Anti-PSMA antibodies and uses thereof

JP2024535712A5Pending Publication Date: 2025-09-02JANSSEN BIOTECH INC
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Patent Information

Application Number
JP2024512988
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2021-08-27
Filing Date
2022-08-25
Publication Date
2025-09-02

AI Technical Summary

Technical Problem

There is a need for improved treatments for advanced prostate cancer, particularly those targeting prostate-specific membrane antigen (PSMA), as current therapies are limited for prostate cancer that has metastasized and hormone therapy is ineffective.

Method used

Development of antibodies and antigen-binding fragments that specifically bind to PSMA, including biparatopic antibodies with two binding domains, and their use in radioconjugates for targeted cancer therapy.

Benefits of technology

The antibodies and radioconjugates provide targeted therapy for PSMA-expressing prostate cancer, potentially enhancing treatment efficacy for advanced stages where current therapies are inadequate.

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Abstract

Disclosed herein are antibodies or antigen-binding fragments thereof that bind to prostate-specific membrane antigen (PSMA), polynucleotides, vectors, host cells, radioconjugates, antibody-drug conjugates, and methods of using same to treat cancer.
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Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 237,663, entitled "ANTI-PSMA ANTIBODIES AND USES THEREOF," filed August 27, 2021, the disclosure of each of which is incorporated herein by reference in its entirety.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy was created on July 11, 2022, is named JBI6621USNP1_SL.xml, and is 282,897 bytes in size.

[0003] (Technical field) Provided herein are antibodies or antigen-binding fragments thereof that bind to prostate specific membrane antigen (PSMA), polynucleotides, vectors, host cells, radioconjugates, antibody-drug conjugates, and methods of using them to treat cancer.

[0004] (background) Prostate cancer is the second most common cancer and the sixth leading cause of cancer-related deaths in men worldwide. Globally, approximately 1.1 million new cases and 300,000 deaths are reported annually, accounting for 4 percent of all cancer deaths. It is estimated that one in six men will be diagnosed with the disease during their lifetime. In the United States, more than 90% of prostate cancers are detected at localized or limited stages. At these early stages, the five-year survival rate approaches 100%. However, if the cancer metastasizes, the five-year survival rate drops to 28%, and there remains a need for effective treatments for advanced prostate cancer.

[0005] Prostate-specific membrane antigen (PSMA) is a type II membrane protein highly expressed in prostatic intraepithelial neoplasia (PIN), a condition in which some prostate cells begin to look and behave abnormally, and in primary and metastatic prostate cancer (Bostwick DG, et al., Prostate-specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: A study of 184 cases. Cancer 1998; 82(11): 2256-2261). PSMA expression in cancer tissue correlates with disease stage and Gleason score (Kawakami M, et al. Enhanced expression of prostate-specific membrane antigen gene in prostate cancer as revealed by in situ hybridization. Cancer Res 1997; 57(12): 2321-2324).PSMA expression is also higher in prostate cancer cells from hormone-refractory patients (Wright GL et al., Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 1996; 48(2): 326-334), and increased PSMA expression has been shown to be an independent marker of disease recurrence (Mitsiades CS, et al. Molecular staging by RT-pCR analysis for PSA and PSMA in peripheral blood and bone marrow samples is an independent predictor of time to biochemical failure following radical prostatectomy for clinically localized prostate cancer. Clin Exp Metastasis 2004; 21(6): 495-505). High levels of PSMA expression correlate with early prostate-specific antigen (PSA) recurrence in surgically treated prostate cancer. PSMA expression levels correlate with disease grade, strongly supporting PSMA as a superior target for prostate cancer characterization and subsequent treatment.

[0006] Current treatments for prostate cancer include surgery, radiation therapy, and hormone therapy. When prostate cancer grows despite lowering testosterone levels through hormone therapy, treatment options are limited.

[0007] This clearly demonstrates the need for improved treatments and effective therapies for PSMA-expressing advanced prostate cancer.

[0008] (overview) Provided herein is an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3, and light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are: a. RYGMH (SEQ ID NO: 4), LISYDGSNRYYADSVKG (SEQ ID NO: 5), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; b. SYYWN (SEQ ID NO: 10), RIYSSGNTDYNPSLKS (SEQ ID NO: 11), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; c. GYGMH (SEQ ID NO: 16), VISYDGSNRYYADSVKG (SEQ ID NO: 17), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; d. SYGMH (SEQ ID NO: 22), VISYDGSNKYYADSVKG (SEQ ID NO: 23), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), AARDDSLSGYV (SEQ ID NO: 27), respectively; e. SYDMH (SEQ ID NO: 28), VISFDGSNKYYVDSVKG (SEQ ID NO: 29), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; f. TYGMH (SEQ ID NO: 34), FISYDGSNKYYADSVKG (SEQ ID NO: 35), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; g. IYSMN (SEQ ID NO: 40), SISSSSSYIFYADSVKG (SEQ ID NO: 41), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; h. SYSLN (SEQ ID NO: 46), SISSSSSYISYADAVKG (SEQ ID NO: 47), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; i. SYYWS (SEQ ID NO: 272), RIYSSGSTNYNPSLKS (SEQ ID NO: 273), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; j. GFTLSRY (SEQ ID NO: 124), SYDGSN (SEQ ID NO: 125), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; k. GGSISSY (SEQ ID NO: 130), YSSGN (SEQ ID NO: 131), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; l. VRTFSGY (SEQ ID NO: 136), SYDGSN (SEQ ID NO: 125), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; m. GFTFTSY (SEQ ID NO: 142), SYDGSN (SEQ ID NO: 125), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; n. GFTFSSY (SEQ ID NO: 148), SFDGSN (SEQ ID NO: 149), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; o. GFTFSTY (SEQ ID NO: 154), SYDGSN (SEQ ID NO: 125), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; p. GFTLSIY (SEQ ID NO: 160), SSSSSY (SEQ ID NO: 161), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; q. GFTFSSY (SEQ ID NO: 166), SSSSSY (SEQ ID NO: 167), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; r. GGSIISY (SEQ ID NO: 290), YSSGS (SEQ ID NO: 291), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; s. GFTLSRYGMH (SEQ ID NO: 172), LISYDGSNRY (SEQ ID NO: 173), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; t. GGSISSYYWN (SEQ ID NO: 178), RIYSSGNTD (SEQ ID NO: 179), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; u. VRTFSGYGMH (SEQ ID NO: 184), VISYDGSNRY (SEQ ID NO: 185), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; v. GFTFTSYGMH (SEQ ID NO: 190), VISYDGSNKY (SEQ ID NO: 191), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; w. GFTFSSYDMH (SEQ ID NO: 196), VISFDGSNKY (SEQ ID NO: 197), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; x. GFTFSTYGMH (SEQ ID NO: 202), FISYDGSNKY (SEQ ID NO: 203), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; GFTLSIYSMN (SEQ ID NO: 208), SISSSSSYIF (SEQ ID NO: 209), SSYGADY (SEQ ID NO: 42), RASQDITNFLA, (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; z. GFTFSSYSLN (SEQ ID NO: 214), SISSSSSYIS (SEQ ID NO: 215), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWL (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSF (SEQ ID NO: 51), respectively; aa. GGSIISYYWS (SEQ ID NO: 296), RIYSSGSTN (SEQ ID NO: 297), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; bb. GFTLSRYG (SEQ ID NO: 220), ISYDGSNR (SEQ ID NO: 221), ARERESSGWFEGYFDY (SEQ ID NO: 222), NIGSKS (SEQ ID NO: 223), DNS, and QVWDSSSDHVV (SEQ ID NO: 9), respectively; cc. GGSISSYY (SEQ ID NO: 226), IYSSGNT (SEQ ID NO: 227), ARGRGANVGLFDY (SEQ ID NO: 228), NSNIGANYD (SEQ ID NO: 229), GNI, and QSYDFSLSGSV (SEQ ID NO: 15), respectively; dd. VRTFSGYG (SEQ ID NO: 232), ISYDGSNR (SEQ ID NO: 233), ARDGNWGSLDLYFDL (SEQ ID NO: 234), SSNIGADYD (SEQ ID NO: 235), VNN, and QSYDNTLSGVV (SEQ ID NO: 21), respectively; ee. GFTFTSYG (SEQ ID NO: 238), ISYDGSNK (SEQ ID NO: 239), AREHYDSSGYYHGYYGMDV (SEQ ID NO: 240), SSNIGSNY (SEQ ID NO: 241), SNN, and AARDDSLSGYV (SEQ ID NO: 27), respectively. ff. GFTFSSYD (SEQ ID NO: 244), ISFDGSNK (SEQ ID NO: 245), ARTYYDILTGYSHYSYGMDV (SEQ ID NO: 246), QGISNY (SEQ ID NO: 247), ATS, and QKYNSAPFT (SEQ ID NO: 33), respectively; gg. GFTFSTYG (SEQ ID NO: 250), ISYDGSNK (SEQ ID NO: 251), AGRDNLRFLEWFMDV (SEQ ID NO: 252), QSVRSN (SEQ ID NO: 253), GAS, and HQYNDWPPYT (SEQ ID NO: 39), respectively; hh. GFTLSIYS (SEQ ID NO: 256), ISSSSSYI (SEQ ID NO: 257), ARSSYGADY (SEQ ID NO: 258), QDITNF (SEQ ID NO: 259), TAS, and QKYNSAPLT (SEQ ID NO: 45), respectively; ii. GFTFSSYS (SEQ ID NO: 262), ISSSSSYI (SEQ ID NO: 263), ARDRGFLEDYYYYYGMDV (SEQ ID NO: 264), QGISNW (SEQ ID NO: 265), VAS, and QQAYSFPLT (SEQ ID NO: 51), respectively; or jj. Each of them contains the amino acid sequences of GGSIISYY (SEQ ID NO: 302), IYSSGST (SEQ ID NO: 303), AKVGVWPGAFDI (SEQ ID NO: 304), SSNIGSNT (SEQ ID NO: 305), SSN, and AAWDDSLNGVV (SEQ ID NO: 277).

[0009] Also, SEQ ID NOs: 52 and 53, respectively; SEQ ID NOs: 54 and 55, respectively; SEQ ID NOs: 56 and 57, respectively; SEQ ID NOs: 58 and 59, respectively; SEQ ID NOs: 60 and 61, respectively; SEQ ID NOs: 62 and 63, respectively; SEQ ID NOs: 64 and 65, respectively; SEQ ID NOs: 66 and 67, respectively; or Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL) of SEQ ID NOs: 278 and 279, respectively, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0010] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the VH of SEQ ID NO: 52, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the VL of SEQ ID NO: 53.

[0011] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a VH that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the VH of SEQ ID NO: 54, and a VL that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the VL of SEQ ID NO: 55.

[0012] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284, and 288.

[0013] The present disclosure also provides an antibody or antigen-binding fragment thereof comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 84 or 85.

