ala-pABC-unit 9-compound 1.

[0054] In some embodiments, the linker comprises a Formula (II)-Val-Cit-pAB. In some embodiments, the linker comprises a Formula (II)-Val-Cit-pAB-unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pAB. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pAB-unit 9 moiety. In some embodiments, LD comprises Mal-Formula (II)-Val-Cit-pAB-unit 9-compound 1.

[0055] In some embodiments, the linker comprises a Formula (II)-Val-Ala-pAB. In some embodiments, the linker comprises a Formula (II)-Val-Ala-pAB-unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pAB. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pAB-unit 9 moiety.

[0056] In some embodiments, the LD is LP25: [ka] Includes:

[0057] In some embodiments, the linker comprises a Formula (II)-Val-Cit-pAB-unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pAB-unit 11 moiety. In some embodiments, LD comprises Mal-Formula (II)-Val-Cit-pAB-unit 11-compound 1.

[0058] In some embodiments, the linker comprises a Formula (II)-Val-Ala-pAB-unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pAB-unit 11 moiety.

[0059] In some embodiments, the LD is LP26: [ka] Includes:

[0060] In various embodiments, the present disclosure provides a compound of formula (I): Ab-(LD)p (I) where Ab is an anti-PSMA antibody or antigen-binding fragment thereof disclosed herein; LD is a linker-payload conjugate disclosed herein; and p is an integer from 1 to 20. The present invention provides an antibody-drug conjugate of the formula:

[0061] 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.

[0062] In some embodiments, the cleavable linker comprises a cleavable moiety that is positioned such that upon cleavage, neither the linker nor any part of the antibody or antigen-binding fragment remains bound to D.

[0063] In some embodiments, the linker-payload conjugate is attached to the antibody or antigen-binding fragment via a Mal moiety. In some embodiments, the Mal moiety is attached to the antibody or antigen-binding fragment via a cysteine ​​residue in the antibody or antigen-binding fragment. In some embodiments, the cysteine ​​residue is in the light chain of the antibody or antigen-binding fragment. In some embodiments, the cysteine ​​residue is in the heavy chain of the antibody or antigen-binding fragment.

[0064]

[0060] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs having the amino acid sequences of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2), and SEQ ID NO: 27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs having the amino acid sequences of SEQ ID NO: 32 (LCDR1), SEQ ID NO: 34 (LCDR2), and SEQ ID NO: 36 (LCDR3).

[0065]

[0061] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs having the amino acid sequences of SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), and SEQ ID NO: 30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs having the amino acid sequences of SEQ ID NO: 37 (LCDR1), SEQ ID NO: 38 (LCDR2), and SEQ ID NO: 36 (LCDR3).

[0066]

[0062] 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.

[0067] In some embodiments, the LD comprises LP16, LP20, LP26, or LP28.

[0068] In some embodiments, the LD is LP16: [ka] Includes:

[0069] In some embodiments, the LD is LP20: [ka] Includes:

[0070] In some embodiments, the LD is LP26: [ka] Includes:

[0071] In some embodiments, the LD is LP28: [ka] Includes:

[0072]

[0068] In various embodiments, the present disclosure provides a pharmaceutical formulation comprising an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate disclosed herein and a pharmaceutically acceptable carrier.

[0073] In various embodiments, the present disclosure provides a compound of formula (I): Ab-(LD)p (I) (In the formula, Ab is an anti-PSMA antibody or antigen-binding fragment disclosed herein; LD is a linker-payload conjugate disclosed herein; p is the average number of LD moieties per Ab, and the average p of the antibody-drug conjugates in the composition is about 2 to about 8. The present invention provides a composition comprising multiple copies of an antibody-drug conjugate of the present invention.

[0074]

[0070] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); LD is LP16: [ka] Includes:

[0075]

[0071] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); LD is LP20: [ka] Includes:

[0076]

[0072] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); LD is LP26: [ka] Includes:

[0077]

[0073] In some embodiments, the antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); LD is LP28: [ka] Includes:

[0078]

[0074] 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.

[0079] In various embodiments, the present disclosure provides methods of treating a patient having or at risk of having cancer, the method comprising administering to the patient a therapeutically effective amount of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate disclosed herein. In various embodiments, the present disclosure provides methods of reducing or inhibiting cancer growth, the method comprising administering a therapeutically effective amount of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate disclosed herein. In some embodiments, the cancer expresses PSMA. In some embodiments, the cancer is prostate cancer.

[0080] In various embodiments, the present disclosure provides for the use of an anti-PSMA ADC, antibody, antigen-binding fragment thereof, or linker-payload conjugate disclosed herein in the treatment of cancer. In some embodiments, the cancer expresses PSMA. In some embodiments, the cancer is prostate cancer.

[0081] In various embodiments, the present disclosure provides methods of making an anti-PSMA ADC, the method comprising reacting an antibody or antigen-binding fragment thereof disclosed herein with a linker-payload conjugate disclosed herein. In various embodiments, the present disclosure provides methods of making an antibody-drug conjugate, the method comprising conjugating an antibody or antigen-binding fragment disclosed herein with a linker-payload conjugate disclosed herein under conditions suitable for conjugation.

[0082] In various embodiments, the present disclosure provides an LD complex (V): [ka] The method of producing a compound of formula (III) disclosed herein: [ka] or a salt thereof, having the following structure: [ka] to form the LD complex (V) (In the formula, Z b is NH) The method includes generating

[0083] In some embodiments, P b has the (S) configuration and the activated linker is Z bIn some embodiments, the compound of formula (III) is compound 1.

[0084] In various embodiments, the present disclosure provides an LD complex (VI): [ka] The method of producing a compound of formula (III) disclosed herein: [ka] or a salt thereof, having the following structure: [ka] and reacting with an activated linker, including a suitable linker having the formula LD complex (VI) (In the formula, Z b is NH) The method includes generating

[0085] In some embodiments, P b has the (S) configuration and the activated linker is Z b In some embodiments, the compound of formula (III) is compound 1.

[0086] In various embodiments, the present disclosure provides compositions comprising a linker-payload conjugate disclosed herein. In some embodiments, the present disclosure provides compositions comprising a linker-payload conjugate produced according to the methods disclosed herein. [Brief explanation of the drawings]

[0087] [Figure 1-1] Alignment of J591 VH and VL with human germline sequences is shown, with underlined residues being human-specific and lowercase residues being mouse-specific. [Figure 1-2] Alignment of J591 VH and VL with human germline sequences is shown, with underlined residues being human-specific and lowercase residues being mouse-specific. [Figure 2] Figure 1 shows an in silico model of J591 Fv generated using BioLuminate software. CDR residues are shown as space-fills, and framework residues adjacent to the CDRs that differ between mouse and HCzu1-Lczu1 are shown as ball-and-stick figures. Residue numbering is according to Kabat. [Figure 3] Figure 1 shows similar PSMA binding of humanized heavy chain (HC) variants 1-10 paired with Lczu1. Hczu1-10 were paired with LCzu1 and analyzed for binding to PSMA by ELISA. [Figure 4-1] This shows the superhumanization of J591. The resulting PSMA antibody has strong binding affinity. The binding of the humanized J591 variants to PSMA was analyzed by ELISA. [Figure 4-2] This shows the superhumanization of J591. The resulting PSMA antibody has strong binding affinity. The binding of the humanized J591 variants to PSMA was analyzed by ELISA. [Figure 5A] 1 shows the thermal stability of deJ591. [Figure 5B] 1 shows the thermal stability of humanized J591 variants HC1-LC1, HC2-LC1, HC3-LC1, HC14-LC1, and HC14-LC5 compared to deJ591. [Figure 5C] 1 shows the thermal stability of the HC14-LC5 (H14L5) IgG1 antibody engineered to contain site-specific binding residues compared to deJ591 and J591. [Figure 6A] 1 shows the immunogenicity prediction scores of 9-mer peptide sequences of the heavy chain variable domain of J591. [Figure 6B] 1 shows the immunogenicity prediction scores of the 9-mer peptide sequences of the heavy chain variable domain of deJ591. [Figure 6C]1 shows the immunogenicity prediction scores of the 9-mer peptide sequences of the heavy chain variable domain of zuJ591-H14. [Figure 7A] 1 shows the immunogenicity prediction scores of the 9-mer peptide sequences of the light chain variable domain of J591. [Figure 7B] 1 shows the immunogenicity prediction scores of the 9-mer peptide sequence of the light chain variable domain of deJ591. [Figure 7C] 1 shows the immunogenicity prediction scores of the 9-mer peptide sequences of the light chain variable domain of zuJ591-L5. [Figure 8] 1 shows anti-PSMA specific binding to PSMA-expressing LNCaP cells. [Figure 9] PSMA-dependent ADCP activity assessed by flow cytometry is shown. The percentage of macrophages that engulfed at least one target cell is shown. [Figure 10] 1 shows the target cell dependence of anti-PSMA ADC internalization as measured by flow cytometry. [Figure 11] 1 shows ADCP-dependent IFNβ production by anti-PSMA ADC treatment. [Figure 12] 1 shows ADCP-dependent myeloid cell activation by anti-PSMA ADC treatment. [Figure 13] 1 shows the anti-tumor activity of anti-PSMA ADCs in vivo in a PSMA-positive LNCaP xenograft model. [Figure 14A] 1 shows a heatmap of type 1 interferon gene expression 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). [Figure 14B] 1 shows that treatment with anti-PSMA-LP3 ADCs modulated cytokines specific to the STING pathway. [Figure 14C] 1 shows the shift in macrophage polarization from M2 to M1 in the tumor microenvironment upon treatment with anti-PSMA-LP3 ADC. [Figure 15A]Tumor volume (left) and percent body weight change (right) are shown in castrated mice xenografted with human prostate cancer 22RV1 upon treatment with anti-PSMA antibody or anti-PSMA ADC. [Figure 15B] Tumor volume (left) and percent body weight change (right) in human prostate cancer 22RV1 xenografted mice (non-castrated) upon treatment with anti-PSMA antibody or anti-PSMA ADC. Sp = S-thiophosphate linker attachment point on compound 1; Rp = R-thiophosphate linker attachment point on compound 1. [Figure 16A] 1 shows a model of in vivo efficacy of anti-PSMA ADCs in a 22RV1 xenograft model. [Figure 16B] Shown are concentrations of murine TNFα (left) or IFNβ (right) in plasma 6 hours after injection of anti-PSMA ADC. [Figure 17] The percent change in DAR of anti-PSMA ADCs is shown. [Figure 18A] The time course of DAR is shown for the S-linked linker. [Figure 18B] The time course of DAR is shown for the S-linked linker. [Figure 18C] The time course of DAR is shown for the S-linked linker. [Figure 19A] Free compound 1 over time is shown for the S-linked linker. [Figure 19B] Free compound 1 over time is shown for the S-linked linker. [Figure 19C] Free compound 1 over time is shown for the S-linked linker. [Figure 20A] Percent monomer over time is shown for the S-linked linker. [Figure 20B] Percent monomer over time is shown for the S-linked linker. [Figure 20C] Percent monomer over time is shown for the S-linked linker. [Figure 21A] The time course of DAR is shown for N-linked linkers. [Figure 21B]The time course of DAR is shown for N-linked linkers. [Figure 21C] The time course of DAR is shown for N-linked linkers. [Figure 21D] The time course of DAR is shown for N-linked linkers. [Figure 21E] The time course of DAR is shown for N-linked linkers. [Figure 21F] The time course of DAR is shown for N-linked linkers. [Figure 21G] The time course of DAR is shown for N-linked linkers. [Figure 22A] Free Compound 1 over time is shown for the N-linked linker. [Figure 22B] Free Compound 1 over time is shown for the N-linked linker. [Figure 22C] Free Compound 1 over time is shown for the N-linked linker. [Figure 22D] Free Compound 1 over time is shown for the N-linked linker. [Figure 22E] Free Compound 1 over time is shown for the N-linked linker. [Figure 22F] Free Compound 1 over time is shown for the N-linked linker. [Figure 22G] Free Compound 1 over time is shown for the N-linked linker. [Figure 23A] Percent monomer over time is shown for N-linked linkers. [Figure 23B] Percent monomer over time is shown for N-linked linkers. [Figure 23C] Percent monomer over time is shown for N-linked linkers. [Figure 23D] Percent monomer over time is shown for N-linked linkers. [Figure 23E] Percent monomer over time is shown for N-linked linkers. [Figure 23F]Percent monomer over time is shown for N-linked linkers. [Figure 23G] Percent monomer over time is shown for N-linked linkers. [Figure 24A] 1 shows the release rate of Compound 1 from the anti-PSMA ADC in mouse plasma over time. [Figure 24B] 1 shows the mean DAR of anti-PSMA ADCs in mouse plasma over time. [Figure 24C] Shown is the percent change from the starting DAR of the anti-PSMA ADC in mouse plasma. [Figure 24D] Free Compound 1 in mouse plasma over time. [Figure 25] 1 shows the mouse plasma stability of the S-linked anti-PSMA Compound 1 ADC. [Figure 26] The structure of Compound 1 and the monophosphate form of Compound 1 are shown. [Figure 27A] The mean DAR of anti-PSMA ADC LP3 (Random DAR4 and RESPECT-L DAR4) is shown. [Figure 27B] 1 shows the metabolism of anti-PSMA ADC LP3 Random DAR4. [Figure 27C] 1 shows the metabolism of the anti-PSMA ADC LP3 RESPECT-L DAR4. [Figure 28A] 1 shows the stability of N-linked anti-PSMA ADCs in mouse plasma over 10 days of treatment. [Figure 28B] 1 shows the stability of N-linked anti-PSMA ADCs in mouse plasma on day 7. [Figure 29] 1 shows the DAR of N-linked anti-PSMA Compound 1 ADC in mouse plasma on days 7 / 10. [Figure 30] 1 shows hIFN-β production in C4-2 / THP1 co-cultures upon treatment with anti-PSMA ADCs. [Figure 31] 31 shows the mean tumor volume and percent weight loss in xenograft tumors treated with anti-PSMA ADCs. [Figure 32]1 shows the anti-tumor activity of anti-PSMA-LP ADCs in the 22Rv1 xenograft model (cohort 1). Mean tumor growth and mean body weight change are shown. [Figure 33-1] 33 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 1). n=3; each dot represents an individual value. Data are presented as mean±SEM. [Figure 33-2] 33 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 1). n=3; each dot represents an individual value. Data are presented as mean±SEM. [Figure 34] 1 shows the anti-tumor activity of anti-PSMA-LP ADCs in the 22Rv1 xenograft model (cohort 1). Mean tumor growth and mean body weight change are shown. [Figure 35-1]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 1). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 35-2]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 1). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 36] 1 shows the anti-tumor activity of anti-PSMA-LP ADCs in the 22Rv1 xenograft model (cohort 3). Mean tumor growth and mean body weight change are shown. [Figure 37-1]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 3). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 37-2]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 3). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 38] 1 shows the anti-tumor activity of anti-PSMA-LP ADCs in a C4-2 xenograft model, with mean tumor growth and mean body weight change shown. [Figure 39-1]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 3). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 39-2]

[0023] Figure 1 shows serum cytokine analysis of PSMA-LP ADC in the 22Rv1 xenograft model (cohort 3). n=3; each dot represents an individual value. Data are presented as mean ± SEM. [Figure 40] Pharmacokinetics of anti-PSMA LP3 ADC (random DAR4) in normal mice at an IV dose of 1 mpk. [Figure 41] Pharmacokinetics of anti-PSMA LP3 ADC (RESPECT-L DAR2) in C4-2 tumor-bearing mice at IV doses of 3 and 9 mg / kg. [Figure 42] 1 shows levels of Compound 1 in plasma from C4-2 tumor-bearing mice administered anti-PSMA LP 3 ADC (RESPECT-L DAR2) or anti-PSMA LP1 ADC (RESPECT-L DAR4). [Figure 43] 1 shows intratumor 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). [Figure 44] 1 shows tumor PK parameters in C4-2 tumor-bearing mice administered anti-PSMA LP3 ADC (RESPECT-L DAR2) and anti-PSMA LP1 ADC (RESPECT-L DAR4). [Figure 45] Figure 1 shows the scheme of the two-stage payload release assay, with LP2 shown as an example. [Figure 46-1] Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA S-conjugated ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. [Figure 46-2]Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA S-conjugated ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. [Figure 47-1] Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA N-linked ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. [Figure 47-2] Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA N-linked ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. [Figure 47-3] Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA N-linked ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. [Figure 47-4] Figure 1 shows in vitro IFN-β release after treatment with anti-PSMA N-linked ADCs. Panels labeled A (left column) show IFN-β release from THP-1 monocultures, and panels labeled B (right column) show IFN-β release from C4-2 and THP-1 cocultures. DETAILED DESCRIPTION OF THE INVENTION

[0088] [Detailed explanation]

[0130] The compositions and methods of the present disclosure may 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.