[0014] The present disclosure also provides an antibody or antigen-binding fragment thereof comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 86 or 85.

[0015] The present disclosure also provides an antibody or antigen-binding fragment thereof comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 88 or 89.

[0016] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 84 and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0017] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 86 and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0018] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively; VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 88 and an LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0019] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively; VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 90 and an LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0020] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20, and 21, respectively; VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 92 and an LC of SEQ ID NO: 93, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0021] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26, and 27, respectively; VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 94 and an LC of SEQ ID NO: 95, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0022] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively; VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 96 and an LC of SEQ ID NO: 97, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0023] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38, and 39, respectively; VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 98 and an LC of SEQ ID NO: 99, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0024] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively; VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 100 and an LC of SEQ ID NO: 101, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0025] Also, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50, and 51, respectively; VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67, and / or An isolated antibody or antigen-binding fragment thereof is disclosed, comprising an HC of SEQ ID NO: 102 and an LC of SEQ ID NO: 103, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0026] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, wherein the isolated antibody or antigen-binding fragment thereof is a biparatopic antibody comprising two antigen-binding domains, wherein the first antigen-binding domain binds to a first epitope on PSMA and the second binding domain binds to a second epitope on PSMA.

[0027] In some embodiments, a biparatopic antibody comprises two antigen-binding domains: the first antigen-binding domain is a Fab or Fab fragment comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, LCDR3 of SEQ ID NO: 9, VH of SEQ ID NO: 52, VL of SEQ ID NO: 53, HC of SEQ ID NO: 268, and LC of SEQ ID NO: 269; and the second antigen-binding domain is in the form of an scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, HC of SEQ ID NO: 282; or The first antigen-binding domain is a Fab or Fab fragment comprising an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 5, an HCDR3 of SEQ ID NO: 6, an LCDR1 of SEQ ID NO: 7, an LCDR2 of SEQ ID NO: 8, an LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, an HC of SEQ ID NO: 284, and an LC of SEQ ID NO: 269, and the second antigen-binding domain is in the form of an scFv comprising an HCDR1 of SEQ ID NO: 272, an HCDR2 of SEQ ID NO: 273, an HCDR3 of SEQ ID NO: 274, an LCDR1 of SEQ ID NO: 275, an LCDR2 of SEQ ID NO: 276, an LCDR3 of SEQ ID NO: 277, a VH of SEQ ID NO: 278, a VL of SEQ ID NO: 279, and an HC of SEQ ID NO: 288.

[0028] In some embodiments, the disclosed isolated antibodies or antigen-binding fragments thereof are of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0029] In some embodiments, the isolated antibody or antigen binding is of the IgG1 isotype.

[0030] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises an Ig constant region or a fragment of an Ig constant region, wherein the Ig constant region or constant region of the fragment comprises at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

[0031] In some embodiments, the at least one mutation that results in reduced binding of the protein to an FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 / A327 G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S, S267E / L328F, L234F / L235E / D265A, L234A / L235A / G237A / P238S / H268A / A330S / P331S, S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236 deletion / G237A / P238S, where residue numbering is according to the EU index.

[0032] In some embodiments, the mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an FcγR is L234A_L235A_D265S.

[0033] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0034] In some embodiments, the isolated antibody or antigen-binding fragment thereof comprises an Ig constant region or a fragment of an Ig constant region, wherein the Ig constant region or constant region of the fragment comprises at least one mutation that modulates the half-life of the antibody.

[0035] In some embodiments, the at least one mutation that modulates the half-life of the antibody is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, where residue numbering is according to the EU index.

[0036] In some embodiments, the mutations that modulate the half-life of the antibody or antigen-binding fragment thereof are M252Y / S254T / T256E mutations.

[0037] The present disclosure also provides polynucleotides encoding the isolated antibodies or antigen-binding fragments thereof of the present disclosure.

[0038] Optionally, the polynucleotide encoding the isolated antibody or antigen-binding fragment thereof that binds PSMA comprises the polynucleotide sequence of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

[0039] Optionally, the polynucleotide encoding the isolated antibody or antigen-binding fragment thereof that binds PSMA is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the polynucleotide sequence of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

[0040] The present disclosure also provides a vector comprising a polynucleotide of the present disclosure.

[0041] The present disclosure also provides a host cell comprising a polynucleotide or vector of the disclosure.

[0042] The present disclosure also provides radioconjugates comprising at least one radiometal complex conjugated to an antibody or antigen-binding fragment thereof having binding specificity for PSMA, wherein the radiometal complex comprises a radioactive metal ion.

[0043] The present disclosure also provides radioconjugates comprising at least one radiometal complex conjugated to any of the antibodies or antigen-binding fragments thereof of the present disclosure, wherein the radiometal complex comprises a radioactive metal ion.

[0044] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 4, 5, and 6, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, and 9, respectively.

[0045] The present disclosure also provides radioconjugates, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (VH) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, and a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53.

[0046] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 52, and the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO: 53.

[0047] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment thereof comprises an HC of SEQ ID NO: 86 and an LC of SEQ ID NO: 85, and wherein the antibody or antigen-binding fragment thereof is an IgG1 comprising an Ig constant region or a fragment of an Ig constant region, and the Ig constant region or fragment of the constant region comprises at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

[0048] In some embodiments, the at least one mutation that results in reduced binding of the protein to an FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 / A327 G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S, S267E / L328F, L234F / L235E / D265A, L234A / L235A / G237A / P238S / H268A / A330S / P331S, S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236 deletion / G237A / P238S, where residue numbering is according to the EU index.

[0049] In some embodiments, the mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an FcγR is L234A_L235A_D265S.

[0050] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment thereof comprises an HC of SEQ ID NO: 86 and an LC of SEQ ID NO: 85, and wherein the antibody or antigen-binding fragment thereof is an IgG1 comprising an Ig constant region or a fragment of an Ig constant region, and wherein the Ig constant region or fragment of the constant region comprises at least one mutation that modulates the half-life of the antibody.

[0051] In some embodiments, the at least one mutation that modulates the half-life of the antibody is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, where residue numbering is according to the EU index.

[0052] In some embodiments, the mutations that modulate the half-life of the antibody or antigen-binding fragment thereof are M252Y / S254T / T256E mutations.

[0053] The present disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to an antibody or antigen-binding fragment thereof, the radiometal complex comprising: 225 Ac, 111 In, 177 Lu, ,32 P, 47 Sc, 67 Cu, 77 As, 89 Sr, 90 Y, 99 Tc, 105 Rh, 109 Pd, 111 Ag, 131 I, 134 Ce, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 255 Fm, 227 Th, 177 Lu, 62 Cu, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 111 In, and 34 The radioactive metal ion comprises a chelator complexed with a radioactive metal ion selected from the group consisting of Xe.

[0054] In some embodiments, the radioactive metal ion is 225 It is Ac.

[0055] In some embodiments, the radioactive metal ion is 111 In.

[0056] In some embodiments, the radioactive metal ion is 134 It's Xe.

[0057] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0060] The present disclosure also provides a pharmaceutical composition comprising any of the disclosed antibodies or antigen-binding fragments thereof, or any of the disclosed radioconjugates, and a pharmaceutically acceptable carrier.

[0061] The present disclosure also provides a method of treating PSMA expressing cancer in a subject, comprising administering to the subject a therapeutically effective amount of any of the disclosed antibodies or antigenic fragments thereof, any of the disclosed radioconjugates, or any of the disclosed pharmaceutical compositions for a time sufficient to treat the cancer.

[0062] In some embodiments, the subject has prostate cancer.

[0063] In some embodiments, the subject has renal cancer.

[0064] The present disclosure also provides methods of detecting PSMA in a sample using the radioconjugates of the present disclosure.

[0065] The present disclosure also provides kits comprising any of the antibodies or antigen-binding fragments thereof, any of the radioconjugates, or any of the pharmaceutical compositions of the present disclosure.

[0066] DETAILED DESCRIPTION OF THE INVENTION In the "Background" section and throughout this specification, various publications, articles, and patents are cited or described, and each of these references is incorporated herein by reference in its entirety. The discussion of documents, operations, materials, devices, articles and the like which is included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0067] The disclosed isolated anti-PSMA antibodies, antigen-binding fragments thereof, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods may be more readily understood by reference to the following detailed description in conjunction with the accompanying figures, which form a part of this disclosure: It is to be understood that the disclosed antibodies, antigen-binding domains, antibody fragments, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods are not limited to those specifically described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments, by way of example only, and is not intended to limit the claimed antibodies, antigen-binding domains, antibody fragments, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods.

[0068] Unless otherwise stated, any discussion of possible mechanisms or modes of action or reasons for improvement is intended to be exemplary only, and the disclosed antibodies, antigen-binding fragments thereof, polynucleotides, vectors, cells, radioconjugates, antibody-drug conjugates, compositions, kits, and methods are not limited by the merits or demerits of any such proposed mechanisms or modes of action or reasons for improvement.

[0069] Throughout this context, the description refers to antibodies, antigen-binding fragments thereof, radioconjugates, antibody-drug conjugates, and methods of using such antibodies, antigen-binding fragments thereof, radioconjugates, and antibody-drug conjugates. Where the present disclosure describes or claims features or embodiments relating to antigen-binding domains, radioconjugates, and antibody-drug conjugates, such features or embodiments are equally applicable to methods of using such antigen-binding domains, radioconjugates, and antibody-drug conjugates. Similarly, where the present disclosure describes or claims features or embodiments relating to antigen-binding domains, radioconjugates, and methods of using antibody-drug conjugates, such features or embodiments are equally applicable to antigen-binding domains, radioconjugates, and antibody-drug conjugates. When a range of numerical values ​​is recited or established herein, this range includes its endpoints, and all individual integers and rational numbers within that range, and also includes each of the narrower ranges formed by all the various possible combinations of these endpoints and internal integers and rational numbers, forming a subset of the larger group of values ​​within the recited range to the same extent as if each of those narrower ranges were explicitly recited. When a range of numerical values ​​is recited herein as being higher than the recited value, the range is nevertheless finite, with its upper limit defined by a value operable within the context of the invention described herein. When a range of numerical values ​​is recited herein as being lower than the recited value, the range is nevertheless defined by a lower limit defined by a non-zero value. It is not intended that the scope of the invention be limited to the specific values ​​recited when defining the range. All ranges are inclusive and combinable.

[0070] 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 is intended to include at least that particular value, unless the context clearly indicates otherwise.

[0071] It is understood that certain features of the invention that are described herein for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is deemed combinable with any other embodiment, and such combinations are deemed to be separate embodiments. Conversely, different features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. Finally, while embodiments may be described as part of a series of steps or as part of a more general structure, each step thereof may be deemed to be an independent embodiment in itself, combinable with the others.

[0072] Unless otherwise stated, any description of a possible mechanism or mechanism of action or reason for improvement is intended to be illustrative only, and the methods of the present disclosure are not limited by the merits or demerits of the proposed mechanism or mechanism of action or reason for improvement.

[0073] Various terms relating to aspects of the present specification are used throughout the specification and claims. Unless otherwise indicated, such terms shall be given their ordinary meaning in the art. Other specifically defined terms shall be construed in a manner consistent with the definition provided herein.

[0074] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0075] The transitional phrases "comprising," "consisting essentially of," and "consisting of" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by" and is inclusive or open-ended and does not exclude other, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of the claim to the specified materials or steps and those "which do not materially affect the basic and novel characteristics" of the claimed disclosure. Embodiments described with the phrase "comprising" (or its equivalents) also provide as embodiments embodiments described independently with "consisting of" and "consisting essentially of." An embodiment described with the phrase "consisting essentially of" (or its equivalents) also provides as an embodiment an embodiment described independently with "consisting of."

[0076] As used herein and in the appended claims, the phrase "and fragments thereof," when added to a list, includes fragments of one or more members of the associated list. A list may include Markush groups, such as, by way of example, the phrase "the group consisting of peptides A, B, and C and fragments thereof" designates or recites a Markush group that includes A, B, C, fragments of A, fragments of B, and / or fragments of C.

[0077] All publications, including but not limited to patents and patent applications, cited herein are incorporated by reference as if fully set forth.

[0078] Antibodies that bind to PSMA The present disclosure relates to isolated antibodies and antigen-binding fragments thereof that specifically bind to PSMA.

[0079] As used herein, the term "antibody" has a broad meaning and includes immunoglobulin molecules, including monoclonal antibodies, including murine, human, humanized, and chimeric monoclonal antibodies, antigen-binding fragments, multispecific antibodies, e.g., bispecific, trispecific, tetraspecific, dimeric, tetrameric, multimeric, or biparatopic antibodies, single-chain antibodies, domain antibodies, and any other modified form of immunoglobulin molecule that contains an antigen-binding site of the required specificity. The term antibody includes full-length antibodies, whole antibodies, intact antibodies, antibody fragments, antigen-binding fragments, and antigen-binding domains.

[0080] In general, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. The structure of antibodies is well known. Immunoglobulins can be assigned to five major classes (i.e., IgA, IgD, IgE, IgG, and IgM) depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Thus, antibodies of the present invention can be of any of the five major classes or corresponding subclasses. Preferably, antibodies of the present invention are IgG1, IgG2, IgG3, or IgG4. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, kappa and lambda, based on the amino acid sequence of their constant domains. Thus, antibodies of the present invention can contain either a kappa or a lambda light chain constant domain. According to some embodiments, antibodies of the present invention comprise heavy and / or light chain constant regions from a rat or human antibody. In addition to the heavy and light constant domains, antibodies contain an antigen-binding region consisting of a light chain variable region and a heavy chain variable region, each of which contains three domains (i.e., complementarity-determining regions 1-3; CDR1, CDR2, and CDR3). The light chain variable region domains are alternatively referred to as LCDR1, LCDR2, and LCDR3, and the heavy chain variable region domains are alternatively referred to as HCDR1, HCDR2, and HCDR3.

[0081] The "complementarity-determining region" (CDR) is the region of an antibody that binds to an antigen. There are three CDRs in VH (HCDR1, HCDR2, and HCDR3), and there are three CDRs in VL (LCDR1, LCDR2, and LCDR3). CDRs can be defined using various descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). Correspondence between various descriptions and the numbering of variable regions has been described (see, e.g., Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun (2001), J Mol Biol 309:657-70; the International ImMunoGeneTics (IMGT) database, a web resource, http: / / www_imgt_org). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms "CDR," "HCDR1," "HCDR2," "HCDR3," "LCDR1," "LCDR2," and "LCDR3" include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless expressly stated otherwise in the specification. For example, the correspondence between numbering systems, including Kabat numbering and the IMGT specific numbering system, is well known to those skilled in the art (see, eg, Kabat, supra; Chothia, supra; Martin, supra; Lefranc et al., supra).

[0082] [Table 1]

[0083] The term "variable region" or "variable domain" refers to the heavy or light chain domain that is involved in binding an antibody to an antigen. The heavy or light chain variable domain (VH and VL, respectively) contains four framework regions (FR) and three complementarity-determining regions (CDR).

[0084] As used herein, the term "isolated" refers to a homogenous population of molecules (e.g., synthetic polynucleotides or synthetic polypeptides) that have been substantially separated and / or purified from other components of the system in which they are produced, such as recombinant cells, and to proteins that have been subjected to at least one purification or isolation step. "Isolated" refers to molecules that are substantially free of other cellular material and / or chemicals and includes molecules isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0085] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to PSMA is substantially free of antibodies that do not bind to PSMA). In addition, an isolated antibody is substantially free of other cellular material and / or chemicals. "Isolated antibody" encompasses antibodies that have been isolated to a high degree of purity, such as antibodies that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure.

[0086] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations. Monoclonal antibodies of the invention can be produced by hybridoma methods, phage display techniques, single lymphocyte gene cloning techniques, or recombinant DNA methods. For example, monoclonal antibodies can be produced by hybridomas comprising B cells obtained from a transgenic non-human animal, e.g., a transgenic mouse or rat, having a genome comprising human heavy chain transgenes and light chain transgenes.

[0087] As used herein, the term "prostate-specific membrane antigen" or "PSMA" refers to a type II membrane protein expressed on certain cells. The amino acid sequence of human PSMA is encoded by the FOLH1 gene. Unless otherwise specified, PSMA as used herein refers to human PSMA. The amino acid sequence of human PSMA can be retrieved from Uniprot (accession number Q04609). The amino acid sequence of full-length human PSMA is set forth in SEQ ID NO: 336. In SEQ ID NO: 336, the extracellular domain spans residues 4-750, the transmembrane domain spans residues 0-43, and the cytoplasmic domain spans residues 1-19.

[0088] SEQ ID NO: 336 (full length human PSMA) MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0089] The term "PSMA" includes any PSMA variants, isoforms, and interspecies homologs that are naturally expressed by cells (including prostate cells) or that can be expressed on cells transfected with a gene or cDNA encoding the polypeptide. In certain embodiments, the PSMA is human PSMA.

[0090] "Specifically binds," "specific binding," "specifically binding," or "binds" refers to the binding of a proteinaceous molecule to an antigen or to an epitope within an antigen with greater affinity than its affinity for other antigens.

[0091] "Epitope" refers to the portion of an antigen to which an antibody specifically binds. Epitopes typically consist of surface groupings of chemically active (such as polar, nonpolar, or hydrophobic) moieties, e.g., amino acids or polysaccharide side chains, and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Epitopes may be composed of contiguous and / or discontinuous amino acids that form a conformational spatial unit. In discontinuous epitopes, amino acids in different parts of the linear sequence of the antigen are brought into close proximity in three-dimensional space due to folding of the protein molecule.

[0092] Typically, proteinaceous molecules are present at approximately 1×10 -7 M or less, e.g., about 5 × 10 -8 M or less, approximately 1×10 -8 M or less, approximately 1×10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or about 1 x 10 -12 The equilibrium dissociation constant (K D ) binds to an antigen or an epitope within an antigen, typically D is the K for binding to nonspecific antigens (e.g., BSA, casein) D is at least 100 times smaller than

[0093] The term "KD" refers to D The dissociation constant of an antibody is obtained from the ratio of its K to its K (i.e., K / Ka) and is expressed as a molar concentration (M). D Values ​​can be determined using methods in the art in light of the present disclosure. For example, the K DThe K of an antibody can be determined by using surface plasmon resonance, for example, by using a biosensor system, such as a Biacore® system, or by using biolayer interferometry techniques, for example, an Octet RED96 system. D The smaller the value of , the higher the affinity with which the antibody binds to the target antigen.

[0094] As used herein, an antibody that "binds to PSMA" or "specifically binds to PSMA" is an antibody that binds to PSMA in a concentration of 1×10 -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 K below M D refers to an antibody that binds to PSMA, preferably human PSMA.

[0095] The terms "isolated antibody," "antigen-binding fragment thereof," and "anti-PSMA antibody" are used interchangeably and refer to an antibody that binds to PSMA and contains at least one binding domain that specifically binds to PSMA.

[0096] As used herein, the term "biparatopic antibody" refers to an antibody that specifically binds to two different epitopes on the same target protein, e.g., PSMA.

[0097] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments of the present disclosure are biparatopic antibodies that bind to PSMA.

[0098] In some embodiments, a biparatopic antibody of the present disclosure comprises at least one receptor binding domain for a first epitope on a PSMA target protein and a second receptor binding domain for a second epitope on the same PSMA target protein. D and K for the second epitopeD In some embodiments, the K for the first epitope is the same. D and K for the second epitope D In some embodiments, the K for the first epitope is different. D and K for the second epitope D is approximately 1 x 10 -7 M or less, preferably 1 × 10 -8 M or less, preferably 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 It is below M.

[0099] The anti-PSMA antibodies of the present disclosure include whole antibodies, antibody fragments that specifically bind to PSMA, and antigen-binding fragments thereof that specifically bind to PSMA.

[0100] In some embodiments, the anti-PSMA antibodies of the present disclosure include whole or full-length antibodies, Fv fragments, single-chain scFv fragments (scFv), Fab, F(ab)2, or single-chain antibodies. In some embodiments, the anti-PSMA antibodies of the present disclosure are whole or full-length antibodies.

[0101] In some embodiments, the anti-PSMA antibodies of the present disclosure are full-length antibodies, whole antibodies, and intact antibodies.

[0102] The terms "full-length antibody," "whole antibody," and "intact antibody" are used interchangeably herein to refer to antibodies with a structure similar to that of a natural antibody. An "intact antibody" is composed of two heavy chains (HC) and two light chains (LC), inter-connected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be assigned to five major classes, namely, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy-chain constant domain. IgA and IgG are further subdivided into isotypes, IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, namely, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0103] In some embodiments, the anti-PSMA antibodies of the present disclosure are antibody fragments or antigen-binding domains that specifically bind to PSMA.

[0104] As used herein, the terms "antibody fragment" and "antigen-binding fragment" refer to molecules other than intact antibodies. Antigen-binding fragments may be synthetic, enzymatically obtainable, or genetically engineered polypeptides, and include portions of immunoglobulins that bind to antigens, such as VH, VL, VH and VL, Fab, Fab', F(ab'), Fd, and Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds-diabodies), single-chain antibody molecules (scFv), single domain antibodies (sdab), scFv dimers (bivalent diabodies), multispecific antibodies formed from portions of antibodies comprising one or more CDRs, camelized single domain antibodies, nanobodies, domain antibodies, domain antibodies consisting of one VH domain or one VL domain. "antibody, dAb), shark variable IgNAR domain, camelized VH domain, VHH domain, minimal recognition unit consisting of amino acid residues mimicking the CDRs of an antibody, e.g., a FR3-CDR3-FR4 portion, HCDR1, HCDR2 and / or HCDR3, and LCDR1, LCDR2 and / or LCDR3, alternative scaffolds that bind antigen, bivalent domain antibodies, multispecific proteins comprising antigen-binding fragments, or any other antibody fragment that binds antigen but does not comprise the complete antibody structure."