[0089]

[0131] Throughout this specification, descriptions refer to compositions and methods of using said compositions. Where the present disclosure describes or claims features or embodiments relating to compositions, such features or embodiments are equally applicable to methods of using said compositions. Similarly, where the present disclosure describes or claims features or embodiments relating to methods of using a composition, such features or embodiments are equally applicable to compositions.

[0090]

[0132] When a range of values ​​is expressed, it includes embodiments using any specific value within that range. Moreover, reference to values ​​stated in ranges includes each and every value within that range. All ranges are inclusive of their endpoints and are combinable. When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise.

[0091]

[0133] All references cited herein are incorporated by reference for any purpose. In the event of a conflict between a reference and the specification, the specification will control.

[0092]

[0134] It is also understood that certain features of the disclosed compositions and methods, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0093] [Definition]

[0135] Throughout this specification and claims, various terms relating to the description of aspects are used. Such terms should be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0094]

[0136] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0095]

[0137] The term "about" or "approximately" in the context of numerical values ​​and ranges refers to a value or range that is close to or near the stated value or range such that the embodiment can function as intended, such as having a desired amount of nucleic acid or polypeptide in a reaction mixture, as would be apparent to one of ordinary skill in the art from the teachings contained herein. In some embodiments, "about" means plus or minus 10% of the numerical amount.

[0096]

[0138] The term "agent" is used herein to refer to a chemical compound, a mixture of compounds, a biological macromolecule, or an extract made from biological material. The terms "therapeutic agent," "drug," or "drug moiety" refer to an agent that can modulate a biological process and / or has biological activity.

[0097]

[0139] As used herein, the terms "aliphatic" or "aliphatic group" refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or 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 to 4 aliphatic carbon atoms.

[0098]

[0140] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. The terms "room temperature" and "ambient temperature" refer to temperatures between 15°C and 30°C.

[0099]

[0141] "Antibody drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to a compound or derivative thereof that is linked to an antibody (e.g., an anti-PSMA antibody) and can be defined by the general formula: Ab-(LD)p (Formula I), where 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. In some embodiments, the linker 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 the antibody or antigen-binding fragment and the therapeutic compound, e.g., by a spacer unit. Exemplary cleavable linkers are described and exemplified herein.

[0100]

[0142] The term "antibody" is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination thereof, via at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain (HC) of an antibody is composed of a heavy chain variable domain (VH) and a heavy chain constant region (CH). The light chain (LC) is composed of a light chain variable domain (VL) and a light chain constant domain (CL). As used herein, the terms "domain" and "region" may be used interchangeably (e.g., the term "variable domain" may be used interchangeably with the term "variable region" and are understood to refer to the same portion of an antibody). For the purposes of this application, mature heavy and light chain variable domains each comprise three complementarity determining regions (CDR1, CDR2, and CDR3; also called "hypervariable regions") within four framework regions (FR1, FR2, FR3, and FR4) arranged from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs may be identified according to the Kabat and / or IMGT numbering systems (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991); International ImMunoGene Tics Information System (IMGT®)). An "antibody" may be naturally occurring, such as monoclonal antibodies produced by conventional hybridoma technology, or artificially created. The term "antibody" includes full-length monoclonal and polyclonal antibodies, as well as antibody fragments such as Fab, Fab', F(ab')2, Fv, and single-chain antibodies. Antibodies may be any one of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or their subclasses (e.g., isotypes IgG1, IgG2, IgG3, IgG4).Antibodies of any of the foregoing classes or subclasses may also comprise one of two functionally similar classes of light chain: Igκ (also referred to herein as "Igkappa" or "κ") and Igλ (also referred to herein as "Iglamda" or "lambda"). The term "antibody" encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule containing an antigen recognition site, so long as it exhibits the desired biological activity.

[0101]

[0143] The term "chimeric antibody," as used herein, refers to an antibody in which the amino acid sequences of the immunoglobulin molecules 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 the immune response in the latter species.

[0102]

[0144] 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.

[0103]

[0145] As used herein, the term "humanized antibody" refers to forms of antibodies containing sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies containing minimal sequence derived from non-human immunoglobulin. Generally, a humanized antibody comprises 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. A humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Humanized antibodies can be further modified by substituting residues within the Fv framework regions and / or substituted non-human residues to refine and optimize antibody specificity, affinity, and / or activity. Humanized antibodies can also be further modified by substituting residues in the Fc domain to reduce their binding to various cellular receptors, such as Fcγ receptors (FcγRs) and other immune molecules.

[0104]

[0146] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies. That is, the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods. See, e.g., U.S. Pat. No. 4,816,567. Monoclonal antibodies may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J. Mol. Biol. 222:581-97.

[0105]

[0147] The monoclonal antibodies described herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies 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.

[0106]

[0148] The terms "antigen-binding fragment" or "antigen-binding portion" of an antibody, as used herein, refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PSMA). Antigen-binding fragments also preferably retain the ability to be internalized by antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immune effector activity. It has been shown that fragments of full-length antibodies can perform the antigen-binding function of the full-length antibody. Examples of binding fragments encompassed by 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 CH1 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 CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment comprising 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) isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be recombinantly produced as a single protein chain that allows the VL and VH regions to pair to form a monovalent molecule (known as a 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 by the term "antigen-binding fragment" or "antigen-binding portion" of an antibody, and are known in the art as an exemplary type of binding fragment that can be internalized within cells upon binding.See, for example, 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 the VH and VL domains are expressed on a single polypeptide chain but use a linker that is too short to allow pairing between the two domains on the same chain, forcing the domains to pair with complementary domains on 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 the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared, for example, by cleavage of the intact protein, for example, by protease or chemical cleavage.

[0107]

[0149] The terms "anti-PSMA antibody" or "antibody that specifically binds to PSMA" refer to any form of antibody or fragment thereof that specifically binds to PSMA, including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments so long as they specifically bind to 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 bind," and "bind specifically" refer to the selective binding of an antibody to a target antigen or epitope over another antigen or epitope. Antibodies can be tested for binding specificity by comparing binding to the appropriate antigen with binding to an unrelated antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to the appropriate antigen with at least 2-fold, or preferably at least 50-fold, at least 100-fold, or at least 1000-fold greater affinity than an unrelated antigen or mixture of antigens, as measured, for example, by surface plasmon resonance, e.g., BIAcore® analysis. In one embodiment, a specific antibody binds to the PSMA antigen but does not bind (or shows minimal binding to) other antigens.

[0108]

[0150] The term "aryl" refers to a group or substituent derived from an aromatic ring, and includes monocyclic aromatic rings, as well as bicyclic, tricyclic, and fused ring systems having a total of 6 to 14 ring members, wherein at least one ring in the system is aromatic. Aryl groups may be substituted with one or more substituents.

[0109]

[0151] The term "heteroaryl" refers to a cyclic group that contains at least one ring atom that is a heteroatom such as O, N, or S. Heteroaryl groups include monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 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 each ring in the system contains 3 to 7 ring members.

[0110]

[0152] The term "at least one" refers to one or more.

[0111]

[0153] The term "bridge" refers to the group of atoms in a macrocyclic bridged STING agonist compound of the present disclosure that spans from a first nucleobase in the macrocyclic bridged STING agonist compound to a second nucleobase in the macrocyclic bridged STING agonist compound.

[0112]

[0154] The term "cancer" refers to the 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 specific examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, bile duct cancer (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, uterine cancer, ovarian cancer, salivary gland cancer, 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 cancer.

[0113]

[0155] The terms "cancer cell" and "tumor cell" refer to individual cells or the total population of cells derived from a tumor, including both non-tumorigenic cells and cancer stem cells. As used herein, the term "tumor cell" is modified by the term "non-tumorigenic" when referring only to tumor cells that lack the ability to reproduce and differentiate, which distinguishes tumor cells from cancer stem cells.

[0114]

[0156] The terms "tumor" and "neoplasm" refer to any mass of tissue resulting from excessive cell growth or proliferation, either benign or malignant, including pre-cancerous lesions.

[0115]

[0157] The terms "chemotherapeutic agent" or "anti-cancer agent" are used herein to refer to compounds effective in treating cancer, regardless of mechanism of action. Inhibition of metastasis or angiogenesis is often a hallmark of chemotherapeutic agents. Stimulation of an anti-tumor immune response may also be a hallmark of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include stimulatory agents, such as STING agonists. Additionally, chemotherapeutic agents include antibodies, biological molecules, and small molecules. Chemotherapeutic agents may be cytotoxic or cytostatic agents.

[0116]

[0158] The term "cytotoxic agent" refers to a substance that causes cell death by interfering with the expression activity and / or function of a cell or by stimulating a response that causes cell death, such as an immune response. Examples of cytotoxic agents include, but are not limited to, STING agonists, such as Compound 1.

[0117]

[0159] An "effective amount" of an ADC disclosed herein is an amount sufficient to carry out a specifically stated purpose, e.g., an amount sufficient to produce a therapeutic effect after administration, such as a reduction in tumor growth rate or tumor volume, a reduction in cancer symptoms, or some other indication of therapeutic effectiveness. The effective amount can be determined by routine methods related to the stated purpose. The term "therapeutically effective amount" refers to an amount of an ADC effective to treat a disease or disorder of interest. 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 alleviate one or more symptoms. A "prophylactically effective amount" refers to an amount effective, in terms of dosage and duration required, to achieve the desired prophylactic result. Typically, because a prophylactic dose is used in patients before they suffer from or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0118]

[0160] The term "epitope" refers to the portion of an antigen that is recognized and specifically bound by an antibody. When the antigen is a polypeptide, the epitope can be formed from consecutive or non-contiguous amino acids juxtaposed by tertiary folding of the polypeptide. The epitope bound by an antibody can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, monitoring antibody binding to fragments or mutated variants of the antigen, or monitoring the solvent accessibility of different portions of the antibody and antigen. Exemplary strategies used to map antibody epitopes 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.

[0119]

[0161] The term "Compound 1," as used herein, refers to the structure of Compound 1, as shown below, or a salt thereof: [ka] Refers to...

[0120]

[0162] Compound 1 is a macrocyclic bridged STING agonist (MBSA) with a locked, biologically active U-shaped structure of a cyclic dinucleotide containing a transannular macrocyclic bridge between the nucleobases. As used herein, "Compound 1" can include salts of Compound 1, such as the diammonium salt and / or sodium salt of Compound 1. The terms "Compound 1 moiety," "E7766," "E7766 agonist moiety," or "E7766 moiety" refer to a component of an ADC having the structure of Compound 1 and attached to a linker of the ADC, e.g., via the N-34 nitrogen, N-39 nitrogen, S-2 sulfur, or S-14 sulfur of the Compound 1 moiety. Compositions and methods for inhibiting tumor growth in a patient, comprising administering Compound 1, are disclosed in WO 2018 / 152450, which is incorporated herein by reference in its entirety for all Compound 1 structures and methods for synthesizing those structures.

[0121]

[0163] The atoms in Compound 1, when referred to herein, may be numbered as shown below: [ka] .

[0122]

[0164] The term "Compound 2," as used herein, refers to the structure of Compound 1, shown below, or a salt thereof: [ka] Refers to...

[0123]

[0165] The atoms in compound 2, when referred to herein, may be numbered as shown below: [ka] .

[0124]

[0166] In various embodiments of the present disclosure, "N-34 nitrogen," "N-39 nitrogen," "S-2 sulfur," or "S-14 sulfur" may be used to refer to a nitrogen or sulfur atom in other STING agonists that corresponds to a numbered nitrogen or sulfur atom in Compound 1 or Compound 2, regardless of whether the atom is numbered according to a naming convention. In some examples, for a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1 or Compound 2, the LD complex bound at the N-34 nitrogen is referred to as "R N " or "RN", and the LD complex bound at the N-39 nitrogen is referred to as "S N " or "SN"

[0125]

[0167] "Fcγ receptor," "Fc gamma receptor," or "FcγR" generally refers to a cell surface protein found on various types of immune cells, such as neutrophils. Binding of the Fc region of an antibody to an Fcγ receptor can induce different effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP).

[0126]

[0168] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0127]

[0169] The term "homolog" refers to a molecule that exhibits homology to another molecule, for example, by having the same or similar sequences of chemical residues at corresponding positions.

[0128]

[0170] The terms "IgG1 Fc," "IgG1 Fc domain," or "IgG1 Fc-containing antibody," as used herein, refer to an antibody having at least the IgG1 CH2 and CH3 domains, as specified by SEQ ID NO: 70 and SEQ ID NO: 71, respectively.

[0129]

[0171] "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.

[0130]

[0172] As used herein, the term "inhibit" or "inhibition" means to reduce by a measurable amount, which can include, but does not necessarily mean, complete prevention or inhibition.

[0131]

[0173] As used herein, "internalizing" with respect to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that, upon binding to a cell, can be taken up through the lipid bilayer membrane of the cell into an internal compartment, preferably a degradative compartment within the cell (i.e., "internalized"). For example, an internalizing anti-PSMA antibody is one that can be taken up into the cell after binding to PSMA on the cell membrane.

[0132]

[0174] The term "KD" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. KD is the k a / k d The rate can be determined using a standard assay such as BIAcore® or an ELISA assay.

[0133]

[0175] "k on " or "k a The term "on rate constant" refers to the on rate constant of an antibody when it associates with an antigen to form an antibody / antigen complex. The rate can be determined using a standard assay such as a BIAcore® or ELISA assay.

[0134]

[0176] "k off " or "kd The term "off-rate constant" refers to the off-rate constant for dissociation of an antibody from the antibody / antigen complex. The rate can be determined using a standard assay such as a BIAcore® or an ELISA assay.

[0135]

[0177] A "linker" or "linker moiety" is any chemical moiety that can covalently attach a compound, usually a drug moiety such as a chemotherapeutic agent, to another moiety, such as an antibody moiety. A 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 under which the compound or antibody remains active. A "cleavable linker" is any linker that includes a cleavable moiety and thus can be susceptible to cleavage. The cleavable moiety can be a cleavable peptide moiety. The term "cleavable peptide moiety" refers to any chemical bond linking amino acids (natural or synthetic amino acid derivatives) that can be cleaved by an agent present in the intracellular environment.

[0136]

[0178] The use of "or" means "and / or" unless the specific context of its use dictates otherwise.

[0137]

[0179] 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., drug loading, or the number of LD moieties per antibody or antigen-binding fragment (Ab) in an ADC of Formula I. In compositions comprising multiple copies of an ADC of Formula I, "p" refers to the average number of LD moieties per antibody or antigen-binding fragment, also referred to as the average drug loading.

[0138]

[0180] A "pharmaceutical composition" refers to a preparation that is in a form that allows for administration thereafter to provide the intended biological activity of the active ingredient and / or achieve a therapeutic effect, and that does not contain additional components that are unacceptably toxic to the subject to whom the formulation is administered. A pharmaceutical composition may be sterile.

[0139]

[0181] "Pharmaceutical excipients" include materials such as adjuvants, carriers, pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservatives, and the like.

[0140]

[0182] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans.

[0141]

[0183] As used herein, the term "π bond" refers to a covalent bond formed by p orbitals of adjacent atoms. A π 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 π bond, and a carbon-carbon triple bond consists of two π bonds.

[0142]

[0184] The term "prostate-specific membrane antigen" or "PSMA," as used herein, refers to any naturally occurring form of human PSMA. This term encompasses full-length PSMA (e.g., NCBI Reference Sequence: NP_004467.1; SEQ ID NO: 67) and any form of human PSMA resulting from cellular processing. This term also encompasses naturally occurring variants of PSMA, including, but not limited to, splice variants, allelic variants, and isoforms. Antibodies that bind to PSMA do not bind to all variants, as would be readily apparent to one skilled in the art. PSMA can be isolated from humans or produced recombinantly or by synthetic methods. The terms "PSMA" and "prostate-specific membrane antigen" are interchangeable with "glutamic acid 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.