[0105] A "dAb" or "dAb fragment" refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544 546 (1989)).

[0106] "Fab" or "Fab fragment" refers to an antibody fragment composed of the VH, CH1, VL, and CL domains.

[0107] "F(ab')2" or "F(ab')2 fragment" refers to an antibody fragment containing two Fab fragments connected by a disulfide bridge in the hinge region.

[0108] "Fd" or "Fd fragment" refers to an antibody fragment composed of the VH and CH1 domains.

[0109] "Fv" or "Fv fragment" refers to an antibody fragment composed of the VH and VL domains from a single arm of an antibody. Fv fragments lack the constant regions of the Fab (CH1 and CL) regions. The VH and VL in an Fv fragment are held together by non-covalent interactions.

[0110] Antigen-binding fragments (e.g., VH and VL) can be linked together via synthetic linkers to form various types of single-chain antibody designs, in which the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding domains, e.g., single-chain Fvs (scFvs) or diabodies. In recombinant expression systems, the linker is a peptide linker and can include any naturally occurring amino acid. Exemplary amino acids that can be included in the linker are Gly, Ser, Pro, Thr, Glu, Lys, Arg, Ile, Leu, His, and The. The linker must be of an appropriate length to link the VH and VL in a manner that allows them to form the correct conformation relative to each other so as to retain the desired activity, such as binding to PSMA. The linker can be approximately 5 to 50 amino acids in length.

[0111] A "single-chain Fv" or "scFv" is a fusion protein comprising at least one antibody fragment comprising a light chain variable region (VL) and at least one antibody fragment comprising a heavy chain variable region (VH), where the VL and VH are contiguously linked via a polypeptide linker and can be expressed as a single-chain polypeptide. An scFv can have the VL and VH variable regions in either order, e.g., based on the N- and C-termini of the polypeptide, and can comprise either a VL-linker-VH or a VH-linker-VL.

[0112] In a recombinant expression system, the linker is a peptide linker and can contain any naturally occurring amino acid. Exemplary amino acids that can be included in the linker are Gly, Ser, Pro, Thr, Glu, Lys, Arg, Ile, Leu, His, and The. The linker must have a length that is appropriate for linking VH and VL in a manner that allows them to form the correct conformation relative to each other so as to maintain the desired activity, such as binding to PSMA.

[0113] The linker can be about 5 to 50 amino acids in length. In some embodiments, the linker is about 10 to 40 amino acids in length. In some embodiments, the linker is about 10 to 35 amino acids in length. In some embodiments, the linker is about 10 to 30 amino acids in length. In some embodiments, the linker is about 10 to 25 amino acids in length. In some embodiments, the linker is about 10 to 20 amino acids in length. In some embodiments, the linker is about 15 to 20 amino acids in length. In some embodiments, the linker is 6 amino acids in length. In some embodiments, the linker is 7 amino acids in length. In some embodiments, the linker is 8 amino acids in length. In some embodiments, the linker is 9 amino acids in length. In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 11 amino acids in length. In some embodiments, the linker is 12 amino acids in length. In some embodiments, the linker is 13 amino acids in length. In some embodiments, the linker is 14 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 16 amino acids in length. In some embodiments, the linker is 17 amino acids in length. In some embodiments, the linker is 18 amino acids in length. In some embodiments, the linker is 19 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 21 amino acids in length. In some embodiments, the linker is 22 amino acids in length. In some embodiments, the linker is 23 amino acids in length. In some embodiments, the linker is 24 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 26 amino acids in length. In some embodiments, the linker is 27 amino acids in length. In some embodiments, the linker is 28 amino acids in length. In some embodiments, the linker is 29 amino acids in length.In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 31 amino acids in length. In some embodiments, the linker is 32 amino acids in length. In some embodiments, the linker is 33 amino acids in length. In some embodiments, the linker is 34 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is 36 amino acids in length. In some embodiments, the linker is 37 amino acids in length. In some embodiments, the linker is 38 amino acids in length. In some embodiments, the linker is 39 amino acids in length. In some embodiments, the linker is 40 amino acids in length. Exemplary linkers that can be used are GIy-rich linkers, GIy- and Ser-containing linkers, GIy- and Ala-containing linkers, Ala- and Ser-containing linkers, and other flexible linkers.

[0114] Other linker sequences may include portions of an immunoglobulin hinge region, CL, or CH1, derived from an immunoglobulin heavy or light chain isotype. Alternatively, a variety of non-proteinaceous polymers may find use as linkers, including polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. Exemplary linkers that may be used are shown in Table 2.

[0115] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL).

[0116] In some embodiments, the scFv comprises, from N- to C-terminus, a VL, an L1, and a VH (VL-L1-VH).

[0117] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:308.

[0118] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:309.

[0119] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:310.

[0120] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:311.

[0121] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:312.

[0122] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:313.

[0123] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:314.

[0124] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:315.

[0125] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:316.

[0126] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:317.

[0127] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:318.

[0128] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:319.

[0129] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:320.

[0130] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:321.

[0131] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:322.

[0132] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:323.

[0133] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:324.

[0134] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:325.

[0135] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:326.

[0136] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:327.

[0137] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:328.

[0138] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:329.

[0139] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:330.

[0140] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:331.

[0141] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:332.

[0142] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:333.

[0143] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:334.

[0144] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:335.

[0145] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:87.

[0146] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:107.

[0147] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:91.

[0148] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:111.

[0149] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:285.

[0150] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:287.

[0151] [Table 2]

[0152] Divalent or bivalent single-chain variable fragments (di-scFv, bi-scFv) can be engineered by linking two scFvs. "(scFv)2" or "tandem scFv" or "bis-scFv" fragments refer to fusion proteins comprising two light chain variable regions (VL) and two heavy chain variable regions (VH), where the two VL regions and the two VH regions are linked consecutively via a polypeptide linker and can be expressed as a single polypeptide chain. Two VL regions and two VH regions are fused by a peptide linker to form a bivalent molecule, VL. A -Linker-VH A -Linker-VL B -Linker-VH B (ScFv)2 can be expressed as a single-chain polypeptide, forming two binding sites that can simultaneously bind to two different antigens or epitopes.

[0153] Any of the VH and VL domains identified herein that bind to PSMA can be engineered into scFv formats in either a VH-linker-VL or VL-linker-VH orientation. Any of the VH and VL domains identified herein can be used to generate sc(Fv)2 structures such as VH-linker-VL-linker-VL-linker-VH, VH-linker-VL-linker-VH-linker-VL, VH-linker-VH-linker-VL-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VL-linker-VH, or VL-linker-VL-linker-VH-linker-VH.

[0154] A "diabody" is a bivalent dimer formed from two chains, each containing a VH and a VL domain. The two domains within a chain are separated by a linker that is too short to promote intrachain dimerization, resulting in the two chains dimerizing in a head-to-tail configuration. The linker can be a pentameric glycine-rich linker (G4S (SEQ ID NO: 337)).

[0155] "VHH" refers to a single-domain antibody or nanobody composed exclusively of the antigen-binding domain of the heavy chain. VHH single-domain antibodies lack the CH1 domains of the light and heavy chains of a traditional Fab region. In some embodiments, the anti-PSMA antibodies of the present disclosure include Fv fragments, single-chain scFv fragments (scFv), (scFv)2, Fab, F(ab)2, diabodies, VHH, dAb, Fd, Fv, or other single-chain antibodies.

[0156] The anti-PSMA antibodies of the present disclosure include chimeric, humanized, or fully human antibodies that specifically bind to PSMA.

[0157] A "human antibody" refers to an antibody optimized to minimize an immune response when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If a human antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy and light chain variable regions "derived" from sequences of human origin when the variable regions of the human antibody are obtained from a system using human germline immunoglobulins or rearranged immunoglobulin genes. Exemplary such systems are phage-displayed human immunoglobulin gene libraries and transgenic non-human animals, such as mice or rats, carrying human immunoglobulin loci. A "human antibody" typically contains amino acid differences compared to immunoglobulins expressed in humans due to differences in the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations or intentional substitutions into frameworks or CDRs, or both.

[0158] Typically, a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. Optionally, a "human antibody" may contain consensus framework sequences derived from human framework sequence analysis, e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a phage-displayed human immunoglobulin gene library, e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and WO 2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0159] Transgenic animals, such as mice, rats, or chickens carrying human immunoglobulin (Ig) loci in their genomes, can be used to generate antigen-binding fragments that bind to PSMA, as described, for example, in U.S. Patent No. 6,150,584, WO 1999 / 45962, WO 2002 / 066630, WO 2002 / 043478, and WO 1990 / 04036. The endogenous immunoglobulin loci of such animals can be disrupted or deleted, and at least one complete or partial human immunoglobulin locus can be inserted into the animal's genome using homologous or non-homologous recombination, using a transchromosome, or using a minigene. Companies such as Regeneron (http: / / _www_regeneron_com), Harbour Antibodies (http: / / _www_harbourantibodies_com), Open Monoclonal Technology, Inc. (OMT) (http: / / _www_omtinc_net), KyMab (http: / / _www_kymab_com), Trianni (http: / / _www.trianni_com), and Ablexis (http: / / _www_ablexis_com) may be working to provide human antibodies targeted to select antigens.

[0160] Antibodies or antigen-binding fragments thereof that bind to PSMA and are produced by immunizing non-human animals can be humanized. Exemplary humanization techniques, including the selection of a human acceptor framework, include CDR grafting (U.S. Pat. No. 5,225,539), SDR grafting (U.S. Pat. No. 6,818,749), resurfacing (Padlan, (1991) Mol Immunol 28:489-499), specificity-determining residue resurfacing (U.S. Patent Application Publication No. 2010 / 0261620), human framework adaptation (U.S. Pat. No. 8,748,356), or superhumanization (U.S. Pat. No. 7,709,226). These methods involve grafting the CDRs or a subset of CDR residues of a parent antibody onto a human framework that can be selected based on overall homology to the parent framework, such as similarity in CDR length or canonical structure identity, or a combination thereof.

[0161] The humanized antigen-binding domain may be further optimized to improve its selectivity or affinity for the desired antigen by incorporating altered framework support residues to retain binding affinity (backmutation), or by introducing diversity into any of the CDRs, e.g., to improve the affinity of the antigen-binding domain, by techniques such as those described in WO 1090 / 007861 and WO 1992 / 22653.

[0162] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences: a. RYGMH (SEQ ID NO: 4), LISYDGSNRYYADSVKG (SEQ ID NO: 5), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; b. SYYWN (SEQ ID NO: 10), RIYSSGNTDYNPSLKS (SEQ ID NO: 11), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; c. GYGMH (SEQ ID NO: 16), VISYDGSNRYYADSVKG (SEQ ID NO: 17), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; d. SYGMH (SEQ ID NO: 22), VISYDGSNKYYADSVKG (SEQ ID NO: 23), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), AARDDSLSGYV (SEQ ID NO: 27), respectively; e. SYDMH (SEQ ID NO: 28), VISFDGSNKYYVDSVKG (SEQ ID NO: 29), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; f. TYGMH (SEQ ID NO: 34), FISYDGSNKYYADSVKG (SEQ ID NO: 35), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; g. IYSMN (SEQ ID NO: 40), SISSSSSYIFYADSVKG (SEQ ID NO: 41), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; h. SYSLN (SEQ ID NO: 46), SISSSSSYISYADAVKG (SEQ ID NO: 47), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; i. SYYWS (SEQ ID NO: 272), RIYSSGSTNYNPSLKS (SEQ ID NO: 273), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; j. GFTLSRY (SEQ ID NO: 124), SYDGSN (SEQ ID NO: 125), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; k. GGSISSY (SEQ ID NO: 130), YSSGN (SEQ ID NO: 131), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; l. VRTFSGY (SEQ ID NO: 136), SYDGSN (SEQ ID NO: 125), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; m. GFTFTSY (SEQ ID NO: 142), SYDGSN (SEQ ID NO: 125), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; n. GFTFSSY (SEQ ID NO: 148), SFDGSN (SEQ ID NO: 149), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; o. GFTFSTY (SEQ ID NO: 154), SYDGSN (SEQ ID NO: 125), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; p. GFTLSIY (SEQ ID NO: 160), SSSSSY (SEQ ID NO: 161), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; q. GFTFSSY (SEQ ID NO: 166), SSSSSY (SEQ ID NO: 167), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; r. GGSIISY (SEQ ID NO: 290), YSSGS (SEQ ID NO: 291), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; s. GFTLSRYGMH (SEQ ID NO: 172), LISYDGSNRY (SEQ ID NO: 173), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; t. GGSISSYYWN (SEQ ID NO: 178), RIYSSGNTD (SEQ ID NO: 179), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; u. VRTFSGYGMH (SEQ ID NO: 184), VISYDGSNRY (SEQ ID NO: 185), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; v. GFTFTSYGMH (SEQ ID NO: 190), VISYDGSNKY (SEQ ID NO: 191), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; w. GFTFSSYDMH (SEQ ID NO: 196), VISFDGSNKY (SEQ ID NO: 197), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; x. GFTFSTYGMH (SEQ ID NO: 202), FISYDGSNKY (SEQ ID NO: 203), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; GFTLSIYSMN (SEQ ID NO: 208), SISSSSSYIF (SEQ ID NO: 209), SSYGADY (SEQ ID NO: 42), RASQDITNFLA, (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; z. GFTFSSYSLN (SEQ ID NO: 214), SISSSSSYIS (SEQ ID NO: 215), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWL (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSF (SEQ ID NO: 51), respectively; aa. GGSIISYYWS (SEQ ID NO: 296), RIYSSGSTN (SEQ ID NO: 297), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; bb. GFTLSRYG (SEQ ID NO: 220), ISYDGSNR (SEQ ID NO: 221), ARERESSGWFEGYFDY (SEQ ID NO: 222), NIGSKS (SEQ ID NO: 223), DNS, and QVWDSSSDHVV (SEQ ID NO: 9), respectively; cc. GGSISSYY (SEQ ID NO: 226), IYSSGNT (SEQ ID NO: 227), ARGRGANVGLFDY (SEQ ID NO: 228), NSNIGANYD (SEQ ID NO: 229), GNI, and QSYDFSLSGSV (SEQ ID NO: 15), respectively; dd. VRTFSGYG (SEQ ID NO: 232), ISYDGSNR (SEQ ID NO: 233), ARDGNWGSLDLYFDL (SEQ ID NO: 234), SSNIGADYD (SEQ ID NO: 235), VNN, and QSYDNTLSGVV (SEQ ID NO: 21), respectively; ee. GFTFTSYG (SEQ ID NO: 238), ISYDGSNK (SEQ ID NO: 239), AREHYDSSGYYHGYYGMDV (SEQ ID NO: 240), SSNIGSNY (SEQ ID NO: 241), SNN, and AARDDSLSGYV (SEQ ID NO: 27), respectively. ff. GFTFSSYD (SEQ ID NO: 244), ISFDGSNK (SEQ ID NO: 245), ARTYYDILTGYSHYSYGMDV (SEQ ID NO: 246), QGISNY (SEQ ID NO: 247), ATS, and QKYNSAPFT (SEQ ID NO: 33), respectively; gg. GFTFSTYG (SEQ ID NO: 250), ISYDGSNK (SEQ ID NO: 251), AGRDNLRFLEWFMDV (SEQ ID NO: 252), QSVRSN (SEQ ID NO: 253), GAS, and HQYNDWPPYT (SEQ ID NO: 39), respectively; hh. GFTLSIYS (SEQ ID NO: 256), ISSSSSYI (SEQ ID NO: 257), ARSSYGADY (SEQ ID NO: 258), QDITNF (SEQ ID NO: 259), TAS, and QKYNSAPLT (SEQ ID NO: 45), respectively; ii. GFTFSSYS (SEQ ID NO: 262), ISSSSSYI (SEQ ID NO: 263), ARDRGFLEDYYYYYGMDV (SEQ ID NO: 264), QGISNW (SEQ ID NO: 265), VAS, and QQAYSFPLT (SEQ ID NO: 51), respectively; jj. GGSIISYY (SEQ ID NO: 302), IYSSGST (SEQ ID NO: 303), AKVGVWPGAFDI (SEQ ID NO: 304), SSNIGSNT (SEQ ID NO: 305), SSN, and AAWDDSLNGVV (SEQ ID NO: 277), respectively.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0164] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0165] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 16, 17, 18, 29, 20, and 21, respectively.

[0166] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26, and 27, respectively.

[0167] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively.

[0168] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38, and 39, respectively.

[0169] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively.

[0170] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50, and 51, respectively.

[0171] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof that binds to PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276, and 277, respectively.

[0172] The present disclosure also provides Heavy chain complementarity determining region (HCDR) 1, HCDR2, and HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 52, and light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3 of the light chain variable region (VL) of SEQ ID NO: 53, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 54 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 55, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 56 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 57, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 58 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 59, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 60 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 61, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 62 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 63, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 64 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 65, or HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 66 and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 67, or An isolated antibody or antigen-binding fragment thereof is provided, comprising HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO:278, and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO:279.

[0173] In some embodiments, the isolated protein comprising the antigen-binding domain comprises HCDR1, HCDR2, and HCDR3 of the VH of SEQ ID NO: 52 and LCDR1, LCDR2, and LCDR3 of the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment thereof binds to PSMA.

[0174] In some embodiments, the isolated protein comprising the antigen-binding domain comprises HCDR1, HCDR2, and HCDR3 of the VH of SEQ ID NO: 54 and LCDR1, LCDR2, and LCDR3 of the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment thereof binds to PSMA.

[0175] In some embodiments, the present disclosure provides: VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, or VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55, or VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57, or VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59, or VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, or VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63, or VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65, or VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67, or An isolated antibody or antigen-binding fragment thereof is provided, comprising a VH of SEQ ID NO: 278 and a VL of SEQ ID NO: 279, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:52 and a VL of SEQ ID NO:53.

[0177] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:54 and a VL of SEQ ID NO:55.

[0178] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:56 and a VL of SEQ ID NO:57.

[0179] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:58 and a VL of SEQ ID NO:59.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:60 and a VL of SEQ ID NO:61.

[0181] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:62 and a VL of SEQ ID NO:63.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:64 and a VL of SEQ ID NO:65.

[0183] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:66 and a VL of SEQ ID NO:67.

[0184] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:278 and a VL of SEQ ID NO:279.

[0185] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284, and 288.

[0186] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:84.

[0187] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:85.

[0188] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:86.

[0189] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:88.

[0190] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:89.

[0191] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:90.

[0192] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:84 and a light chain of SEQ ID NO:85.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:86 and a light chain of SEQ ID NO:85.

[0194] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:88 and a light chain of SEQ ID NO:89.

[0195] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:90 and a light chain of SEQ ID NO:89.

[0196] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:92 and a light chain of SEQ ID NO:93.

[0197] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:94 and a light chain of SEQ ID NO:95.

[0198] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:96 and a light chain of SEQ ID NO:97.

[0199] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:98 and a light chain of SEQ ID NO:99.

[0200] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:100 and a light chain of SEQ ID NO:101.

[0201] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a heavy chain of SEQ ID NO:102 and a light chain of SEQ ID NO:103.

[0202] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a first heavy chain of SEQ ID NO:268, a second heavy chain of SEQ ID NO:282, and a light chain of SEQ ID NO:269.

[0203] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a first heavy chain of SEQ ID NO:284, a second heavy chain of SEQ ID NO:288, and a light chain of SEQ ID NO:269.

[0204] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 84 and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0205] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 86 and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0206] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively; VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 88 and an LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0207] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively; VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 90 and an LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0208] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20, and 21, respectively; VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 92 and an LC of SEQ ID NO: 93, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0209] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26, and 27, respectively; VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 94 and an LC of SEQ ID NO: 95, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0210] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively; VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 96 and an LC of SEQ ID NO: 97, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0211] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38, and 39, respectively; VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 98 and an LC of SEQ ID NO: 99, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0212] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively; VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 100 and an LC of SEQ ID NO: 101, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0213] In some embodiments, the present disclosure provides: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50, and 51, respectively; VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67, and / or An isolated antibody or antigen-binding fragment thereof is provided, comprising an HC of SEQ ID NO: 102 and an LC of SEQ ID NO: 103, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0214] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA.

[0215] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a CDR1 sequence having the amino acid sequence of SEQ ID NO: 4, a CDR2 sequence having the amino acid sequence of SEQ ID NO: 5, a CDR3 sequence having the amino acid sequence of SEQ ID NO: 6, a CDR1 sequence having the amino acid sequence of SEQ ID NO: 7, a CDR2 sequence having the amino acid sequence of SEQ ID NO: 8, and a CDR3 sequence having the amino acid sequence of SEQ ID NO: 9, in combination with a light chain variable region comprising a heavy chain variable region comprising a CDR1 sequence having the amino acid sequence of SEQ ID NO: 272, a CDR2 sequence having the amino acid sequence of SEQ ID NO: 273, and a CDR3 sequence having the amino acid sequence of SEQ ID NO: 274, a CDR1 sequence having the amino acid sequence of SEQ ID NO: 275, a CDR2 sequence having the amino acid sequence of SEQ ID NO: 276, and a CDR3 sequence having the amino acid sequence of SEQ ID NO: 277, wherein the antibody or antigen-binding fragment thereof binds to PSMA, optionally to two different epitopes on PSMA.