[0143]

[0185] The term "protecting group," as used herein, refers to any chemical group introduced into a molecule by chemically modifying a functional group in order to obtain chemoselectivity in a subsequent chemical reaction.

[0144]

[0186] Methods for adding (a process commonly referred to as "protection") and removing (a process commonly referred to as "deprotection") protecting groups are well known in the art and are described, for example, in P. J. Kocienski, Protecting Groups, 3rd edition (Thieme, 2005), and Greene and Wuts, Protective Groups in Organic Synthesis, 4 th edition (John Wiley & Sons, New York, 2007), both of which are incorporated herein by reference in their entireties.

[0145]

[0187] Non-limiting examples of useful protecting groups for amines that can be used in the present disclosure include monovalent protecting groups such as t-butyloxycarbonyl (Boc), benzyl (Bn), 9-fluorenylmethyloxycarbonyl (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.

[0146]

[0189] Non-limiting examples of useful protecting groups for alcohols that can be used in the present disclosure include, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-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).

[0147]

[0190] Non-limiting examples of useful protecting groups for carboxylic acids that can be used in the present disclosure include, for example, methyl or ethyl esters, 9-fluorenylmethyl, methoxymethyl (MOM), tetrahydropyranyl (THP), tetrahydrofuranyl, β-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM), acetyl (Ac), phenacyl, substituted phenacyl esters, t-butyl, allyl, phenyl (Ph), silyl esters, benzyl and substituted benzyl esters, 2,6-dialkylphenyl, and substituted alkyl esters such as pentafluorophenyl (PFP).

[0148]

[0191] Non-limiting examples of amine bases that can be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropylethylamine (i-PrEtN; 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 bis(trimethylsilyl)amide (KHMDS).

[0149]

[0191] Non-limiting examples of carbonate bases that can be used in the present disclosure include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium bicarbonate (NaHCO3), and potassium bicarbonate (KHCO3).

[0150]

[0192] Non-limiting examples of phosphate bases that can be used in the present disclosure include, for example, sodium phosphate tribasic (NaPO), potassium phosphate tribasic (KPO), potassium phosphate dibasic (KHPO), and potassium phosphate monobasic (KHPO).

[0151]

[0193] Non-limiting examples of acids that may be used in the present disclosure include, for example, acetic acid (AcOH), trifluoroacetic acid (TFA), hydrochloric acid (HCl), camphorsulfonic acid (CSA), methanesulfonic acid (MsOH), formic acid (FA), phosphoric acid (HPO), and sulfuric acid (HSO).

[0152]

[0194] Non-limiting examples of peptide coupling reagents include, for example, N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCI), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMT-MM), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), and N,N,N,N'-tetramethyl-O-(N-succinimidyl)uronoium tetrafluoroborate (TSTU).

[0153]

[0195] For amino acid sequences, sequence identity and / or similarity may be determined using standard techniques known in the art, such as, but not limited to, 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 search for similarity method of Pearson and Lipman (1988) Proc. Nat. Acad. Sci. USA 85:2444, computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the BestFit sequence program described in Devereux et al. (1984) Nucl. Acid Res. 12:387-95, preferably using default settings, or by inspection. Preferably, percent identity is calculated by FastDB based on the following parameters: mismatch penalty of 1; gap penalty of 1; gap size penalty of 0.33; and joining penalty of 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.

[0154]

[0196] An example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP is a simplification of the progressive alignment method of Feng & Doolittle (1987) J Mol. Evol. 35:351-60; this method is similar to the method described in Higgins and Sharp (1989) CABIOS 5:151-3. Useful PILEUP parameters include a default gap weight of 3.00, a default gap length weight of 0.10, and weighted end gaps.

[0155]

[0197] 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, obtained 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. Adjustable parameters are set to the following values: overlap span = 1, overlap fraction = 0.125, word threshold (T) = 11. The HSP S and HSP S2 parameters are dynamic values ​​established by the program itself depending on the composition of the particular sequence and the particular database in which the subject sequence is being searched, but the values ​​can be adjusted to increase sensitivity.

[0156]

[0198] An additional useful algorithm is gapped BLAST, as 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 triggers ungapped extension, a gap length k is charged with a cost of 10+k, Xu is set to 16, and Xg is set to 40 in the database search phase and 67 in the output phase of the algorithm. Gapped alignment is triggered by a score corresponding to approximately 22 bits.

[0157]

[0199] Generally, the proteins disclosed herein and variants thereof (e.g., variants that retain the function of the original protein), including variants of PSMA and variants of antibody variable domains (including individual variant CDRs), have at least 80% amino acid homology, similarity, or identity, more typically at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and near or 100% amino acid homology, similarity, or identity.

[0158]

[0200] Similarly, "percent (%) nucleic acid sequence identity" with respect to nucleic acid sequences of antibodies and other proteins identified herein is defined as the percentage of nucleotide residues in a candidate sequence that are identical with the nucleotide residues in the coding sequence of the antigen-binding protein. A particular method uses the BLASTN module of WU-BLAST-2 set to default parameters, with overlap span and overlap fraction set to 1 and 0.125, respectively.

[0159]

[0201] As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0160]

[0202] The terms "subject" and "patient" are used interchangeably herein to refer to any animal, e.g., any mammal, including, but not limited to, a human, a non-human primate, a rodent, etc. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a human.

[0161]

[0203] The terms "target negative" or "target antigen negative" refer to the absence of target antigen expression by a cell or tissue. The terms "target positive" or "target antigen positive" refer to the presence of target antigen expression. For example, a cell or cell line that does not express the target antigen can be described as target negative, while a cell or cell line that expresses the target antigen can be described as target positive.

[0162]

[0204] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product >1 g / L).

[0163]

[0205] As used herein, the term "isomer" refers to compounds that have identical molecular formulae but that differ in the arrangement of their atoms or bonds in space. Isomers include stereoisomers, cis-trans isomers, atropisomers, and tautomers.

[0164]

[0206] As used herein, the term "stereoisomer" refers to both enantiomers and diastereomers.

[0165]

[0207] It will be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" ( [ka] ) or "hash" ( [ka] A (R) bond indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used herein, a stereoatom designated (R) or (S) indicates the stereochemical designation of the stereoatom under the Cahn-Ingold-Prelog precedence rules. As used in the chemical structures disclosed herein, a chiral center of known absolute stereochemistry (i.e., one stereoisomer) indicates the stereochemical designation of the stereoatom under the Cahn-Ingold-Prelog precedence rules. [ka] A ("straight") bond indicates where there is a mixture (e.g., a racemate or concentrate). As used herein, two bonds to a double bond carbon [ka] A ("straight") bond indicates that the double bond has the depicted E / Z stereochemistry.

[0166]

[0208] Certain compounds disclosed herein can exist as tautomers, and both tautomeric forms are intended, even if only a single tautomeric structure is depicted.

[0167]

[0209] The present disclosure also provides processes for preparing salts of the compounds of the present disclosure.

[0168]

[0210] Salts of the compounds of the present disclosure are formed between acid and basic groups (such as amino functional groups) of the compound, or base and acidic groups (such as carboxyl functional groups) of the compound. Depending on the ratio of basic or acidic groups in the compound to the valence of the acid or base, a single compound may form a salt with one or more molecular units of the acid / base, or multiple units of the compound may form a salt with a single 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.

[0169]

[0211] As used herein, the term "stimulator of interferon genes" or "STING" refers to any naturally occurring form of human STING. The term encompasses full-length STING (e.g., NCBI Reference Sequence: NP_938023.1; SEQ ID NO: 68) and any form of human PSMA resulting from cellular processing. 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 produced recombinantly or by synthetic methods.

[0170]

[0212] As used herein, "treat" or "therapeutic," and grammatically related terms, refer to any improvement in any outcome of a disease, e.g., extending survival, reducing morbidity, and / or reducing side effects that are a by-product of alternative therapies. As is readily understood in the art, complete eradication of the disease is preferred, but is not a requirement for therapeutic intervention. "Treatment" or "treating," as used herein, refers to the administration of the described ADC or antibody to a subject, e.g., a patient. Treatment can be to cure, heal, alleviate, mitigate, alter, remedy, ameliorate, palliate, improve, or affect a disorder, symptoms of a disorder, or a predisposition to a disorder, e.g., cancer.

[0171]

[0213] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0172] [Anti-PSMA antibodies and antigen-binding fragments]

[0214] The present disclosure provides antibodies that specifically bind to PSMA and can be used alone or formulated as therapeutic or diagnostic antibody compositions, e.g., for use in treating or detecting PSMA-expressing cancers. The antibodies can be provided as antibodies, antigen-binding fragments thereof, or as part of ADCs, packaged or prepared for therapeutic use.

[0173]

[0215] The antibodies disclosed herein may bind to PSMA with a dissociation constant (KD) of ≦1 mM, ≦100 nM, or ≦10 nM, or any amount therebetween, as measured, for example, by BIAcore® analysis. In some embodiments, the KD is ≦10 nM, ≦5 nM, ≦1 nM, or ≦0.5 nM.

[0174]

[0216] In some embodiments, the antibody is a four-chain antibody (also called an immunoglobulin) comprising two heavy chains and two light chains, hi 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.

[0175]

[0217] In some embodiments, the antibody is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody binds to PSMA expressed on the surface of a cell and enters the cell upon or after binding. In some embodiments, the drug moiety of the ADC is released from the antibody moiety of the ADC after the ADC enters and resides in a PSMA-expressing cell (i.e., after the ADC is internalized). In some embodiments, the internalizing antibody binds to PSMA expressed on the cell surface of a cell, and the cell is then phagocytosed (e.g., antibody-dependent cellular phagocytosis occurs). In some embodiments, the drug moiety of the ADC is released from the antibody moiety of the ADC after the ADC enters and resides in a phagocytic cell (e.g., macrophage, dendritic cell).

[0176]

[0218] Antibodies disclosed herein that specifically bind to a PSMA protein may comprise three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) having amino acid sequences 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 amino acid sequences selected from the LC CDRs listed in Tables 1 and / or 3 below, as defined by the Kabat numbering system. In some embodiments, the antibody comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) having amino acid sequences 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 amino acid sequences selected from the LC CDRs listed in Table 5 below, as defined by the IMGT numbering system.

[0177]

[0219] In some embodiments, the antibodies disclosed herein comprise a VH domain having an amino acid sequence selected from SEQ ID NOs: 1-14 listed in Tables 2 and / or 7 below. In some embodiments, the antibodies comprise a VL domain having an amino acid sequence selected from SEQ ID NOs: 15-20 listed in Tables 2 and / or 7 below.

[0178]

[0220] In some embodiments, the antigen-binding fragments disclosed herein retain PSMA binding. In some embodiments, the antigen-binding fragments retain PSMA binding by comprising three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) that comprise amino acid sequences 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) that comprise amino acid sequences selected from the LC CDRs listed in Tables 1 and / or 3 below, as defined by the Kabat numbering system. In some embodiments, the antigen-binding fragments retain PSMA binding by comprising three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) that comprise amino acid sequences 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) that comprise amino acid sequences selected from the LC CDRs listed in Table 5 below, as defined by the IMGT numbering system. In some embodiments, the antigen-binding fragments disclosed herein may retain PSMA binding by comprising a VH domain comprising an amino acid sequence selected from SEQ ID NOs: 1-14 listed in Tables 2 and / or 7 below, and a VL domain comprising an amino acid sequence selected from SEQ ID NOs: 15-20 listed in Tables 2 and / or 7 below.

[0179]

[0221] In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of 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, the 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, the antibody or antigen-binding fragment comprises an IgG1 domain.

[0180]

[0222] In some embodiments, the anti-PSMA antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences 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. 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 IgG1 domain.

[0181]

[0223] In some embodiments, the anti-PSMA antibodies and antigen-binding fragments disclosed herein have favorable 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 other anti-PSMA antibodies, e.g., J591 and deJ591. See U.S. Patent Nos. 11,059,903 and 7,045,605.

[0182]

[0224] Anti-PSMA antibodies or antigen-binding fragments may be selected to improve or preserve a variety of factors, including retaining target binding affinity, increasing thermal stability, and / or minimizing immunogenicity. In some embodiments, anti-PSMA antibodies are selected to demonstrate superiority in more than one category. In some embodiments, anti-PSMA antibodies are selected to demonstrate improvements in more than one category, even if they are not necessarily the best antibody in any one category.

[0183]

[0225] In some embodiments, an anti-PSMA antibody or antigen-binding fragment comprising three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system, and three LCDRs comprising the amino acid sequences of SEQ ID NO:32 (LCDR1), SEQ ID NO:35 (LCDR2), and SEQ ID NO:37 (LCDR3); or three HCDRs comprising the amino acid sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3), as defined by the IMGT numbering system, is selected to demonstrate retained target binding affinity, enhanced thermostability, and minimized immunogenicity compared to other anti-PSMA antibodies, such as J591 and / or deJ591. In some embodiments, an anti-PSMA antibody or antigen-binding fragment comprising three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system, and three LCDRs comprising the amino acid sequences of SEQ ID NO:32 (LCDR1), SEQ ID NO:35 (LCDR2), and SEQ ID NO:37 (LCDR3); or three HCDRs comprising the amino acid sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3), as defined by the IMGT numbering system, is selected to demonstrate retained target binding affinity and minimized immunogenicity compared to other anti-PSMA antibodies, such as J591, deJ591, and / or the anti-PSMA antibodies disclosed herein.

[0184]

[0226] 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 to demonstrate retained target binding affinity, enhanced thermal stability, and minimized 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 to demonstrate retained target binding affinity and minimized immunogenicity compared to other anti-PSMA antibodies, e.g., J591, deJ591, and / or the anti-PSMA antibodies disclosed herein.

[0185]

[0227] In some embodiments, the antibodies disclosed herein may comprise an IgG constant domain, e.g., an IgG1 domain, or an IgG1 domain that has been modified to reduce binding to an Fc receptor, e.g., an Fcγ receptor (FcγR), compared to a wild-type constant domain-containing (e.g., wild-type IgG1-containing) antibody. The reduction in binding to an Fc receptor, e.g., an FcγR, can be measured as compared to binding of an unmodified antibody to the same receptor. The reduction in binding can be at least about 10-fold, preferably at least about 100-fold, compared to an antibody containing an unmodified constant domain. The reduction in binding can be measured using any assay known in the art. For example, the reduction in binding can be measured using a fluorescence resonance energy transfer (FRET) assay.

[0186]

[0228] In some embodiments, the antibodies disclosed herein may comprise an IgG constant domain, e.g., an IgG1 domain, or an IgG1 domain that has been modified to increase binding to an Fc receptor, e.g., an Fcγ receptor (FcγR), compared to a wild-type constant domain-containing (e.g., wild-type IgG1-containing) antibody. The increase in binding to an Fc receptor, e.g., FcγR, can be measured as compared to binding of an unmodified antibody to the same receptor. The increase in binding can be at least about 5-fold, preferably at least about 10-fold, compared to an antibody containing an unmodified constant domain. For example, the 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.

[0187]

[0229] In some embodiments, the antibodies disclosed herein may comprise an IgG1 domain containing the mutations L234A, L235A, P238S, H268Q, and / or K274Q (e.g., including all of these mutations) according to Kabat EU numbering. 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 may reduce antibody binding to Fcγ receptors (FcγRs), which may reduce non-antigen-mediated uptake of antibodies or ADCs by immune cells such as neutrophils, thus reducing neutropenia. Reduced neutropenia can be measured using any assay known in the art. For example, a reduction in neutropenia can be measured using a flow cytometry assay.

[0188]

[0230] In some embodiments, an antibody that specifically binds to a PSMA protein comprises a heavy chain having an amino acid sequence selected from SEQ ID NOs: 47-60 listed in Table 8 below, and / or comprises a set of CDRs and / or a variable domain derived from an amino acid sequence in Table 8. In some embodiments, an antibody that specifically binds to a PSMA protein comprises a light chain having an amino acid sequence selected from SEQ ID NOs: 61-66 listed in Table 8 below, and / or comprises a set of CDRs and / or a variable domain derived from an amino acid sequence in Table 8.

[0189]

[0231] The amino acid and nucleic acid sequences of exemplary antibodies of the disclosure are shown in Tables 1-9. The monoclonal antibody Kabat CDR and variable region consensus sequences (Tables 1 and 2, respectively) reflect an alignment of the heavy and light chain variable region sequences represented by SEQ ID NOS: 1-20 ( FIG. 1 ). Residues that differ between clones are represented by an "X" in SEQ ID NOS: 42-46. The anti-PSMA antibodies or antigen-binding fragments 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 and three light chain CDR sequences.

[0190] [Table 5]

[0191] [Table 6]

[0192] [Table 7]

[0193] [Table 8]

[0194] Table 9

[0195] Table 10

[0196] Table 11

[0197] Table 12

[0198] Table 13

[0199] Table 14

[0200] Table 15

[0201] Table 16

[0202] Table 17

[0203] Table 18

[0204] Table 19

[0205] Table 20

[0206] Table 21

[0207] Table 22

[0208] Table 23

[0209] Table 24

[0210] Table 25

[0211] Table 26

[0212] Table 27

[0213] Table 28

[0214] Table 29

[0215] Table 30

[0216] Table 31

[0217] Table 32

[0218] Table 33

[0219] Table 34

[0220] Table 35

[0221] Table 36

[0222] Table 37

[0223] Table 38

[0224] Table 39

[0225] Table 40

[0226] Table 41

[0227] Table 42

[0228]

[0232] The anti-PSMA antibodies or antigen-binding fragments provided by SEQ ID NOs: 1-39 and 42-46 may 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 reduced immunogenicity compared to other anti-PSMA antibodies, such as J591 and / or deJ591.

[0229]

[0233] In some embodiments, the sequences of the heavy chain variable domain, light chain variable domain, full-length heavy chain, and full-length light chain can be "mixed and matched" to create variants of anti-PSMA antibodies. Such "mixed and matched" anti-PSMA antibodies can be tested using binding assays known in the art (e.g., ELISA and other assays described in the Examples). In various embodiments, the antibodies disclosed herein can comprise any set of heavy and light chain variable domains or a set of six CDR sequences from a set of heavy and light chains listed in the table above. In some embodiments, the antibody further comprises human heavy and light chain constant domains or fragments thereof. In various embodiments, the antibody can comprise any set of full-length heavy chain and full-length light chain sequences listed in the table above. In some embodiments, the antibody can comprise a human IgG heavy chain constant domain and a human kappa light chain constant domain. In some embodiments, the antibody can comprise a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant domain. In various embodiments, antibodies of the invention comprise a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain with a human Ig kappa light chain constant domain. In some embodiments, the constant domain is a modified version of a human constant domain, for example, comprising one or more of the following modifications of the human IgG1 heavy chain constant domain: L234A, L235A, P238S, H268Q, and / or K274Q.

[0230]

[0234] 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, which is NINPNNGGTTYX as defined by the Kabat numbering system. 1 X 2 KFX 3 X 4 In some embodiments, in SEQ ID NO: 44, X 1 is A or N, and X 2 is E or Q, and X 3 is Q or E, and X 4is G or D. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E or Q, and X 3 is Q or E, and X 4 is G or D. In some embodiments, in SEQ ID NO: 44, X 1 is A or N, and X 2 is Q and X 3 is Q and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is AN and X 2 is Q and X 3 is E and / or X 4 is D.

[0231]

[0235] 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, which comprises X5ASQDVGTAX6X7 as defined by the Kabat numbering system. 5 is R or K, and X 6 is V or L, and X 7 is D or N. In some embodiments, in SEQ ID NO: 45, X 5 is R and X 6 is V and / or X 7 is D. In some embodiments, in SEQ ID NO: 45, X 5 is K and X 6 is V and / or X 7is D. In some embodiments, in SEQ ID NO: 45, X 5 is R and X 6 is L and / or X 7 is N.

[0232]

[0236] 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, which is represented by WASTRHX as defined by the Kabat numbering system. 8 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 is T.

[0233]

[0237] 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. 1 is A and X 2 is E and X 3 is Q and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and / or X 4is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and / or X 4 is G. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and / or X 4 is D. In some embodiments, in SEQ ID NO: 45, X 5 is R and X 6 is V and / or X 7 is D. In some embodiments, in SEQ ID NO: 45, X 5 is K and X 6 is V and / or X 7 is D. In some embodiments, in SEQ ID NO: 45, X 5 is R and 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.

[0234]

[0238] In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is A and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is E and X 3 is Q and X 4is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is G; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1is N and X 2 is Q and X 3 is Q and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is G; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is D; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is D; in SEQ ID NO: 45, X 5 is R and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8is T. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is D; in SEQ ID NO: 45, X 5 is K and X 6 is V and X 7 is D; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is D; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is S. In some embodiments, in SEQ ID NO: 44, X 1 is N and X 2 is Q and X 3 is E and X 4 is D; in SEQ ID NO: 45, X 5 is R and X 6 is L and X 7 is N; in SEQ ID NO: 46, X 8 is T.

[0235]

[0239] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0236]

[0240] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0237]

[0241] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0238]

[0242] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0239]

[0243] 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: 26, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0240]

[0244] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0241]

[0245] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0242]

[0246] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0243]

[0247] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0244]

[0248] 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: 26, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0245]

[0249] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0246]

[0250] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0247]

[0251] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0248]

[0252] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0249]

[0253] 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: 26, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0250]

[0254] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0251]

[0255] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0252]

[0256] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0253]

[0257] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0254]

[0258] 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: 26, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0255]

[0259] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0256]

[0260] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0257]

[0261] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0258]

[0262] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0259]

[0263] 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: 26, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0260]

[0264] 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: 22, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0261]

[0265] 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: 23, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0262]

[0266] 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: 24, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0263]

[0267] 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: 25, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 27, as defined by the Kabat numbering system; 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.

[0264]

[0268] 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: 28, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 29, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 30, as defined by the IMGT numbering system (International ImMunoGeneTics Information System (IMGT®)); 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.

[0265]

[0269] 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: 28, a heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 29, and a heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 31, as defined by the IMGT numbering system; 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.

[0266]

[0270] In some embodiments, the anti-PSMA antibodies, or antigen-binding fragments thereof, provided herein comprise the heavy chain variable region of SEQ ID NO: 42, which comprises the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKX 9 SGYTFTEYTIHWVQQAPGKGLEWX 10 GNINPNNGGTTYX 11 X 12 KFX 13 X 14 RVTITX 15 DX 16 STX 17 TAYMELSSLRSEDTAVYYCAX 18 GWNFDYWGQGTLLTVSS (where X 9 is V or T, and X 10 is M or I, and X 11 is A or N, and X 12 is E or Q, and X 13 is Q or E, and X 14 is G or D, and X 15 is A or V, and X 16 is T or K, and X 17 is D or S, and X 18 is T or A). In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise the light chain variable region of SEQ ID NO: 43, which comprises the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCX 19 ASQDVGTAX 20 X 21 WYQQKPGKAPKLLIYWASTRHX 22 GVPSRFSGSGSGTDFLTISSLQPEDFATYYCQQYNSYPLTFGQGTKLEIK (where X 19 is R or K, and X 20 is L or V, and X 21 is N or D, and X 22 In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain variable region of SEQ ID NO: 42 and a light chain variable region of SEQ ID NO: 43, wherein X is S or T. 9 is V or T, and X 10 is M or I, and X 11 is A or N, and X12 is E or Q, and X 13 is Q or E, and X 14 is G or D, and X 15 is A or V, and X 16 is T or K, and X 17 is D or S, and X 18 is T or A, and X 19 is R or K, and X 20 is L or V, and X 21 is N or D, and X 22 is S or T.

[0267]

[0271] In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and / or X 18is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and / or X 18 is A. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and / or X 18 is T. In some embodiments, in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and / or X 22 is T. In some embodiments, in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and / or X 22 is S. In some embodiments, in SEQ ID NO: 43, X 19 is R and X20 is V and X 21 is D and / or X 22 is S. In some embodiments, in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and / or X 22 is S.

[0268]

[0272] In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is A and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is E and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is Q and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is G and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is S and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 teeth E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is A, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is S and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X16 is K and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42 X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is V and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is I and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is T and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is T. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18is T, and in SEQ ID NO: 43, X 19 is K and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is V and X 21 is D and X 22 is S. In some embodiments, in SEQ ID NO: 42, X 9 is V and X 10 is M and X 11 is N and X 12 is Q and X 13 is E and X 14 is D and X 15 is A and X 16 is T and X 17 is D and X 18 is T, and in SEQ ID NO: 43, X 19 is R and X 20 is L and X 21 is N and X 22 is S.

[0269]

[0273] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 antibodies or antigen-binding fragments provided herein comprise 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 antibodies or antigen-binding fragments 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: 19. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments 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: 19. The light chain variable region comprises the amino acid sequence of SEQ ID NO:20.

[0270]

[0274] 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: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 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 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 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.

[0271]

[0275] 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.

[0272]

[0276] 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.

[0273]

[0277] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO: 1. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO:2. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO: 3. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO: 14.In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain variable region having 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% identity to SEQ ID NO: 15. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain variable region having 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% identity to SEQ ID NO: 19.

[0274]

[0278] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO: 40 (i.e., do not share 100% identity with SEQ ID NO: 40), and the anti-PSMA antibodies or antigen-binding fragments thereof provide improved properties over other anti-PSMA antibodies, e.g., J591 and / or deJ591. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain variable region having 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% identity to SEQ ID NO: 41 (i.e., do not share 100% identity with SEQ ID NO: 41), and the anti-PSMA antibodies or antigen-binding fragments thereof provide improved properties over 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 having at least 86% identity to SEQ ID NO: 40 and a light chain variable region having at least 87% identity to SEQ ID NO: 41 (wherein neither variable region is 100% identical), and the anti-PSMA antibody or antigen-binding fragment provides improved properties over other anti-PSMA antibodies, e.g., J591 and / or deJ591, including greater stability and / or less immunogenicity.

[0275]

[0279] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO:40, and the anti-PSMA antibodies or antigen-binding fragments comprise at least the following amino acids that differ from SEQ ID NO:40:

[0276] [Table 43]

[0277] wherein the anti-PSMA antibody or antigen-binding fragment provides improved properties over other anti-PSMA antibodies, such as J591 and / or deJ591. The improved properties 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 a BLAST algorithm, and then counting amino acid positions from the N-terminus of the aligned sequence.

[0278]

[0280] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO:41, and the anti-PSMA antibodies or antigen-binding fragments comprise at least the following amino acids that differ from SEQ ID NO:41:

[0279] [Table 44]

[0280] wherein the anti-PSMA antibody or antigen-binding fragment provides improved properties over other anti-PSMA antibodies, such as J591 and / or deJ591. The improved properties 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 a BLAST algorithm, and then counting amino acid positions from the N-terminus of the aligned sequence.

[0281] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain variable region having 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% identity to SEQ ID NO: 42, and the anti-PSMA antibodies or antigen-binding fragments provide improved properties over other anti-PSMA antibodies, e.g., J591 and / or deJ591. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein comprise a light chain variable region having 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% identity to SEQ ID NO: 43, and the anti-PSMA antibodies or antigen-binding fragments provide improved properties over other anti-PSMA antibodies, e.g., J591 and / or deJ591. The anti-PSMA antibodies or antigen-binding fragments do not comprise a heavy chain variable region having 100% identity to SEQ ID NO: 40 and a light chain variable region having 100% identity to SEQ ID NO: 41. Improved properties include superior stability and / or reduced immunogenicity.

[0282] In various embodiments, any of the anti-PSMA antibodies disclosed herein may comprise a human IgG1 Fc domain. In some embodiments, the anti-PSMA antibody comprises a human IgG1 Fc domain that has been modified to reduce binding to FcγR compared to an IgG1 Fc-containing antibody having a wild-type IgG1 Fc domain. In some embodiments, the anti-PSMA antibody comprises a mutant human IgG1 Fc domain that includes one or more (e.g., all) of the following modifications relative to the human IgG1 heavy chain constant domain: L234A, L235A, P238S, H268Q, and K274Q.

[0283] 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.

[0284]

[0284] In some embodiments, the anti-PSMA antibodies provided herein comprise a heavy chain comprising an amino acid sequence selected from SEQ ID NOs: 47-60 and a light chain comprising an amino acid sequence selected from SEQ ID NOs: 61-66.

[0285] 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 the heavy chain amino acid sequence of SEQ ID NO:52 and the 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.

[0286] 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.

[0287]

[0287] 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.

[0288]

[0288] In any of the above antibodies, the heavy chain amino acid sequence may lack a C-terminal lysine.

[0289] In various embodiments, amino acid substitutions can be made to retain the binding affinity and / or specificity of the antibodies disclosed herein and / or to provide one or more additional beneficial properties, for example, by making one or more changes in the framework, constant domain, and / or CDR sequences. In some embodiments, the substitutions are of a single residue. For example, in some embodiments, an anti-PSMA antibody comprises a human IgG1 Fc domain containing amino acid substitutions to reduce binding to FcγR compared to an IgG1 Fc-containing antibody having a wild-type IgG1 Fc domain. In some embodiments, the anti-PSMA antibody comprises a mutant human IgG1 Fc domain containing substitutions L234A, L235A, P238S, H268Q, and K274Q. Insertions are typically on the order of about 1 to about 20 amino acid residues, although much larger insertions can be tolerated as long as biological function (e.g., binding to PSMA) is retained. Deletions typically range from about 1 to about 20 amino acid residues, although, depending on the fold, deletions can be much larger. Substitution, deletion, insertion, or any combination thereof can be used to obtain the final derivative or variant. Generally, these changes are made to a few amino acids to minimize the modification of the molecule, especially the immunogenicity and specificity of the antigen-binding protein. However, in certain circumstances, larger changes can be tolerated. Conservative substitutions are generally made according to the following chart shown in Table 11.

[0290] [Table 45]

[0291] In various embodiments in which variant antibody sequences are used in ADCs, the variants may exhibit the same qualitative biological activity and elicit the same immune response, but the variants may also be selected to modify the characteristics of the antigen-binding protein as needed. For example, the anti-PSMA antibodies provided herein may contain a human IgG1 Fc domain that has been mutated to reduce binding to FcγR compared to an IgG1 Fc-containing antibody having a wild-type IgG1 Fc domain. Alternatively, the variants may be designed to alter the biological activity of the antigen-binding protein.

[0292] Any of the anti-PSMA antibodies and antigen-binding fragments disclosed herein can be used, for example, as 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, the linker toxins in the ADCs disclosed herein are surprisingly 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.

[0293] [Linker] In various embodiments, the anti-PSMA antibodies and antigen-binding fragments disclosed herein can be linked to a drug moiety (e.g., a cytotoxic payload, such as Compound 1) by a linker to create an antibody-drug conjugate (ADC).

[0294] In some embodiments, the linker in the ADC is stable extracellularly sufficiently to exert a therapeutic effect. In some embodiments, the linker is stable extracellularly such that the ADC remains intact when present under extracellular conditions (e.g., before being transported or delivered to a cell). The term "intact" as used in the context of an ADC means that the antibody moiety remains attached to the drug moiety (e.g., Compound 1). As used herein, "stable" in the context of a linker or an ADC comprising a 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% of the linkers in a sample of the ADC are cleaved (or otherwise intact, in the case of the entire ADC) when present under extracellular conditions when the ADC is evaluated over a 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.

[0295] Whether a linker is stable extracellularly can be determined, for example, by placing the ADC in plasma for a predetermined 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 may allow the ADC to localize to target tumor cells and prevent premature release of the drug. Premature release of the drug may reduce the therapeutic index of the ADC by indiscriminately damaging both normal and tumor tissue. In some embodiments, the linker is stable outside the target cell and, upon entry into the cell, releases the drug moiety from the ADC so that the drug moiety can bind to its target (e.g., STING). Thus, an effective linker (i) maintains the specific binding properties of the antibody moiety; (ii) enables delivery of the drug moiety, e.g., intracellular delivery, by stably binding to the antibody moiety; (iii) remains stable and intact until the ADC is transported or delivered to its target site; and (iv) enables the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage.