[0216] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA; the first antigen-binding domain is a Fab or a Fab fragment comprising an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 5, an HCDR3 of SEQ ID NO: 6, an LCDR1 of SEQ ID NO: 7, an LCDR2 of SEQ ID NO: 8, an LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, an HC of SEQ ID NO: 268, and an LC of SEQ ID NO: 269; The second antigen-binding domain is in the form of an scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, and HC of SEQ ID NO: 282.

[0217] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA; the first antigen-binding domain is a Fab or Fab fragment comprising an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 5, an HCDR3 of SEQ ID NO: 6, an LCDR1 of SEQ ID NO: 7, an LCDR2 of SEQ ID NO: 8, an LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, an HC of SEQ ID NO: 284, and an LC of SEQ ID NO: 269; The second antigen-binding domain is in the form of an scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, and HC of SEQ ID NO: 288.

[0218] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and comprises a heavy chain of SEQ ID NO: 268 and a light chain of SEQ ID NO: 269, and a second binding domain binds to a different epitope on PSMA and comprises a heavy chain of SEQ ID NO: 282.

[0219] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and comprises a heavy chain of SEQ ID NO: 284 and a light chain of SEQ ID NO: 269, and a second binding domain binds to a different epitope on PSMA and comprises a heavy chain of SEQ ID NO: 288.

[0220] In some embodiments, the present disclosure provides: a first binding domain that binds to a first epitope on PSMA, the first binding domain comprising: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or a first binding domain comprising an HC of SEQ ID NO: 268 and an LC of SEQ ID NO: 269; a second binding domain that binds to a second epitope on PSMA, wherein the second binding domain comprises: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276, and 277, respectively; VH of SEQ ID NO: 278 and VL of SEQ ID NO: 279, and / or and a second binding domain comprising the HC of SEQ ID NO: 282.

[0221] In some embodiments, the present disclosure provides: a first binding domain that binds to a first epitope on PSMA, the first binding domain comprising: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53, and / or a first binding domain comprising an HC of SEQ ID NO: 284 and an LC of SEQ ID NO: 269; a second binding domain that binds to a second epitope on PSMA, wherein the second binding domain comprises: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276, and 277, respectively; VH of SEQ ID NO: 278 and VL of SEQ ID NO: 279, and / or and a second binding domain comprising the HC of SEQ ID NO: 288.

[0222] Homologous antibodies and antigen-binding fragments thereof Derivatives, homologous antigen-binding domains, functional equivalents, or variants of the antibodies or antigen-binding fragments thereof are also the subject of this disclosure. Antibodies of the present disclosure include homologous antibodies, homologous antigen-binding domains, functional equivalents, or variants of the disclosed antibodies or antigen-binding fragments thereof that bind to PSMA, including polypeptides having amino acid sequences substantially identical to, or having conservative substitutions in, the amino acid sequences of the variable or hypervariable domains of the antibodies of the present disclosure. Homologous antibodies and antigen-binding domains, functional equivalents, or variants of the present disclosure have sufficient homology with the sequence of the antibodies or antigen-binding fragments thereof that bind to PSMA and are functionally similar to the unmodified anti-PSMA antibody to retain binding to PSMA or retain at least one of the activities of the unmodified antibody.

[0223] The terms "antibody derivative," "homologous antigen-binding domain," "functional equivalent," or "variant" refer to an antibody that contains one or more mutations, substitutions, deletions, and / or additions of one or more amino acid residues. Such additions, substitutions, or deletions may be located at any position in the molecule. When several amino acids are added, substituted, or deleted, any combination of additions, substitutions, or deletions is contemplated, provided that the resulting antibody still possesses at least the advantageous properties of the antibodies of the present disclosure.

[0224] In some embodiments, the present disclosure provides amino acid sequence modifications of the antibodies or antigen-binding fragments thereof described herein. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody, including, but not limited to, specificity, thermal stability, expression levels, effector functions, glycosylation (e.g., fucosylation), reduced immunogenicity, or solubility. Thus, in addition to the antibodies and antigen-binding fragments described herein, antibody variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA and / or by mutating, substituting, deleting, and / or adding one or more amino acid residues to the antibodies and antigen-binding fragments described herein.

[0225] In some embodiments, the antibodies and antigen-binding fragments thereof provided herein are chemically modified, for example, by covalently attaching any type of molecule to the antibody. Antibody derivatives can include antibodies that have been chemically modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to cellular ligands or other proteins, etc. Any of a number of chemical modifications can be performed by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. Additionally, the antibody can contain one or more non-classical amino acids.

[0226] Diversity may also include substitutions, deletions, or insertions of one or more codons encoding the antibody or polypeptide, resulting in a change in the amino acid sequence compared to the native sequence antibody or polypeptide. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties.

[0227] The sequences of the present disclosure may comprise an amino acid sequence having at least 80% identity or homology to the sequences of the antibodies or antigen-binding fragments thereof described above. In some embodiments, the sequence identity may be about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to the antigen-binding domain that binds PSMA of the present disclosure. Variants of the PSMA-binding antigen-binding domain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 amino acid substitutions in the PSMA-binding antigen-binding domain are within the scope of the present disclosure, so long as they retain or have improved functional properties compared to the parent antigen-binding domain. Functional equivalents or variants of the PSMA-binding antigen-binding domain include one or more deletions and / or additions of one or more amino acid residues. Such additions, substitutions, or deletions can be located at any position in the molecule. When several amino acids are added, substituted, or deleted, any combination of additions, substitutions, or deletions is contemplated, provided that the resulting antibody still possesses at least the advantageous properties of the antibodies of the present disclosure.

[0228] The term "identical" or percent "identity," in the context of two or more nucleic acid or polypeptide sequences (e.g., anti-PSMA antibodies and the polynucleotides encoding them), refers to two or more sequences or subsequences that are the same or have a specified percentage of the same amino acid residues or nucleotides when compared and aligned for maximum correspondence, as determined using one of the following sequence comparison algorithms or by visual inspection. Percent (%) amino acid sequence identity to a reference polypeptide is defined as the percentage of amino acid residues in a given sequence that are identical with amino acid residues in the reference polypeptide sequence. The percent (%) identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions × 100), taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. The percent identity between two amino acid sequences can be determined using various algorithms within the skill of the art using publicly available software such as the BLAS, BLAST-2, ALIGN.Megalin (DNASTAR), or GAP programs available in the GCG software package.

[0229] A polypeptide is typically substantially identical to a second polypeptide, e.g., the two peptides differ only by conservative substitutions. Antibodies of the present disclosure also include those in which binding characteristics, functional, or physical properties have been improved by directed mutation. In some embodiments, a variant antigen-binding domain that binds to PSMA contains one or two conservative substitutions in any of the CDR regions while retaining the desired functional properties of the parent antigen-binding fragment that binds to PSMA.

[0230] In certain embodiments, substitutions are conservative amino acid substitutions made at one or more predicted non-essential amino acid residues. A "conservative modification" or "conservative substitution" refers to an amino acid modification that does not significantly affect or alter the binding characteristics of the antibody containing the amino acid modification. Conservative modifications include amino acid substitutions, additions, and deletions. A conservative amino acid substitution is one in which an amino acid is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are well-defined and include amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine), amides (e.g., asparagine, glutamine), beta-branched side chains (e.g., threonine, valine, isoleucine), and sulfur-containing side chains (cysteine, methionine). Additionally, any naturally occurring residue in the polypeptide can also be substituted with alanine, as previously described for alanine scanning mutagenesis (MacLennan et al., (1988) Acta Physiol Scand Suppl 643:55-67; ​​Sasaki et al., (1988) Adv Biophys 35:1-24).

[0231] Standard techniques known to those of skill in the art can be used to introduce mutations into the nucleotide sequences encoding the molecules provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis that results in amino acid substitutions.

[0232] Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resulting mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed and the activity of the protein determined.

[0233] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., antibody-directed enzyme prodrug therapy) or a polypeptide which increases the serum half-life of the antibody.

[0234] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53.

[0235] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 55.

[0236] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 56, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 57.

[0237] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 58, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 59.

[0238] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 60, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 61.

[0239] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 62, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 63.

[0240] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 64, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 65.

[0241] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 66, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 67.

[0242] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 278, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 279.

[0243] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL of SEQ ID NO: 53.

[0244] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 52 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53.

[0245] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:52 and a VL that is at least 95% identical to the VL of SEQ ID NO:53.

[0246] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:52, and a VL of SEQ ID NO:53.

[0247] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:52 and a VL that is at least 95% identical to the VL of SEQ ID NO:53.

[0248] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:52 and a VL that is at least 99% identical to the VL of SEQ ID NO:53.

[0249] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO:52 and a VL that is at least 99% identical to the VL of SEQ ID NO:53.

[0250] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO:52 and a VL that is at least 95% identical to the VL of SEQ ID NO:53.

[0251] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0252] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0253] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 52 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0254] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 52 and a VL that is at least 95% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0255] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0256] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 52 and a VL that is at least 95% identical to a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0257] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 52 and a VL that is at least 99% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0258] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 52 and a VL that is at least 99% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0259] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 52 and a VL that is at least 95% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0260] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 84, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0261] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0262] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0263] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 84, and a LC of SEQ ID NO: 85.

[0264] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 84 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85.

[0265] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:84 and a LC that is at least 95% identical to the LC of SEQ ID NO:85.

[0266] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:84 and a LC that is at least 99% identical to the LC of SEQ ID NO:85.

[0267] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:84 and a LC that is at least 99% identical to the LC of SEQ ID NO:85.

[0268] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:84 and a LC that is at least 95% identical to the LC of SEQ ID NO:85.

[0269] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 86, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0270] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0271] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 86, and a LC of SEQ ID NO: 85.

[0272] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 86 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85.

[0273] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:86 and a LC that is at least 95% identical to the LC of SEQ ID NO:85.

[0274] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:86 and a LC that is at least 99% identical to the LC of SEQ ID NO:85.

[0275] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:86 and a LC that is at least 99% identical to the LC of SEQ ID NO:85.

[0276] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:86 and a LC that is at least 95% identical to the LC of SEQ ID NO:85.

[0277] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 88, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0278] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0279] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0280] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 88, and a LC of SEQ ID NO: 89.

[0281] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 88 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 89.

[0282] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:88 and a LC that is at least 95% identical to the LC of SEQ ID NO:89.

[0283] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 95% identical to the HC of SEQ ID NO:88 and a LC that is at least 99% identical to the LC of SEQ ID NO:89.

[0284] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:88 and a LC that is at least 99% identical to the LC of SEQ ID NO:89.

[0285] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 99% identical to the HC of SEQ ID NO:88 and a LC that is at least 95% identical to the LC of SEQ ID NO:89.