[0296] Linkers can affect the physicochemical properties of ADCs. Because many cytotoxic agents are inherently hydrophobic, linking them to antibodies with additional hydrophobic moieties can lead to aggregation. ADC aggregates are insoluble, often limiting drug loading on antibodies and potentially adversely affecting ADC efficacy. Protein aggregates in biologics are also commonly associated with increased immunogenicity. As shown below, the linkers disclosed herein result in ADCs with low aggregation levels and desirable drug loading levels. In various embodiments, the linker is conjugated to the antibody or antigen-binding fragment via a cysteine. In various embodiments, the linker is conjugated to the antibody or antigen-binding fragment via a lysine. Suitable methods for conjugating linkers of the present disclosure to antibodies include techniques directed to attachment to lysines on the heavy chain of the antibody, cysteines on the heavy chain of the antibody, and cysteines on the light chain of the antibody, as disclosed, for example, 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 herein by reference in their entireties. In some embodiments, the linker is conjugated to the antibody or antigen-binding fragment at a cysteine ​​on the light chain, e.g., cysteine-80 on the light chain. In some embodiments, the linker is conjugated to the antibody or antigen-binding fragment at a cysteine ​​on the heavy chain, e.g., cysteine-118 on the heavy chain.

[0297]

[0296] Linkers as 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, for example, when internalized by target cells, while non-cleavable linkers generally rely on degradation of the antibody moiety itself.

[0298] 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.

[0299] In some embodiments, the linker is a cleavable linker. Cleavable linkers are designed to release a drug when subjected to a specific environmental factor, for example, when internalized into a target cell. A cleavable linker refers to any linker that includes 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, photolabile bonds, disulfide bonds, and esterase-labile bonds. A linker that includes a cleavable moiety can allow for release of the drug moiety from the ADC by cleavage at a specific site in the linker.

[0300] In some embodiments, the linker is cleavable under intracellular conditions such that cleavage of the linker sufficiently releases the drug moiety from the antibody moiety in the intracellular environment to activate the drug and / or exert its therapeutic effect. In some embodiments, the drug moiety is not cleaved from the antibody moiety until the ADC enters a cell that expresses an antigen specific for the antibody moiety of the ADC, at which point it is cleaved from the antibody moiety. In some embodiments, the linker comprises a cleavable moiety positioned such that upon cleavage, neither the linker moiety nor the antibody moiety remain attached to the drug moiety. Exemplary cleavable linkers include acid-labile linkers, protease / peptidase-sensitive linkers, photolabile linkers, dimethyl-containing linkers, disulfide-containing linkers, or sulfonamide-containing linkers.

[0301] In some embodiments, the linker is cleavable by a cleaving agent, e.g., an enzyme, present in the intracellular environment (e.g., within a lysosome, endosome, or pit). The linker can be, for example, a peptide linker that is cleaved by an intracellular peptidase or protease enzyme, such as, 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 that comprises a cleavable peptide moiety. The term "cleavable peptide moiety" refers to any chemical bond connecting amino acids (natural or synthetic amino acid derivatives) that can be cleaved by an agent present in the intracellular environment. In some embodiments, cleavable peptide linkers are more stably conjugated to the antibodies disclosed herein compared to acid-labile linkers.

[0302] In some embodiments, the linker is an enzyme-cleavable linker, and the cleavable peptide moiety in the linker is cleavable by an enzyme. In some embodiments, the cleavable peptide moiety is cleavable by a lysosomal enzyme, for example, cathepsin or legumain (also known as asparaginyl endopeptidase or vacuolar processing enzyme). In some embodiments, the linker is a linker cleavable by cathepsin. In some embodiments, the linker is a linker cleavable by legumain. In some embodiments, the cleavable peptide moiety in the linker is cleavable 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 moiety is cleavable by cathepsin B. An exemplary dipeptide that can be cleaved by cathepsin B is valine-citrulline (Val-Cit). See, e.g., Dubowchik et al (2002) Bioconjugate Chem. 13:855-69. Another exemplary dipeptide that can be cleaved by cathepsin B is valine-alanine (Val-Ala). See, e.g., Fu and Ho (2002) Antib. Ther. 1(2):33-43.

[0303]

[0302] In some embodiments, the cleavable peptide moiety in the linker is cleavable by a lysosomal cysteine ​​endopeptidase such as legumain. An exemplary monopeptide that can be cleaved by legumain is asparagine (Asn). Another exemplary monopeptide that can be cleaved by legumain is aspartic acid (Asp).

[0304] In some embodiments, the linker or cleavable peptide moiety in the 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). Exemplary tetrapeptides include, but are not limited to, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly (SEQ ID NO: 141)). Other exemplary amino acid units include, but are not limited to, Gly-Phe-Leu-Gly (SEQ ID NO: 142), Ala-Leu-Ala-Leu (SEQ ID NO: 143), Phe-N9-tosyl-Arg, and Phe-N9-Nitro-Arg, as described, for example, in U.S. Patent No. 6,214,345. In some embodiments, an amino acid unit can include an amino acid residue that includes 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 aspartic acid (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-Ala. The amino acid unit may comprise naturally occurring and / or minor amino acid residues, such as citrulline, and / or analogs of non-naturally occurring amino acids. The amino acid unit can be designed and optimized for enzymatic cleavage by specific enzymes, for example, tumor-associated proteases, legumain, or lysosomal proteases such as cathepsin B, C, D, or S.

[0305] In some embodiments, the linker in the ADCs disclosed herein may comprise an antibody-binding moiety, which may, for example, be used to link the antibody moiety to the linker, which may then be indirectly linked to the drug moiety, for example, via a cleavable moiety (e.g., a cleavable peptide).

[0306] In some embodiments, the linker comprises an antibody binding moiety that comprises a maleimide moiety (Mal). As used herein, the term "maleimide moiety" means a compound that contains a maleimide group and reacts with sulfhydryl groups, such as sulfhydryl groups of cysteine ​​residues on an antibody moiety. Other functional groups that react with sulfhydryl groups (thiols) and therefore can be used in place of Mal include, but are not limited to, iodoacetamide, bromoacetamide, vinylpyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate.

[0307] In some embodiments, the linker is attached to the antibody or antigen-binding fragment via a Mal moiety. In some embodiments, the Mal moiety reacts with a cysteine ​​residue on the antibody or antigen-binding fragment. In some embodiments, the Mal moiety is linked to the antibody or antigen-binding fragment via a cysteine ​​residue.

[0308] 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 via the MC moiety. In some embodiments, the MC moiety reacts with a cysteine ​​residue on the antibody or antigen-binding fragment. In some embodiments, the MC moiety is linked to the antibody or antigen-binding fragment via a cysteine ​​residue.

[0309] 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 cleavable linker comprises Mal-Val-Ala.

[0310] In some embodiments, the linker comprises an MC portion and a cleavable peptide portion. In some embodiments, the cleavable peptide portion 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 portion attaches the antibody portion to the cleavable peptide portion in the linker. In some embodiments, the cleavable peptide portion 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.

[0311] In some embodiments, any linker in the ADCs disclosed herein may comprise at least one spacer unit linking the antibody moiety to the drug moiety. In some embodiments, the spacer unit connects a cleavage site (e.g., a cleavable peptide moiety) in the linker to the antibody moiety. In some embodiments, the spacer unit connects a cleavage site (e.g., a cleavable peptide moiety) in the linker to the drug moiety. In some embodiments, the linker and / or 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.

[0312] In some embodiments, the spacer unit in the linker comprises one or more PEG moieties. In some embodiments, the spacer unit is -(PEG) m-, where m is an integer from 1 to 10. In some embodiments, m ranges from 1 to 4, or 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(ε-PEG8-OMe)-PEG2.

[0313] In some embodiments, the spacer unit in the linker comprises an alkyl moiety. In some embodiments, the spacer unit is -(CH) n -, where 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.

[0314] In some embodiments, the spacer unit is: [ka] In some embodiments, the spacer unit comprises: [ka] and (PEG). In some embodiments, the spacer unit comprises a [ka] In some embodiments, the spacer unit comprises: [ka] Contains formula (II).

[0315] In some embodiments, linkers disclosed herein can be used in LD 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 compared to other linkers comprising alternative spacer units, including, for example, improved conjugation stability, improved plasma stability, and / or in vivo anti-tumor activity. In some embodiments, without being bound by theory, benefits of using a linker comprising Formula (II) with a STING agonist disclosed herein, e.g., a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1, can include improved conjugation stability, improved plasma stability, and / or in vivo anti-tumor activity. In some embodiments, a payload comprising a linker comprising Formula (II) and a STING agonist disclosed herein, e.g., a compound of Formula (III), Formula (IV), or Table 14, exhibits superior properties when conjugated to an anti-PSMA antibody disclosed herein. Exemplary evidence of the superior benefits of such LDs and antibody drug conjugates is provided in Examples 4, 9, 12, and 15.

[0316] A spacer unit can be used, for example, to link an antibody moiety directly or indirectly to a drug moiety. In some embodiments, the spacer unit directly links the antibody moiety to the drug moiety. In some embodiments, the antibody moiety and the drug moiety are attached via a spacer unit comprising one or more alkyl moieties (e.g., (CH2)3, or (CH2)4, or (CH2)5). In some embodiments, the antibody moiety and the drug moiety are attached via a spacer unit comprising one or more PEG moieties (e.g., (PEG)2, or (PEG)3, or (PEG)4). In some embodiments, the antibody moiety and the drug moiety are attached via a spacer unit comprising Formula (II). In some embodiments, the spacer unit indirectly links the antibody moiety to the drug moiety. In some embodiments, the spacer unit indirectly links the antibody moiety to the drug moiety via a cleavable moiety (e.g., a cleavable peptide) and / or an antibody binding moiety, such as a maleimide moiety or a carbobenzoxy-L-glutaminyl-glycine moiety, that links the spacer unit to the antibody moiety.

[0317] In some embodiments, the spacer unit is attached to the antibody portion (i.e., antibody or antigen-binding fragment) via a maleimide moiety (Mal). A spacer unit that is attached to an antibody or antigen-binding fragment via a Mal is referred to herein as a "Mal-spacer unit." In some embodiments, the Mal-spacer unit reacts with a cysteine ​​residue of the antibody or antigen-binding fragment. In some embodiments, the Mal-spacer unit is linked to the antibody or antigen-binding fragment via a cysteine ​​residue. 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 spacer unit is attached to the antibody portion (i.e., antibody or antigen-binding fragment) via a maleimide caproid moiety (MC). A spacer unit that is attached to an antibody or antigen-binding fragment via a MC is referred to herein as a "MC-spacer unit." In some embodiments, the MC-spacer unit reacts with a cysteine ​​residue of the antibody or antigen-binding fragment. In some embodiments, the MC-spacer unit is linked to the antibody or antigen-binding fragment via a cysteine ​​residue. In some embodiments, the MC-spacer unit comprises a PEG moiety. In some embodiments, the MC-spacer unit comprises an alkyl moiety. In some embodiments, the Mal-spacer unit comprises Formula (II).

[0318] In some embodiments, the linker comprises a Mal-spacer unit or an 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 an MC-spacer unit and an amino acid unit. In some embodiments, the linker comprises Mal-(CH2) nand amino acid units, where n is 3 to 5, or 3, 4, or 5. In some embodiments, the linker is MC-(CH2) n and amino acid units, where n is 3 to 5, or 3, 4, or 5.

[0319] In some embodiments, the linker is Mal-(PEG) m and amino acid units, where m is 2 to 4, or 2, 3, or 5. In some embodiments, the linker is MC-(PEG) m and amino acid units, where m is 2 to 4, or 2, 3, or 5. In some embodiments, the linker further comprises a cleavable dipeptide, such as Val-Cit or Val-Ala. In some embodiments, the linker further comprises Mal-(PEG) n -Val-Cit, where n is any number between 1 and 10. In some embodiments, the linker is Mal-(PEG) n -Val-Ala, where n is any number between 1 and 10. In some embodiments, the linker is MC-(PEG) n -Val-Cit, where n is any number between 1 and 10. In some embodiments, the linker is MC-(PEG) n -Val-Ala, where n is any number between 1 and 10.

[0320] In some embodiments, the linker comprises 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.

[0321] 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.

[0322] In various embodiments, the cleavable moiety in the linker is directly attached to the drug moiety and / or the antibody moiety. In other embodiments, a spacer unit is used to attach the cleavable moiety in the linker to the drug moiety and / or the antibody moiety. In various embodiments, the drug moiety can be any STING agonist drug moiety disclosed herein, such as a compound of Formula (III), a compound of Formula (IV), or a compound disclosed in Table 14. In various embodiments, the drug moiety is attached to the cleavable moiety in the linker by 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 by a spacer unit. In some embodiments, the drug moiety, e.g., Compound 1, is attached to the cleavable moiety in the linker by a self-immolative unit. In some embodiments, the drug moiety, e.g., Compound 1, is attached to the cleavable moiety in the linker by a self-immolative unit, and the cleavable moiety comprises an amino acid unit, e.g., one or more alkyl moieties or PEG moieties or a further spacer unit comprising Formula (II) attaches the cleavable moiety to the antibody moiety. In some embodiments, a drug moiety, e.g., Compound 1, is linked to an anti-PSMA antibody via a Mal-spacer unit in a linker linked to a cleavable peptide moiety and a pAB or pABC self-immolative unit. In some embodiments, a drug moiety, e.g., Compound 1, is linked to an anti-PSMA antibody via an MC-spacer unit in a linker linked to a cleavable peptide moiety and a pAB or pABC self-immolative unit.

[0323] A spacer unit may be "self-immolative" or "non-self-immolative." A "non-self-immolative" spacer unit is one in which some or all of the spacer unit remains attached to the drug moiety upon cleavage of the linker. Examples of non-self-immolative units include, but are not limited to, a glycine spacer unit and a glycine-glycine spacer unit. A non-self-immolative unit may eventually degrade over time, but does not readily release the linked native drug completely under cellular conditions. A "self-immolative" unit includes any structure that allows for release of the native drug moiety after administration to a subject, e.g., under intracellular conditions. A "native drug" is one in which no part of the spacer unit or other chemical modification remains after cleavage / degradation of the spacer unit.

[0324] Self-immolative chemistries are known in the art and may be readily selected for the ADCs of the present disclosure. In various embodiments, the spacer unit in the linker that connects the cleavable moiety to the drug moiety (e.g., Compound 1) is self-immolative and undergoes self-immolation under intracellular conditions simultaneously with, or immediately before or after, cleavage of the cleavable moiety.

[0325] In various embodiments, the linkers disclosed herein can include at least one self-immolative unit. Any of the linkers disclosed herein can include a first self-immolative unit. The phrase "first self-immolative unit" can refer to a linker that includes one self-immolative unit or a linker that includes one or more self-immolative units. In some embodiments, the linkers disclosed herein include a first self-immolative unit and a second self-immolative unit.

[0326] In certain embodiments, at least one self-immolative unit in a linker comprises a p-aminobenzyl unit. In some embodiments, p-aminobenzyl alcohol (pABOH) is attached to an amino acid unit or other cleavable moiety in the linker via an amide bond, and a carbamate, methylcarbamate, or carbonate is formed between 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 p-aminobenzyl (pAB). In some embodiments, at least one self-immolative unit is or comprises p-aminobenzyloxycarbonyl (pABC). Without being bound by theory, it is believed that the 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.

[0327]

[0326] In various embodiments, the structure of p-aminobenzyl (pAB) used in the ADCs of the present disclosure is shown below: [ka] .

[0328]

[0327] In various embodiments, the structure of p-aminobenzyloxycarbonyl (pABC) used in the ADCs of the present disclosure is shown below: [ka] .

[0329]

[0328] The structure of pAB or pABC in the self-immolative unit may be substituted.

[0330] In some embodiments, pAB is methyl, fluoro, chloro, trifluoromethyl, C-C10 Aryl and C5-C 12 and heteroaryl. Exemplary substituted pAB units are disclosed in Table 12. In some embodiments, the linkers disclosed herein can include a self-immolative unit selected from the self-immolative units disclosed in Table 12 below.

[0331] [Table 46]

[0332] [Table 47]

[0333] Exemplary Substituted pAB Moieties The linker moiety may be modified to achieve desirable ADC properties, such as stability, tolerability, and / or efficacy. For example, a linker containing a modified pAB or pABC moiety may enhance ADC stability and / or in vivo ADC tolerability (e.g., as determined by percent body weight loss) while minimizing loss of ADC efficacy compared to linkers containing pAB or pABC. Certain additional modifications to the linker-drug structure, such as the attachment point of the spacer unit or modified drug moiety, may be required to achieve one or more (e.g., all of these) properties. For example, a particular modification or combination of modifications may need to be made to improve ADC stability while avoiding loss of efficacy. For example, in some embodiments, an ADC containing LP1, LP2, LP16, LP20, LP26, or LP28 may achieve desirable ADC properties, such as stability, tolerability, and / or efficacy, when compared to other anti-PSMA ADCs.

[0334] In some embodiments, any of the linkers disclosed herein can include an additional self-immolative unit. In some embodiments, the additional self-immolative unit connects 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 conjugates disclosed herein can provide superior technical advantages, such as superior stability and / or improved activity, compared to other linker-payload conjugates that include any of the payload compounds disclosed herein. Any of the linkers disclosed herein can include a second self-immolative unit.

[0335] 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.

[0336] [Table 48]

[0337] [Table 49]

[0338]

[0333] Units 2 and 9 to 13 include all stereoisomers.

[0339] In some embodiments, the additional self-immolative unit comprises a unit 1 (MEC) portion. In some embodiments, the MEC portion connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-MEC portion"). In some embodiments, the additional self-immolative unit comprises a unit 2 portion. In some embodiments, the unit 2 portion connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-unit 2 portion"). In some embodiments, the additional self-immolative unit comprises a unit 3 portion. In some embodiments, the unit 3 portion connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-unit 3 portion"). In some embodiments, the additional self-immolative unit comprises a unit 1 (MEC) portion. In some embodiments, the unit 4 portion connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-unit 4 portion"). In some embodiments, the additional self-immolative unit comprises a unit 5 portion. In some embodiments, the unit 5 moiety connects the first self-immolative unit to the 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 connects the first self-immolative unit to the 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 connects the first self-immolative unit to the 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 connects the first self-immolative unit to the 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 connects the first self-immolative unit to the 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 connects the first self-immolative unit to the 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 connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-unit 11 moiety"). In some embodiments, the additional self-immolative unit comprises a unit 112 moiety. In some embodiments, the unit 12 moiety connects the first self-immolative unit to the 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 connects the first self-immolative unit to the drug moiety (e.g., Compound 1) ("self-immolative unit-unit 13 moiety").

[0340] In various embodiments, the cleavable moiety in the linker is directly or indirectly attached to a sulfur in the drug moiety. The drug moiety can be any suitable drug moiety disclosed herein, such as a compound of Formula (III), a compound of Formula (IV), or a compound disclosed in Table 14. 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, one or more self-immolative units comprise pAB. In some embodiments, 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, 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 peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises the 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.

[0341] In various embodiments, the cleavable moiety in the linker is directly or indirectly attached to a nitrogen in the drug moiety. The drug moiety can be a STING agonist drug moiety disclosed herein, such as a compound of Formula (III), a compound of Formula (IV), or a compound disclosed in Table 14. 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, one or more self-immolative units comprise pAB. In some embodiments, one or more self-immolative units comprise pABC. In some embodiments, one or more self-immolative units comprise an MEC moiety. In some embodiments, one or more self-immolative units comprise a pABC-MEC moiety. In some embodiments, the carboxylate moiety of pABC is linked to the n-methyl moiety of MEC to form an N-methyl carbamate moiety. In some embodiments, one or more self-immolative units comprise a unit 8 moiety. In some embodiments, one or more self-immolative units comprise a pABC-unit 8 moiety. In some embodiments, one or more self-immolative units comprise a unit 9 moiety. In some embodiments, one or more self-immolative units comprise a pABC-unit 9 moiety. In some embodiments, one or more self-immolative units comprise a unit 11 moiety. In some embodiments, one or more self-immolative units comprise a pABC-unit 11 moiety.

[0342] In some embodiments, the linker comprises a third spacer unit between the first spacer unit and the second spacer unit. In some embodiments, the second and / or third spacer unit is selected from a portion 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, pABC attaches the cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, pABC attaches the cleavable moiety in the linker to the N-39 nitrogen in Compound 1.

[0343] In some embodiments, the pABC-MEC moiety attaches a cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-MEC moiety attaches a cleavable moiety in the linker to the N-39 nitrogen in Compound 1. In some embodiments, the pABC or pABC-MEC moiety undergoes self-destruction upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native, active form. In some embodiments, release of Compound 1 from the antibody and linker occurs in a stepwise manner, with the cleavable moiety in the linker being cleaved first, then the pABC moiety undergoing self-destruction, and then the MEC moiety undergoing self-destruction. In some embodiments, the cleavable moiety comprises an amino acid unit. In some embodiments, the linker comprises the 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 a 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 a Val-Ala-pABC-MEC moiety.

[0344] In some embodiments, the pABC-unit 8 moiety attaches a cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 8 moiety attaches a 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-destruction upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native, active form. In some embodiments, release of Compound 1 from the antibody and linker occurs in a stepwise manner, with the cleavable moiety in the linker cleaved first, then the pABC moiety undergoes self-destruction, and then the unit 8 moiety undergoes self-destruction. 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 a 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 a Val-Ala-pABC-unit 8 moiety.

[0345] In some embodiments, the pABC-unit 9 moiety attaches a cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 9 moiety attaches a 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-destruction upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native, active form. In some embodiments, release of Compound 1 from the antibody and linker occurs in a stepwise manner, with the cleavable moiety in the linker cleaved first, then the pABC moiety undergoes self-destruction, and then the unit 9 moiety undergoes self-destruction. 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 a 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 a Val-Ala-pABC-unit 9 moiety.

[0346] In some embodiments, the pABC-unit 11 moiety attaches a cleavable moiety in the linker to the N-34 nitrogen in Compound 1. In some embodiments, the pABC-unit 11 moiety attaches a 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-destruction upon cleavage of the cleavable moiety, and Compound 1 is released from the ADC in its native, active form. In some embodiments, release of Compound 1 from the antibody and linker occurs in a stepwise manner, with the cleavable moiety in the linker cleaved first, then the pABC moiety undergoes self-destruction, and then the unit 11 moiety undergoes self-destruction. 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 a 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 a Val-Ala-pABC-unit 11 moiety.

[0347] In some embodiments, at least one self-immolative unit (e.g., a pAB, pABC, pABC-MEC portion, a pABC-unit 8 portion, a pABC-unit 9 portion, or a pABC-unit 11 portion) undergoes self-immolation upon cleavage of a cleavable peptide portion in the linker. In some embodiments, the self-immolation of at least one self-immolative unit (e.g., a pAB, pABC, pABC-MEC portion, a pABC-unit 8 portion, a pABC-unit 9 portion, or a pABC-unit 11 portion) occurs stepwise after cleavage of a cleavable peptide portion in the linker, starting with the self-immolative portion closest to the cleavable peptide portion. In some embodiments, at least one self-immolative unit (e.g., pAB, pABC, pABC-MEC moiety, pABC-unit8 moiety, pABC-unit9 moiety, or pABC-unit11 moiety) undergoes stepwise self-immolation after cleavage of a cleavable peptide moiety in the linker, with the first self-immolative unit (e.g., pABC or pAB) followed by the second self-immolative unit (e.g., MEC moiety, unit8 moiety, unit9 moiety, unit11 moiety). In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises amino acid unit-pAB. In some embodiments, the linker comprises amino acid unit-pABC. In some embodiments, the linker comprises amino acid unit-pABC-MEC moiety. In some embodiments, the linker comprises amino acid unit-pABC-unit8 moiety. In some embodiments, the linker comprises amino acid unit-pABC-unit9 moiety. In some embodiments, the linker comprises amino acid unit-pABC-unit11 moiety. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises a Val-Cit-pAB. In some embodiments, the linker comprises a Val-Cit-pABC. In some embodiments, the linker comprises a Val-Cit-pABC-MEC moiety. In some embodiments, the linker comprises a Val-Cit-pABC-unit 8 moiety. In some embodiments, the linker comprises a Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises a Val-Cit-pABC-unit 11 moiety.In some embodiments, the amino acid unit is Val-Ala. In some embodiments, the linker comprises MC-Val-Ala-pAB. In some embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises a Val-Ala-pABC-MEC moiety. In some embodiments, the linker comprises a Val-Ala-pABC-unit 8 moiety. In some embodiments, the linker comprises a Val-Ala-pABC-unit 9 moiety. In some embodiments, the linker comprises a Val-Ala-pABC-unit 11 moiety.

[0348] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises an MC-spacer unit, a cleavable amino acid unit, and pAB. In some embodiments, the linker comprises MC-Val-Cit-pAB. In some embodiments, the linker comprises MC-Val-Ala-pAB.

[0349] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises an MC-spacer unit, a cleavable amino acid unit, and pABC. In some embodiments, the linker comprises MC-Val-Cit-pABC. In some embodiments, the linker comprises MC-Val-Ala-pABC.

[0350] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, a pABC, and an MEC portion. In some embodiments, the linker comprises an MC-Val-Cit, pABC-MEC portion. In some embodiments, the linker comprises an MC-Val-Ala-pABC-MEC portion.

[0351] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via 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 an MC-Val-Cit-pABC-unit 8 moiety. In some embodiments, the linker comprises an MC-Val-Ala-pABC-unit 8 moiety.

[0352] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via 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 an MC-Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises an MC-Val-Ala-pABC-unit 9 moiety.

[0353] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises an MC unit, a cleavable amino acid unit, pABC, and a unit 11 moiety. In some embodiments, the linker comprises an MC-Val-Cit-pABC-unit 11 moiety. In some embodiments, the linker comprises an MC-Val-Ala-pABC-unit 11 moiety.

[0354] In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC) and an amino acid. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, and pAB. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, and pABC. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, pABC, and an MEC moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, pABC, and a unit 8 moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, pABC, and a unit 9 moiety. In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimidocaproyl moiety (MC), an amino acid, pABC, and a unit 11 moiety.

[0355] In various aspects, the antibody portion of the ADC is conjugated to the drug moiety via a linker, wherein the linker comprises a Mal-spacer unit, a cleavable amino acid unit, and 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 portion of the ADC is conjugated to the drug moiety via a linker, wherein the linker comprises a Mal-spacer unit, a cleavable amino acid unit, and 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.

[0356] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, a pABC, and an MEC portion. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-MEC portion. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-MEC portion.

[0357] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and a unit 8 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 8 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 8 moiety.

[0358] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and a unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 9 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 9 moiety.

[0359] In various aspects, the antibody portion of the ADC is conjugated to the drug portion via a linker, wherein the linker comprises a Mal unit, a cleavable amino acid unit, pABC, and a unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 11 moiety. In some embodiments, the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 11 moiety.

[0360] In some embodiments, the drug moiety is Compound 1.

[0361] In some embodiments, the drug moiety is Compound 2.

[0362] [drug portion] 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, and acyclic dinucleotides. In some embodiments, the drug moiety is an acyclic dinucleotide. In some embodiments, the drug moiety is a macrocyclic bridged STING agonist.

[0363] The drug moiety of the linker-drug conjugates and ADCs disclosed herein can have the following formula: [ka] a compound, an isomer thereof, a deuterated derivative of the compound or isomer; or a salt of the compound, isomer or deuterated derivative; wherein, independently for each occurrence: P a and P b are independently selected from the (R) and (S) configurations when not racemic; Q a and Q b each of which is independently selected from NH and O; ·V a and V b each of which is independently selected from F and OH; W is selected from H and NH2; X a and X b each of which is independently selected from OH and SH; Y a and Y b are independently selected from O and S; ·Each Z a and Zb is independently selected from CH, O, and NH; and · [ka] indicates that the bond is a single bond ( [ka] ), a double bond in the (E) or (Z) configuration ( [ka] ), or triple bond ( [ka] ) means that (However, Z a and Z b At least one of X is NH, or a and X b at least one of which is SH).

[0364]

[0359] The atoms in formulas (III) and (IV) referred to herein may be numbered as shown below: [ka]

[0365] In some embodiments, P a and P b Each of P is racemic. a is racemic, and P b is selected from the (R) and (S) configurations. In some embodiments, P a is selected from the (R) and (S) configurations, and P b is racemic. In some embodiments, P a and P bis selected from the (R) and (S) configurations.

[0366] In some embodiments, P a is in the (R) 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 (S) configuration. 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 (S) configuration, and P b is in the (R) configuration.

[0367] 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.

[0368] 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.

[0369] In some embodiments, W is H. In some embodiments, W is NH.

[0370] In some embodiments, X a is OH and X bis 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.

[0371] 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.

[0372] In some embodiments, Z a is NH and Z b is selected from CH, O, and NH. In some embodiments, Z a is NH and Z b is CH. In some embodiments, Z a is NH and Z b is O. In some embodiments, Z a is NH and Z b is NH.

[0373] In some embodiments, Z a is O and Z b is selected from CH, O, and NH. In some embodiments, Z a is O and Z b is CH. In some embodiments, Z a is O and Z b is O. In some embodiments, Z a is O and Z b is NH.

[0374] In some embodiments, Z a is CH2 and Z b is selected from CH, O, and NH. In some embodiments, Z a is CH2 and Z b is CH. In some embodiments, Z a is CH2 and Z b is O. In some embodiments, Z a is CH2 and Z b is NH.

[0375] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond in the (E) configuration. In some embodiments, [ka] is a double bond in the (Z) configuration. In some embodiments, [ka] is a triple bond.

[0376] In some embodiments, X a and X b At least one of is SH, and Z a and Z b Each of X is independently selected from CH, O, and NH. a is SH and Z a and Z b Each of X is independently selected from CH, O, and NH. bis SH and Z a and Z b Each of X is independently selected from CH, O, and NH. a and X b Each of the is SH and Z a and Z b are each independently selected from CH, O, and NH.

[0377] In some embodiments, Z a and Z b At least one of 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 the is NH and X a and X b is selected from OH and SH.

[0378] In some embodiments, the bridge of the drug moiety is an aliphatic group in which 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 in which one CH2 unit is replaced by an NH group. In some embodiments, the bridge is an aliphatic group in which two CH2 units are replaced by NH groups. In some embodiments, the bridge atom is [ka] In some embodiments, the bridging atom comprises: [ka] In some embodiments, the bridging atom comprises: [ka] Includes:

[0379] In some embodiments, D comprises a compound of formula (III): a In some embodiments, D comprises a compound of formula (III), wherein X b is SH. In some embodiments, D comprises a compound of formula (VI), wherein X a is SH. In some embodiments, D comprises a compound of formula (VI), wherein X b is SH.

[0380]

[0375] In some embodiments, D comprises a compound of formula (III) selected from: [ka] [ka] and their salts.

[0381]

[0376] In some embodiments, the compound of formula (III) is selected from: [ka] and its salts.

[0382] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0383] In some embodiments, D is [ka] and salts thereof.

[0384] In some embodiments, D is [ka] and salts thereof.

[0385] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0386] In some embodiments, D is [ka] and salts thereof.

[0387] In some embodiments, the STING agonist is Compound 1. The structure of Compound 1 is shown below: [ka]

[0388] As noted above, the term Compound 1 also encompasses salts of the structure shown above, unless the context dictates otherwise. In some embodiments, the drug moiety is Compound 1. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the S-14 sulfur on Compound 1. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the N-34 nitrogen on Compound 1. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the N-39 nitrogen on Compound 1. In some embodiments, the ADC linker is covalently attached to the S-14 sulfur on Compound 1 via pAB. In some embodiments, pAB is an analog of pAB disclosed above. In some embodiments, the ADC linker is covalently attached to the N-34 nitrogen on Compound 1 via pABC. In some embodiments, the ADC linker is covalently attached to the N-39 nitrogen on Compound 1 via pABC. In some embodiments, the linker of the ADC is covalently attached to the N-34 nitrogen on compound 1 via a second self-immolative unit, as disclosed below. In some embodiments, the linker of the ADC is covalently attached to the N-34 nitrogen on compound 1 via a second self-immolative unit, as disclosed below.