[0286] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0287] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 84, and a LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0288] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 84 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0289] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0290] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0291] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0292] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0293] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0294] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 86, and a LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0295] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 86 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0296] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0297] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0298] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0299] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0300] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0301] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 88, and a LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0302] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 88 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0303] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 95% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0304] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0305] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 88 and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0306] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 88 and an LC that is at least 95% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0307] The present disclosure also provides an isolated antibody comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0308] In some embodiments, the antibody that binds to PSMA comprises an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 84, and an LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0309] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 84 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0310] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0311] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0312] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0313] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0314] The present disclosure also provides an isolated antibody comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0315] In some embodiments, an antibody that binds to PSMA comprises an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 86, and an LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0316] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC of SEQ ID NO: 86 and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0317] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0318] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0319] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0320] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0321] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL of SEQ ID NO: 55.

[0322] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 54 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 55.

[0323] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:54 and a VL that is at least 95% identical to the VL of SEQ ID NO:55.

[0324] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:54, and a VL of SEQ ID NO:55.

[0325] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO:54 and a VL that is at least 95% identical to the VL of SEQ ID NO:55.

[0326] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO:54 and a VL that is at least 99% identical to the VL of SEQ ID NO:55.

[0327] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO:54 and a VL that is at least 99% identical to the VL of SEQ ID NO:55.

[0328] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO:54 and a VL that is at least 95% identical to the VL of SEQ ID NO:55.

[0329] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0330] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0331] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 54 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0332] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 54 and a VL that is at least 95% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0333] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0334] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 54 and a VL that is at least 95% identical to a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0335] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 54 and a VL that is at least 99% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0336] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 54 and a VL that is at least 99% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0337] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 54 and a VL that is at least 95% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0338] The present disclosure also provides an isolated antibody comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0339] In some embodiments, an antibody that binds to PSMA comprises an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 88, and an LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0340] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 88 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0341] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 95% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0342] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0343] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 88 and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0344] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 88 and an LC that is at least 95% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0345] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA; the first antigen-binding domain comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53; The second antigen-binding domain comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 278, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 279.

[0346] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA; the first antigen-binding domain comprises a heavy chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO: 268, and a light chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO: 269; The second antigen-binding domain comprises a heavy chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO:282.

[0347] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA; the first antigen-binding domain comprises a heavy chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO: 284, and a light chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO: 269; The second antigen-binding domain comprises a heavy chain that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to SEQ ID NO:288.

[0348] Half-life extending moieties and Fc engineering In addition to the modifications described above, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure and their functional equivalents may be conjugated to other antibodies, proteins, antigen-binding fragments, or alternative scaffolds that can be used to adjust, alter, improve, or modify antibody characteristics as desired.

[0349] For example, antibodies with increased in vivo half-lives can be generated by conjugating half-life extending moieties, such as albumin, albumin variants, albumin-binding proteins and / or domains, transferrin, and fragments and analogs thereof, immunoglobulins (Igs) or fragments thereof, such as the Fc region, to the antibodies or antigen-binding fragments of the present disclosure. Additional half-life extending moieties include polyethylene glycol (PEG) molecules, e.g., PEG 5000 or PEG 20,000, fatty acids and fatty acid esters of different chain lengths, e.g., laurate, myristate, stearate, arachidate, behenate, oleate, arachidonate, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, etc., polylysine, octane, carbohydrates (dextran, cellulose, oligosaccharides, or polysaccharides), for desired properties. These moieties can be fused directly to the antibodies or antigen-binding fragments of the present disclosure or generated by standard cloning and expression techniques.

[0350] The half-life extending moiety can be attached to the antibody, or antibody fragment or derivative, either through conjugation to the N- or C-terminus of the antibody or antibody fragment, or through the epsilon-amino group present on a lysine residue, with or without a multifunctional linker. Alternatively, the moiety can be attached to a recombinantly produced antibody or antigen-binding fragment of the disclosure using well-known chemical coupling methods.

[0351] For example, a pegylated moiety can be conjugated to an antibody or antigen-binding fragment thereof that binds PSMA by incorporating or engineering a cysteine ​​residue into the C-terminus of the antibody or antigen-binding fragment that binds PSMA so that the cysteine ​​is at a residue position facing away from the PSMA binding site, and attaching the pegylated group to the cysteine ​​using well-known methods.

[0352] In some embodiments, the half-life extending moiety is albumin.

[0353] In some embodiments, the half-life extending moiety is an albumin binding domain.

[0354] In some embodiments, the half-life extending moiety is transferrin.

[0355] In some embodiments, the half-life extending moiety is polyethylene glycol.

[0356] In some embodiments, the half-life extending moiety is an Ig constant region or a fragment of an Ig constant region.

[0357] In some embodiments, the half-life extending moiety is Ig.

[0358] In some embodiments, the half-life extending moiety is a fragment of Ig.

[0359] In some embodiments, the half-life extending moiety is an Ig constant region.

[0360] In some embodiments, the half-life extending moiety is a fragment of an Ig constant region.

[0361] In some embodiments, the half-life extending moiety is an Fc region.

[0362] The Ig constant region or fragment of an Ig constant region, e.g., the Fc region, present in the antibodies or antigen-binding fragments thereof of the present disclosure can be of any allotype or isotype, i.e., IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE.

[0363] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG1 isotype.

[0364] In some embodiments, the Ig constant region or fragment of an Ig constant region is an IgG2 isotype.

[0365] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG3 isotype.

[0366] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG4 isotype.

[0367] Allotypes are not expected to affect Ig constant region properties such as binding or Fc-mediated effector functions. The immunogenicity of therapeutic proteins containing fragment Ig constant regions is associated with an increased risk of infusion reactions and a shorter duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The degree to which therapeutic proteins containing fragment Ig constant regions induce an immune response in the host may be determined, in part, by the Ig constant region allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). Ig constant region allotypes are associated with variations in the amino acid sequence at specific positions in the antibody constant region sequence.

[0368] The antibodies or antigen-binding fragments thereof of the present disclosure, and functional equivalents thereof, can be conjugated to an Ig constant region or a fragment of an Ig constant region to modulate the effector functions, e.g., ADCC, ADCP, and / or ADCP, and / or pharmacokinetic properties, of the antibody or antigen-binding fragment. This can be achieved by introducing mutations in the Fc that modulate binding of the mutated Fc to activating FcγRs (FcγRI, FcγRIIa, FcγRIII), inhibitory FcγRIIb, and / or FcRn.

[0369] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region that comprises at least one mutation in the Ig constant region or in the fragment of the Ig constant region.

[0370] In some embodiments, at least one mutation is in the Fc region.

[0371] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region and comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mutations in the Fc region.

[0372] The neonatal Fc receptor (FcRn) plays a central role in the cellular trafficking and serum half-life of IgG. In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region that contains at least one mutation in the Fc region that modulates binding of the antibody or antigen-binding fragment to FcRn and modulates the half-life of the antibody or antigen-binding fragment.

[0373] In some embodiments, the Ig constant region or fragment of the first Ig constant region comprises at least one mutation that modulates the half-life of the isolated antibody or antigen-binding fragment thereof.

[0374] Positions in Fc that can be mutated to modulate half-life (e.g., binding to FcRn) include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434, and 435. Exemplary mutations that can be made alone or in combination are the mutations T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A, and H435R. Exemplary mutations that can be made, alone or in combination, to increase half-life are the mutations M428L / N434S, M252Y / S254T / T256E, T250Q / M428L, N434A, and T307A / E380A / N434A. In some embodiments, the at least one mutation that modulates the half-life of an antibody or antigen-binding fragment thereof, and functional equivalents thereof, of the disclosure is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, where residue numbering is according to the EU index.

[0375] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region that includes the M252Y / S254T / T256E mutations.

[0376] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure, and functional equivalents thereof, are conjugated to an Ig constant region or a fragment of an Ig constant region that comprises at least one mutation in the Fc region that reduces binding of the protein to activating Fcγ receptors (FcγRs) and / or reduces an Fc effector function, such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody-dependent cell-mediated phagocytosis (ADCP).

[0377] Fc positions that can be mutated to reduce binding of the protein to activating FcγRs and subsequently reduce effector function include positions 214, 233, 234, 235, 236, 237, 238, 265, 267, 268, 270, 295, 297, 309, 327, 328, 329, 330, 331, and 365. Exemplary mutations that may be made alone or in combination are the mutations K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A330S, and P331S in IgG1, IgG2, IgG3, or IgG4. Exemplary combinations of mutations that result in proteins with reduced ADCC are L234A / L235A in IgG1, L234A / L235A / D265S in IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S in IgG2, F234A / L235A in IgG4, S228P / F234A / L235A in IgG4, N297A in all Ig isotypes, V234A / G237A in IgG2, K214T / E233P / L234V / L235A / G in IgG1 The mutations are 236 deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S in IgG2, S267E / L328F in IgG1, L234F / L235E / D265A in IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S in IgG1, S228P / F234A / L235A / G237A / P238S in IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S in IgG4. Alternatively, a hybrid IgG2 / 4 Fc domain may be used, such as an Fc having residues 117-260 from IgG2 and residues 261-447 from IgG4.

[0378] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an IgG1 heavy chain constant region or a fragment of an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises at least one mutation that results in reduced binding of the antibody to an FcγR. In some embodiments, the at least one mutation that results in reduced binding of the antibody to an FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 deletion / A327G / and S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236 deletion / G237A / P238S, wherein residue numbering is according to the EU index.

[0379] In some embodiments, the first Ig constant region or fragment of a first Ig constant region, and / or the second Ig constant region or fragment of a second Ig constant region comprises the following mutation: L234A_L235A_D265S.

[0380] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0381] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure, and functional equivalents thereof, are conjugated to an Ig constant region or a fragment of an Ig constant region comprising at least one mutation in the Fc region that enhances binding of the protein to Fcγ receptors (FcγRs) and / or enhances an Fc effector function, such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and / or phagocytosis (ADCP).

[0382] Fc positions that can be mutated to increase binding of the protein to activating FcγRs and / or enhance Fc effector function include positions 236, 239, 243, 256, 290, 292, 298, 300, 305, 312, 326, 330, 332, 333, 334, 345, 360, 339, 378, 396, or 430 (residue numbering according to the EU index). Exemplary mutations that can be made singly or in combination are G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T, and P396L. Exemplary combinations of mutations that result in proteins with increased ADCC or ADCP are S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L, and G236A / S239D / I332E.

[0383] Fc positions that can be mutated to enhance CDC include positions 267, 268, 324, 326, 333, 345, and 430. Exemplary mutations that can be made singly or in combination are S267E, F1268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F, and E430T. Exemplary combination mutations that result in proteins with increased CDC are K326A / E333A, K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T, and S267E / H268F / S324T.