[0389] In some embodiments, the STING agonist is Compound 2. The structure of Compound 2 is shown below: [ka]

[0390] The term Compound 2 also encompasses salts of the structure shown above, unless the context dictates otherwise. In some embodiments, the drug moiety is Compound 2. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the S-14 sulfur on Compound 2. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the N-34 nitrogen on Compound 2. In some embodiments, a linker, e.g., an ADC linker, is attached to Compound 1 through the N-39 nitrogen on Compound 2. In some embodiments, the ADC linker is covalently attached to the S-14 sulfur on Compound 2 through pAB. In some embodiments, pAB is an analog of pAB disclosed above. In some embodiments, the ADC linker is covalently attached to the N-34 nitrogen on Compound 2 through pABC. In some embodiments, the ADC linker is covalently attached to the N-39 nitrogen on Compound 2 through pABC. In some embodiments, the linker of the ADC is covalently attached to the N-34 nitrogen on compound 2 via a second self-immolative unit, as disclosed below. In some embodiments, the linker of the ADC is covalently attached to the N-34 nitrogen on compound 2 via a second self-immolative unit, as disclosed below. In some embodiments, the STING agonist is selected from the compounds in Table 14 below.

[0391] [Table 50]

[0392] [Table 51]

[0393] [Table 52]

[0394]

[0386] 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.

[0395] In certain embodiments, an intermediate, such as a precursor to a linker disclosed above, is reacted with a drug moiety under appropriate conditions. In certain embodiments, a reactive group on the drug and / or intermediate or linker is used. The product of the reaction between the drug and intermediate, or a derivatized drug, is then reacted with an antibody or antigen-binding fragment under appropriate conditions, for example, according to the methods described below. Alternatively, the linker or intermediate may be first reacted with the antibody or derivatized antibody, and then reacted with the drug or derivatized drug.

[0396] Many different reactions are available for covalently attaching drugs and / or linkers to antibody moieties. This is often achieved by reaction of one or more amino acid residues on the antibody molecule, including the amine groups of lysine, the free carboxylic acid groups of glutamic acid and aspartic acid, the sulfhydryl groups of cysteine, and various portions of aromatic amino acids. For example, nonspecific covalent attachment can be performed by coupling a carboxy (or amino) group on a compound to an amino (or carboxy) group on the antibody moiety using a carbodiimide reaction. Additionally, bifunctional agents such as dialdehydes or imidoesters can be used to link amino groups on a compound to amino groups on the antibody moiety. The Schiff base reaction is also available for attaching drugs to binders. This method involves periodate oxidation of drugs containing glycol or hydroxy groups, thus forming an aldehyde, which is then reacted with the binder. Attachment occurs via the formation of a Schiff base with the amino group of the binder. Isothiocyanates can also be used as coupling agents to covalently attach drugs to binders. Other techniques are known to those skilled in the art and are within the scope of this disclosure.

[0397] [Linker-drug conjugates] The present disclosure provides a linker drug conjugate comprising LD, where L is a cleavable linker covalently bonded 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 various antibodies, including the anti-PSMA antibodies disclosed herein. In the context of LD, D is a compound that forms a covalent bond with L, resulting in the loss of at least one hydrogen radical. In the context of LD, D can be any suitable compound that would benefit from the linkers of the present disclosure. In some embodiments, D is selected from any of the compounds disclosed herein. In the context of LD, L can be selected from any linker disclosed herein. D is a compound having the following formula: [ka] or a salt of the compound, isomer or deuterated derivative thereof; wherein, independently for each occurrence, P a and P b are independently selected from the (R) and (S) configurations when not racemic; Q a and Q b each of which is independently selected from NH and O; ·V a and V b each of which is independently selected from F and OH; W is selected from H and NH2; X a and X b each of which is independently selected from OH and SH; Y a and Y b are independently selected from O and S; ·Each Z a and Zb are independently selected from CH2, O, and NH; and · [ka] indicates that the bond is a single bond ( [ka] ), a double bond in the (E) or (Z) configuration ( [ka] ), or triple bond ( [ka] ) means that (However, Z a and Z b At least one of X is NH, or a and X b at least one of which is SH).

[0398] In some embodiments, P a and P b Each of P is racemic. a is racemic, and P b is selected from the (R) and (S) configurations. In some embodiments, P a is racemic, and P b is selected from the (R) and (S) configurations. In some embodiments, P a and P b is selected from the (R) and (S) configurations.

[0399] In some embodiments, P a is in the (R) 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 (S) configuration. In some embodiments, P a is in the (S) configuration, and P bis in the (R) configuration. In some embodiments, P a is in the (S) configuration, and P b is in the (S) configuration.

[0400] 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.

[0401] 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.

[0402] In some embodiments, W is H. In some embodiments, W is NH.

[0403] 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.

[0404] In some embodiments, Ya 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.

[0405] In some embodiments, Z a is NH and Z b is selected from CH, O, and NH. In some embodiments, Z a is NH and Z b is CH. In some embodiments, Z a is NH and Z b is O. In some embodiments, Z a is NH and Z b is NH.

[0406] In some embodiments, Z a is O and Z b is selected from CH, O, and NH. In some embodiments, Z a is O and Z b is CH. In some embodiments, Z a is O and Z b is O. In some embodiments, Z a is O and Z b is NH.

[0407] In some embodiments, Z a is CH2 and Z b is selected from CH, O, and NH. In some embodiments, Z a is CH2 and Z b is CH. In some embodiments, Z a is CH2 and Z b is O. In some embodiments, Z a is CH2 and Zb is NH.

[0408] In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond in the (E) configuration. In some embodiments, [ka] is a double bond in the (Z) configuration. In some embodiments, [ka] is a triple bond.

[0409] In some embodiments, X a and X b At least one of is SH, and Z a and Z b Each of X is independently selected from CH, O, and NH. a is SH and Z a and Z b Each of X is independently selected from CH, O, and NH. b is SH and Z a and Z b Each of X is independently selected from CH, O, and NH. a and X b Each of the is SH and Z a and Z b are each independently selected from CH, O, and NH.

[0410] In some embodiments, Z a and Z b At least one of 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 the is NH and X a and X b is selected from OH and SH.

[0411] In some embodiments, D comprises a compound of formula (III): a In some embodiments, D comprises a compound of formula (III), wherein X b is SH. In some embodiments, D comprises a compound of formula (VI), wherein X a is SH. In some embodiments, D comprises a compound of formula (VI), wherein X b is SH.

[0412] In some embodiments, the bridge of the linker-drug conjugate is an aliphatic group in which 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 in which one CH2 unit is replaced by an NH group. In some embodiments, the bridge is an aliphatic group in which two CH2 units are replaced by NH groups. In some embodiments, the bridge atom is [ka] In some embodiments, the bridging atom comprises: [ka] In some embodiments, the bridging atom comprises: [ka] 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.

[0413] In some embodiments, D comprises a compound of formula (III) and Z a In some embodiments, D comprises a compound of formula (III), wherein Z b In some embodiments, D comprises a compound of formula (IV), wherein Z a In some embodiments, D comprises a compound of formula (IV), wherein Z b is NH.

[0414] 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.

[0415] In some embodiments, D comprises a compound of formula (III). An exemplary formula (III) is shown below: In some embodiments, D is [ka] [ka] and salts thereof.

[0416]

[0408] In some embodiments, the compound of Formula (III) is selected from: [ka] and salts thereof.

[0417] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0418]

[0410] In some embodiments, D comprises a compound of formula (IV) selected from: [ka] and its salts.

[0419]

[0411] In some embodiments, D comprises a compound of formula (IV) selected from: [ka] and salts thereof.

[0420] In some embodiments, X a or X b is SH, and L is attached to D through a sulfur atom at S-2 sulfur or S-14 sulfur. a or Z b is NH, and L is bonded to D via the nitrogen atom at the N-34 nitrogen or the N-39 nitrogen.

[0421] In some embodiments, D comprises a compound of formula (III): a is SH and L is attached to D at the S-2 sulfur. In some embodiments, D comprises a compound of formula (III), and X ais SH and L is attached to D at the S-14 sulfur. In some embodiments, D comprises a compound of formula (III), and Z a is NH and L is attached to D at the N-34 nitrogen. In some embodiments, D comprises a compound of formula (III), and Z b is NH, and L is attached to D at the N-39 nitrogen.

[0422] In some embodiments, D comprises a compound of formula (IV) wherein L is attached to D at the S-2 sulfur. In some embodiments, D comprises a compound of formula (IV) wherein L is attached to D at the S-14 sulfur. In some embodiments, D comprises a compound of formula (IV) wherein L is attached to D at the N-34 nitrogen. In some embodiments, D comprises a compound of formula (IV) wherein L is attached to D at the N-39 nitrogen.

[0423] In some embodiments, D comprises Compound 1. In some embodiments, D comprises Compound 2.

[0424]

[0416] The present disclosure provides a linker-payload conjugate comprising LD, where L is a cleavable linker covalently attached to D, and D comprises a compound selected from the following: [ka] and salts thereof.

[0425] In some embodiments, L is attached to D through the sulfur atom at S-2 or S-14. 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.

[0426] In some embodiments, L is attached to D through the nitrogen atom of 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.

[0427] In some embodiments of a linker-payload conjugate comprising LD, L is any linker disclosed herein. In some embodiments of a linker-payload conjugate comprising LD, D is any drug moiety disclosed herein.

[0428] In some embodiments of a linker-payload conjugate comprising LD, L is a cleavable linker covalently attached to D, and the cleavable linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety is cleavable by cathepsin B. In some embodiments, the protease is legumain 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 (SEQ ID NO: 141), or Gly-Val-Ala. In some embodiments, the amino acid unit comprises Val-Ala. In some embodiments, the amino acid unit comprises Val-Cit.

[0429] In some embodiments, the linker-payload conjugate comprises Val-Ala and D is selected from a compound in Table 14. In some embodiments, the linker-payload conjugate comprises Val-Cit and D is selected from a compound in Table 14.

[0430]

[0422] In some embodiments, the linker-payload conjugate comprises Formula (II) and D is selected from the compounds in Table 14.

[0431] In some embodiments, the linker-payload conjugate comprises Formula (II)-Val-Ala, and D is selected from a compound in Table 14. In some embodiments, the linker-payload conjugate comprises Formula (II)-Val-Cit, and D is selected from a compound in Table 14.

[0432] In some embodiments, the linker drug conjugate comprises MC-Val-Cit-pABC-MEC-compound. 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. 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. In some embodiments, the linker drug conjugate comprises MC-Val-Ala-pABC-unit 9-compound (e.g., LP20). In some embodiments, the linker drug conjugate comprises MC-Val-Cit-pABC-unit 11-compound. In some embodiments, the linker drug conjugate comprises MC-Val-Ala-pABC-unit 11-compound 1 (eg, LP28).

[0433] In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-MEC-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-unit 8-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-unit 9-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-unit 11-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Ala-pABC-MEC-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Ala-pABC-unit 8-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Ala-pABC-unit 9-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-unit 11-compound 1.

[0434] In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pAB-unit 9-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Ala-pAB-unit 9-Compound 1. In some embodiments, the linker drug conjugate comprises LP25.

[0435] In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pAB-unit 11-Compound 1. In some embodiments, the linker drug conjugate comprises Mal-Formula (II)-Val-Cit-pABC-unit 11-Compound 1. In some embodiments, the linker drug conjugate comprises LP26.

[0436]

[0428] Exemplary linker drug conjugates of the present invention 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.

[0437] Table 53

[0438] Table 54

[0439] Table 55

[0440] Table 56

[0441] Table 57

[0442] Table 58

[0443] Table 59

[0444] Table 60

[0445] Table 61

[0446] Table 62

[0447] [Table 63]

[0448] In some embodiments, an exemplary linker drug conjugate or salt thereof may be referred to as "LP3" and has the structure of LP3 shown below: [ka]

[0449] In some embodiments, an exemplary linker drug conjugate or salt thereof may be referred to as "LP1," having the structure of LP1 shown below: [ka]

[0450] In some embodiments, an exemplary linker drug conjugate or salt thereof may be referred to as "LP2" and has the structure of LP2 shown below: [ka]

[0451]

[0432] In some embodiments, an exemplary linker drug conjugate or salt thereof has the structure of LP16, shown below: [ka]

[0452]

[0433] In some embodiments, an exemplary linker drug conjugate or salt thereof has the structure of LP20, shown below: [ka]

[0453]

[0434] In some embodiments, an exemplary linker drug conjugate or salt thereof has the structure of LP26, shown below: [ka]

[0454]

[0435] In some embodiments, an exemplary linker drug conjugate or salt thereof has the structure of LP28, shown below: [ka]

[0455] In some embodiments, the linker-payloads disclosed herein, e.g., LP1, LP2, LP16, LP20, LP26, LP28, or LP3, have improved properties over conventional linker-STING agonist conjugates. In some embodiments, the linker-payloads disclosed herein, e.g., LP1, LP2, LP3, LP16, LP20, LP26, or LP28, have superior plasma stability over conventional linker-STING agonist conjugates. In some embodiments, the linker-payloads disclosed herein, e.g., LP1, LP2, LP3, LP16, LP20, LP26, or LP28, have superior in vivo anti-tumor activity over conventional linker-STING agonist conjugates. In some embodiments, a linker-payload disclosed herein, e.g., LP1, LP2, LP3, LP16, LP20, LP26, or LP28, is better tolerated in vivo than conventional linker-STING agonist conjugates.

[0456] In some embodiments of linker-payload conjugates disclosed herein, where D is a STING agonist, e.g., a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1, and L is conjugated to D at the N-34 or 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 antitumor activity, tolerability, stimulation of an anti-immune response in the tumor microenvironment) compared to other linker-payload conjugates comprising a compound of Formula (III), Formula (IV), or Table 14 conjugated to D at another point of attachment, e.g., sulfur, e.g., S-2 or S-14. Illustrative evidence of the superior advantages of such linker-payload conjugates is provided in Examples 4, 9, 12, 14, and 15.

[0457] In some embodiments of 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, advantages of using a linker comprising Formula (II) with a STING agonist disclosed herein, e.g., a compound of Formula (III), Formula (IV), or Table 14, e.g., Compound 1, may include improved conjugation stability, improved plasma stability, and in vivo anti-tumor activity. In some embodiments, a linker-payload conjugate comprising a linker comprising Formula (II) and a STING agonist disclosed herein, e.g., a compound of Formula (III), Formula (IV), or Table 14, exhibits superior properties when conjugated to an anti-PSMA antibody disclosed herein. Exemplary evidence of the significant benefits of such linker-payload conjugates, for example, the benefits that can be achieved when conjugated to a variety of different antibodies, is provided in Examples 4, 9, 12, and 15.

[0458] In some embodiments, the ADCs disclosed herein comprise a cleavable linker described herein and an internalizing anti-PSMA antibody or antigen-binding fragment thereof. In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising SEQ ID NO:32 (LCDR1), SEQ ID NO:35 (LCDR2), and SEQ ID NO:37 (LCDR3). In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising SEQ ID NO:33 (LCDR1), SEQ ID NO:36 (LCDR2), and SEQ ID NO:37 (LCDR3). In some embodiments, the anti-PSMA antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences 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.

[0459] 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.

[0460] 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.

[0461]

[0442] The present disclosure includes methods of producing the described linker-drug conjugates. The linker-drug conjugates include a linker and a drug moiety, and can be prepared using a linker having a reactive functional group for covalently attaching the linker to the drug moiety. In some embodiments, the method of producing the linker-drug conjugate includes reacting a drug or a salt thereof with an activated linker.

[0462] 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.

[0463] In some embodiments, the activated linker reacted with a compound disclosed in Table 14; an isomer of a compound; a deuterated derivative of a compound or isomer; or a salt of a compound, isomer, or deuterated derivative is: [ka] In some embodiments, the activated linker reacted with a compound disclosed in Table 14; an isomer of a compound; a deuterated derivative of a compound or isomer; or a salt of a compound, isomer, or deuterated derivative is: [ka] In some embodiments, the linker portion of the activated linker comprises a linker of the disclosure, e.g., as disclosed in this section, e.g., a linker disclosed above.

[0464] In some embodiments, a 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 present disclosure. In some embodiments, the reaction of the compound, isomer, deuterated derivative, or salt is carried out in the presence of an organometallic base. In some embodiments, the organometallic base is selected from LDA, NaHMDS, LiHMDS, and KHMDS. In some embodiments, the organometallic base is LiHMDS.

[0465] In some embodiments, the activated linker [ka] The method for producing (I) comprises reacting a linker of the present disclosure with 4-nitrophenyl carbonochloridate. In some embodiments, the reaction of the linker with 4-nitrophenyl carbonochloridate is carried out in the presence of a base. In some embodiments, the base is pyridine.

[0466] In some embodiments, the activated linker [ka] The method for producing (I) comprises reacting a linker of the present disclosure with pentafluorophenol. In some embodiments, the reaction of the linker with pentafluorophenol is carried out in the presence of a peptide coupling reagent. In some embodiments, the peptide coupling reagent is DCC.

[0467] In some embodiments, the activated linker is an LD complex (V): [ka] It is used in a method for producing

[0468]

[0449] In some embodiments, the method for producing the LD complex (V) comprises reacting a compound of formula (III) or a salt thereof with an activated linker [ka] In some embodiments, Z b is NH. In some embodiments, P b has the (S) configuration and the activated linker is Z b "Preferentially," as used herein (unless the context dictates otherwise), refers to greater than 70% reaction, e.g., 70% of the activated linkers react preferentially with Z. a Z from nitrogen b It means that it reacts with nitrogen.

[0469] In some embodiments, the activated linker is Z a than reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 95% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 95% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 85% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 80% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a 75% more than the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 70% of the reaction with nitrogen, Z b Reacts with nitrogen.

[0470] In some embodiments, the activated linker is an LD complex (VI): [ka] It is used in a method for producing

[0471]

[0452] In some embodiments, the method for producing the LD complex (VI) comprises reacting a compound of formula (III) or a salt thereof with an activated linker [ka] In some embodiments, Z b is NH. In some embodiments, P b has the (S) configuration and the activated linker is Z b reacts preferentially to

[0472] In some embodiments, the activated linker is Z a than reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 95% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 90% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 85% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 80% of the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a 75% more than the reaction with nitrogen, Z b In some embodiments, the activated linker reacts with the nitrogen. a More than 70% of the reaction with nitrogen, Z bReacts with nitrogen.

[0473] [Antibody-drug conjugates] In various embodiments, the anti-PSMA antibody portions or antigen-binding fragments thereof disclosed herein can be conjugated (i.e., covalently attached, for example, by a linker) to a drug moiety, where the drug moiety has cytotoxic or cytostatic effects when not conjugated to the antibody moiety. In some embodiments, the drug moiety exhibits reduced or no cytotoxicity when bound to the conjugate, but resumes cytotoxicity when cleaved from the linker and antibody moiety.

[0474] The development and manufacture of ADCs for use as human therapeutics, e.g., tumor therapeutics, can require more than identifying an antibody that can bind to a desired target and conjugate to a drug that is itself used to treat cancer. Linking an antibody to a drug can have significant and unpredictable effects on the activity of either or both the antibody and drug, effects that will vary depending on the type of linker and / or drug selected. Thus, in some embodiments, the components of an ADC are designed to (i) isolate and preserve one or more therapeutic properties of the antibody and drug moieties alone, (ii) maintain the specific binding properties of the antibody moiety, (iii) optimize drug loading and drug-antibody ratio, (iv) enable delivery of the drug moiety to targeted tumor cells, e.g., intracellular delivery, by stable conjugation to the antibody moiety, (v) reduce toxicity compared to non-targeted and / or systemic delivery of the drug moiety, and (vi) maintain ADC stability as an intact complex until transport or delivery to the target site. The antibody is selected to: (i) minimize aggregation of the ADC before or after administration; (viii) exhibit in vivo anti-cancer therapeutic efficacy comparable to or greater than that of the antibody and drug moiety used alone; (ix) minimize off-target killing by the drug moiety; (x) exhibit desirable pharmacokinetic and pharmacodynamic properties, formulation amenability, and toxicity / immunological profile; (xi) maintain stimulation of an anti-immune response in the tumor microenvironment; and / or (xii) increase phagocytosis of PSMA-expressing cells by myeloid cells (e.g., macrophages or dendritic cells). Screening for each of these properties may be required to identify improved ADCs for therapeutic use. See, e.g., Ab et al. (2015) Mol. Cancer Ther. 14:1605-13.

[0475] In some embodiments, the ADC compounds of the present disclosure have superior stability as intact complexes until transported or delivered to a 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 present disclosure are less immunogenic compared to ADC compounds comprising other antibodies, e.g., J591 or deJ591, and / or other linkers.

[0476] The ADC compounds of the present disclosure can selectively deliver effective doses of cytotoxic or cytostatic agents to cancer cells or tumor tissue. The ADCs of the present disclosure have been found to have potent cytotoxic and / or cytostatic activity against cells expressing PSMA. In some embodiments, the cytotoxic and / or cytostatic activity of the ADC depends on the level of PSMA expression in the cells. In some embodiments, the ADCs of the present disclosure are particularly effective at killing cancer cells expressing high levels of PSMA compared to cancer cells expressing the same antigen at low levels. In some embodiments, the ADCs of the present discl...

Claims

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

1. An anti-PSMA antibody or antigen-binding fragment comprising:

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

2. The anti-PSMA antibody or antigen-binding fragment of claim 1, comprising:

3. 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.

2. The anti-PSMA antibody or antigen-binding fragment of claim 1, comprising:

4. 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. 5. 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) of >80°C, and optionally the antigen-binding fragment is a Fab.

9. 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 linked to at least one linker, and optionally, the at least one linker is cleavable.

10. 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 reagent.

11. A linker-payload conjugate comprising L-D, where L is a linker covalently attached to D, and D has the formula: 【Chemistry 1】 or a salt of said compound, isomer or deuterated derivative; wherein, independently at each occurrence, ・P ａ and P ｂ each, when not racemic, is independently selected from (R)- and (S)-stereochemistry; ・Q ａ and Q ｂ each is independently selected from NH and O; ・V ａ and V ｂ each is independently selected from F and OH; ・W is H and NH ２ Selected from: ・X ａ and X ｂ each is independently selected from OH and SH; ・Y ａ and Y ｂ each is independently selected from O and S; ・Each Z ａ and Z ｂ is CH ２ , O, and NH; and ・ 【Chemistry 2】 indicates that the bond is a single bond ( 【Transformation 3】 ), (E)- or (Z)-configured double bond ( 【Chemistry 4】 ), or triple bond ( 【Transformation 5】 ) means selected from (However, Z ａ and Z ｂ At least one of X is NH, or ａ and X ｂ at least one of which is SH) Linker-payload complex.

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

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

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

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

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

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

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

19. Z ａ and Z ｂ The linker-payload conjugate of any one of claims 11 to 18, wherein is NH. 【Request Item 20】 【Chemistry 6】 represents a double bond in the (E) or (Z) configuration ( 【Transformation 7】 20. The linker-payload conjugate of claim 11, comprising:

21. Crosslinking 【Transformation 8】 is the structure 【Chemistry 9】 20. The linker-payload conjugate of any one of claims 11 to 19, comprising:

22. Y ａ and Y ｂ The linker-payload conjugate of any one of claims 11 to 21, wherein at least one of is O.

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

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

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

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

27. D is 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 12. The linker-payload conjugate of claim 11, comprising a compound of formula (III) selected from:

28. D is 【Chemistry 13】 30. The linker-payload conjugate of claim 11 or 27, comprising a compound of formula (III) selected from:

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

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

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

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

33. X ａ 32. The linker-payload conjugate of claim 31, wherein: is SH and L is attached to D at the S-14 sulfur.

34. Z ａ and Z ｂ 31. The linker-payload conjugate of any one of claims 11 to 30, wherein 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. Z ｂ 35. The linker-payload conjugate of claim 34, wherein is NH and L is attached to D at the N-34 nitrogen.

36. Z ａ 35. The linker-payload conjugate of claim 34, wherein: 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. 38. The linker-payload conjugate of claim 37, wherein the cleavable linker comprises a cleavable peptide moiety.

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

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

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

45. 45. The linker-payload conjugate of claim 43 or 44, wherein the Mal moiety is attached to the antibody or antigen-binding fragment via a cysteine ​​residue of 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. 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 at least one PEG moiety is -(PEG) ｍ -, and m is an integer from 1 to 10.

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

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

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

52. The at least one spacer unit may be PEG ２ -Lys(ε-PEG ８ -OMe)-PEG ２ 48. The linker-payload conjugate of claim 46 or 47, comprising:

53. The at least one spacer unit is 【Chemistry 14】 47. The linker-payload conjugate of claim 46, comprising:

54. The at least one spacer unit is 【Chemistry 15】 54. The linker-payload conjugate of claim 46 or 53, comprising:

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

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

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

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

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

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

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

63. 63. The linker-payload conjugate of claim 62, wherein the linker can be removed from D after the linker is cleaved by the self-immolation of the first self-immolative unit and / or the self-immolation of the second self-immolative unit.

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

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

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

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

69. The second self-immolative unit comprises the following moiety: Table 1 Table 2 66. The linker-payload conjugate of claim 65, comprising one of:

70. The cleavable linker comprises Val-Ala and the second self-immolative unit comprises the following moiety: Table 3 Table 4 66. The linker-payload conjugate of claim 65, comprising one of:

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

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

73. 71. The linker-payload conjugate of any one of claims 62 to 70, wherein the second self-immolative unit comprises a unit 11 moiety.

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

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

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

77. The L-D is LP1: 【Chemistry 16】 12. The linker-payload conjugate of claim 11, comprising:

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

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

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

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

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

83. The L-D is LP16: 【Chemistry 17】 12. The linker-payload conjugate of claim 11, comprising:

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

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

86. 70. The linker-payload conjugate of claim 69, wherein L-D comprises MC-Val-Cit-pABC-unit 8-compound 1.

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

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

89. The L-D is LP28: [Chemistry 18] 12. The linker-payload conjugate of claim 11, comprising:

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

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

92. 70. The linker-payload conjugate of claim 69, wherein L-D comprises MC-Val-Cit-pABC-unit 11-compound 1.

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

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

95. The L-D is LP20: 【Chemistry 19】 12. The linker-payload conjugate of claim 11, comprising:

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

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

98. 70. The linker-payload conjugate of claim 69, wherein L-D comprises MC-Val-Cit-pABC-unit 9-compound 1.

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

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

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

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

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

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

105. 70. The linker-payload conjugate of claim 69, wherein L-D comprises Mal-Formula (II)-Val-Cit-pABC-unit 8-compound 1.

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

107. 70. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pABC-unit 11 moiety.

108. 70. The linker-payload conjugate of claim 69, wherein L-D comprises Mal-Formula (II)-Val-Cit-pABC-unit 11-compound 1.

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

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

111. 70. The linker-payload conjugate of claim 69, wherein L-D comprises Mal-Formula (II)-Val-Cit-pABC-unit 9-compound 1.

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

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

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

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

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

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

118. 71. The linker-payload conjugate of claim 70, wherein L-D comprises Mal-Formula (II)-Val-Ala-pABC-unit 8-compound 1.

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

120. 71. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pABC-unit 11 moiety.

121. 71. The linker-payload conjugate of claim 70, wherein L-D comprises Mal-Formula (II)-Val-Ala-pABC-unit 11-compound 1.

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

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

124. 71. The linker-payload conjugate of claim 70, wherein L-D comprises Mal-Formula (II)-Val-Ala-pABC-unit 9-compound 1.

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

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

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

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

129. 70. The linker-payload conjugate of claim 69, wherein L-D comprises Mal-Formula (II)-Val-Cit-pAB-unit 9-compound 1.

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

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

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

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

134. The L-D is LP25: 【Chemistry 20】 12. The linker-payload conjugate of claim 11, comprising:

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

136. 70. The linker-payload conjugate of claim 69, wherein the linker comprises a Mal-Formula (II)-Val-Cit-pAB-unit 11 moiety.

137. 70. The linker-payload conjugate of claim 69, wherein L-D comprises Mal-Formula (II)-Val-Cit-pAB-unit 11-compound 1.

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

139. 71. The linker-payload conjugate of claim 70, wherein the linker comprises a Mal-Formula (II)-Val-Ala-pAB-unit 11 moiety.

140. The L-D is LP26: 【Chemistry 21】 12. The linker-payload conjugate of claim 11, comprising:

141. 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; p is an integer from 1 to 20. antibody-drug conjugates.

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

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

144. 144. The antibody-drug conjugate of any one of claims 141 to 143, wherein the linker comprises a cleavable moiety positioned such that upon cleavage, neither the linker nor any part of the antibody or antigen-binding fragment remains bound to D.

145. 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 Mal moiety, and the Mal moiety is attached to the antibody or antigen-binding fragment via a cysteine ​​residue of the antibody or antigen-binding fragment.

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

147. The antibody-drug conjugate of claim 145, wherein the cysteine ​​residue is in 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 sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3); and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3).

150. The antibody-drug conjugate of claim 148 or 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 L-D comprises LP16, LP20, LP26, or LP28.

152. The L-D is LP16: 【Chemistry 22】 The antibody-drug conjugate of any one of claims 141 to 151, comprising:

153. The L-D is LP20: 【Chemistry 23】 The antibody-drug conjugate of any one of claims 141 to 151, comprising:

154. The L-D is LP26: 【Chemistry 24】 The antibody-drug conjugate of any one of claims 141 to 151, comprising:

155. The L-D is LP28: 【Chemistry 25】 The antibody-drug conjugate of any one of claims 141 to 151, comprising:

156. 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 to 140, or the antibody-drug conjugate of any one of claims 141 to 155, and a pharmaceutically acceptable carrier.

157. Formula (I): Ab-(L-D) ｐ (I) 1. A composition comprising multiple copies of an antibody drug conjugate of 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; A composition wherein p is the average number of LD moieties per Ab, and the average p of said antibody-drug conjugates in said composition is from about 2 to about 8.

158. The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); The L-D is LP16: 【Chemistry 26】 158. The composition of claim 157, comprising:

159. The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); The L-D is LP20: 【Chemistry 27】 158. The composition of claim 157, comprising:

160. The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); The L-D is LP26: 【Chemistry 28】 158. The composition of claim 157, comprising:

161. The antibody or antigen-binding fragment comprises three HCDRs comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:27 (HCDR3), as defined by the Kabat numbering system; and three LCDRs comprising the amino acid sequences of 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 sequences of SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), and SEQ ID NO:30 (HCDR3), as defined by the IMGT numbering system; and three LCDRs comprising the amino acid sequences of SEQ ID NO:38 (LCDR1), SEQ ID NO:39 (LCDR2), and SEQ ID NO:37 (LCDR3); The L-D is LP28: 【Chemistry 29】 158. The composition of claim 157, comprising:

162. 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. 162. A method of treating a patient having or at risk of having cancer, 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. 162. A method of suppressing or inhibiting the growth of cancer 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. 162. Use of an antibody or antigen-binding fragment of any one of claims 1 to 10, a linker-payload conjugate of any one of claims 11 to 140, an antibody-drug conjugate of any one of claims 141 to 155, a pharmaceutical composition of claim 156, or a composition of any one of claims 157 to 162 in the manufacture of a medicament for the treatment of cancer.

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

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

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

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

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

171. LD complex (V): 【Transformation 30】 12. A method for producing a compound of formula (III) according to claim 11: 【Chemistry 31】 or a salt thereof, having the following structure: 【Chemistry 32】 to form the L-D complex (V), ｂ is NH.

172. P ｂ has the (S) configuration and the activated linker is Z ｂ 172. The method of claim 171, wherein the compound reacts preferentially with

173. LD complex (VI): 【Transformation 33】 12. A method for producing a compound of formula (III) according to claim 11: 【Transformation 34】 or a salt thereof, having the following structure: 【Chemistry 35】 to form the L-D complex (VI), ｂ is NH.

174. P ｂ has the (S) configuration and the activated linker is Z ｂ 174. The method of claim 173, wherein the compound reacts preferentially with

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

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

177. 141. A method for producing an antibody-drug conjugate, the method comprising conjugating an antibody or antigen-binding fragment of any one of claims 1 to 8 with an L-D conjugate of any one of claims 11 to 140 under conditions suitable for conjugation.

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

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

180. The linker-payload conjugate may comprise the following linker-payload conjugate: Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 and salts thereof.

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