[0384] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0385] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0386] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0387] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52, and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., Ig G1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0388] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 52 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., Ig G1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0389] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 52, and a VL that is at least 95% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally , the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0390] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 52 and a VL that is at least 99% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally , the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0391] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 52, and a VL that is at least 99% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally , the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0392] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 52 and a VL that is at least 95% identical to the VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally , the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0393] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0394] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0395] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0396] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 54, and a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., , IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0397] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 54 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., I and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0398] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 54, and a VL that is at least 95% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally Alternatively, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0399] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 95% identical to the VH of SEQ ID NO: 54 and a VL that is at least 99% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally Alternatively, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0400] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 54, and a VL that is at least 99% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally Alternatively, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0401] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 99% identical to the VH of SEQ ID NO: 54 and a VL that is at least 95% identical to the VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally Alternatively, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0402] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 84, wherein the antibody or antigen-binding fragment thereof binds to PSMA, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, a first Ig constant region or or the first Ig constant region or fragment thereof, and / or the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment thereof, and the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0403] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, a first Ig constant region or or the first Ig constant region or fragment thereof, and / or the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment thereof, and the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0404] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ); Optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0405] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 84, and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0406] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 84 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0407] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0408] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 84 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0409] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84, and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0410] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 84 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E.

[0411] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 86, wherein the antibody or antigen-binding fragment binds to PSMA, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, a first Ig constant region or or a fragment of the first Ig constant region, and / or a second Ig constant region or a fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or a fragment of the first Ig constant region, and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0412] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, a first Ig constant region or or the first Ig constant region or fragment thereof, and / or the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment thereof, and the second Ig constant region or fragment thereof, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0413] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ); Optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0414] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 86, and a LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0415] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 86 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0416] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0417] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 86 and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0418] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0419] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E.

[0420] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ); Optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0421] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the HC of SEQ ID NO: 88, and a LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0422] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 88 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0423] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 95% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0424] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 95% identical to the HC of SEQ ID NO: 88 and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0425] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 88, and an LC that is at least 99% identical to the LC of SEQ ID NO: 89, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0426] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises an HC that is at least 99% identical to the HC of SEQ ID NO: 86 and an LC that is at least 95% identical to the LC of SEQ ID NO: 85, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally, the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S and / or M252Y / S254T / T256E.

[0427] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0428] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LC of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. DR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0429] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LC of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. DR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0430] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0431] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0432] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0433] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0434] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0435] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LC of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. DR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0436] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LC of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. DR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0437] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0438] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0439] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0440] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively. R3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0441] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0442] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0443] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 100% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0444] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0445] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0446] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0447] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and HCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1λ), and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0448] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0449] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first Ig constant. The region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0450] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 84 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first wherein the Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0451] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0452] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0453] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0454] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 84, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0455] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0456] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first Ig constant. The region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0457] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 86 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first wherein the Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0458] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0459] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0460] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0461] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0462] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0463] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first Ig constant. The region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0464] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 86 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first wherein the Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0465] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0466] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0467] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0468] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 86, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0469] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0470] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first Ig constant. The region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0471] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises a HC of SEQ ID NO: 88 and a LC that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), and optionally a first wherein the Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region, comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, for example, the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0472] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0473] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 85, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0474] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0475] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an HC that is at least 99% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the HC of SEQ ID NO: 88, and an LC that is at least 95% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55. and optionally the first Ig constant region or fragment of the first Ig constant region, and / or the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, e.g., the first Ig constant region or fragment of the first Ig constant region, and the second Ig constant region or fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0476] Polynucleotides Polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure, and functional equivalents thereof, are also provided. The present disclosure provides isolated polynucleotides encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure.

[0477] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:52.

[0478] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:54.

[0479] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:56.

[0480] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:58.

[0481] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:60.

[0482] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:62.

[0483] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:64.

[0484] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:66.

[0485] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:278.

[0486] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:53.

[0487] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:55.

[0488] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:57.

[0489] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:59.

[0490] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:61.

[0491] In some embodiments, the disclosure includes an isolated polynucleotide encoding the VL of SEQ ID NO:63.

[0492] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:65.

[0493] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:67.

[0494] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:279.

[0495] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:84.

[0496] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:86.

[0497] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:88.

[0498] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:90.

[0499] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:92.

[0500] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:94.

[0501] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:96.

[0502] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:98.

[0503] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:100.

[0504] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:102.

[0505] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:268.

[0506] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:282.

[0507] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:284.

[0508] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:288.

[0509] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:85.

[0510] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:89.

[0511] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:93.

[0512] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:95.

[0513] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:97.

[0514] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:99.

[0515] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:101.

[0516] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:103.

[0517] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:269.

[0518] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:52 and 53.

[0519] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:84 and 85.

[0520] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:86 and 85.

[0521] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:54 and 55.

[0522] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:88 and 89.

[0523] In some embodiments, the disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs: 52, 53, 278, and 279.

[0524] In some embodiments, the present disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs: 268, 269, and 282.

[0525] In some embodiments, the present disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs: 284, 269, and 288.

[0526] In some embodiments, the disclosure provides an isolated polynucleotide of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

[0527] Polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure include polynucleotides having a nucleic acid sequence substantially identical to that of the polynucleotides of the present disclosure. A "substantially identical" nucleic acid sequence is defined herein as a sequence that has at least 80% identity to another nucleic acid sequence when the two sequences are aligned. Two nucleic acid sequences are substantially identical if the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

[0528] Modified nucleotides can be used to generate the polynucleotides of the present disclosure. Exemplary modified nucleotides include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, N 6-substituted adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueuosine, 5"-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N 6 -Isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, beta-D-galactosylqueosine, inosine, N 6 -isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 3-(3-amino-3-N-2-carboxypropyl)uracil, and 2,6-diaminopurine.

[0529] Vectors containing polynucleotides encoding anti-PSMA antibodies Also provided are vectors containing DNA encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure. The disclosed vectors can be used, for example, to produce any of the anti-PSMA antibodies or antigen-binding fragments thereof disclosed above. Polynucleotides encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure can be incorporated into vectors using standard molecular biology methods.

[0530] In some embodiments, the present disclosure provides expression vectors comprising the polynucleotides of the present invention. Such vectors may be plasmid vectors, viral vectors, baculovirus expression vectors, transposon-based vectors, or any other vector suitable for introducing the synthetic polynucleotides of the present invention into a given organism or genetic background by any means. The vectors of the present disclosure may be expression vectors for efficient synthesis of PSMA antibody polypeptides and for expression of the PSMA antibody polypeptides of the present disclosure in prokaryotic and eukaryotic systems, including, but not limited to, yeast and mammalian cell cultures.

[0531] Exemplary vectors that can be used are bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene, La Jolla, Calif., USA); pTrc99A, pKK223-3, pKK233-3, pDR540, and pRIT5 (Pharmacia, Uppsala, Sweden). Eukaryotic: pWLneo, pSV2cat, pOG44, PXR1, pSG (Stratagene), pSVK3, pBPV, pMSG, and pSVL (Pharmacia), pEE6.4 (Lonza), and pEE12.4 (Lonza). Additional vectors include the pUC series (Fermentas Life Sciences, Glen Burnie, Md.), pBluescript series (Stratagene, LaJolla, Calif.), pET series (Novagen, Madison, Wis.), pGEX series (Pharmacia Biotech, Uppsala, Sweden), and pEX series (Clontech, Palo Alto, Calif.). Bacteriophage vectors such as λGT10, λGT11, λEMBL4, and λNM1149, λZapII (Stratagene) can be used. Exemplary plant expression vectors include pBI01, pBI01.2, pBI121, pBI101.3, and pBIN19 (Clontech). Exemplary animal expression vectors include pEUK-Cl, pMAM, and pMAMneo (Clontech). The expression vector can be a viral vector, eg, a retroviral vector, eg, a gamma retroviral vector.

[0532] The vectors of the present disclosure may contain promoter and enhancer sequences. A polynucleotide encoding a PSMA-binding protein of the present disclosure may be operably linked to a control sequence in an expression vector that ensures expression of the PSMA-binding protein. Such regulatory elements may include a transcription promoter, a sequence encoding a suitable mRNA ribosome binding site, and a sequence controlling the termination of transcription and translation. The expression vector may also contain one or more non-transcribed elements, such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' flanking non-transcribed sequences, 5' or 3' non-translated sequences (e.g., essential ribosome binding sites), a polyadenylation site, splice donor and acceptor sites, or a transcription termination sequence. An origin of replication that confers the ability to replicate in a host may also be incorporated.

[0533] The vectors of the present disclosure may also contain one or more internal ribosome entry sites (IRES). Inclusion of an IRES sequence in a fusion vector may be beneficial for enhancing expression of some proteins. In some embodiments, the vector system includes one or more polyadenylation sites (e.g., SV40), which may be upstream or downstream of any of the aforementioned nucleic acid sequences. The components of the vector may be closely linked, positioned to provide optimal spacing for expression of the gene product (i.e., by introducing "spacer" nucleotides between ORFs), or otherwise positioned. Regulatory elements, such as IRES motifs, may also be positioned to provide optimal spacing for expression.

[0534] The vectors of the present disclosure may be circular or linear. They may be prepared to contain a replication system functional in prokaryotic or eukaryotic host cells. Replication systems may be derived from, for example, ColE1, SV40, 2μ plasmid, λ, bovine papilloma virus, etc.

[0535] Recombinant expression vectors can be designed for either transient expression, stable expression, or both, and can be made for constitutive or inducible expression.

[0536] Vectors may also contain selectable markers well known in the art. Selectable markers include positive and negative selectable markers. Marker genes include biocide resistance (e.g., resistance to antibiotics, heavy metals, etc.), complementation for providing prototrophy in auxotrophic hosts, etc. Exemplary marker genes include antibiotic resistance genes (e.g., neomycin resistance gene, hygromycin resistance gene, kanamycin resistance gene, tetracycline resistance gene, penicillin resistance gene, histidinol resistance gene, histidinol x resistance gene), glutamine synthetase gene, HSV-TK or HSV-TK derivatives for ganciclovir selection, or bacterial purine nucleoside phosphorylase gene for 6-methylpurine selection (Gadi et al., 7 Gene Ther. 1738-1743 (2000)). The nucleic acid sequence or cloning site encoding the selectable marker may be upstream or downstream of the nucleic acid sequence or cloning site encoding the polypeptide of interest.

[0537] host cell The present disclosure also provides a host cell comprising any of the vectors of the present disclosure. "Host cell" refers to a cell into which a vector has been introduced. It is understood that the term host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell, as well as to stable cell lines generated from the particular subject cell. Because certain modifications may occur in subsequent generations due to either mutation or environmental influences, such progeny may not be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein. Such host cells may be eukaryotic, prokaryotic, plant, or archaeal. Examples of prokaryotic host cells are bacilli such as Escherichia coli and Bacillus subtilis, and other Enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species. Other microorganisms, such as yeast, are also useful for expression. Examples of suitable yeast host cells are Saccharomyces (e.g., S. cerevisiae) and Pichia. Exemplary eukaryotic cells may be of mammalian, insect, avian, or other animal origin. Mammalian eukaryotic cells include immortalized cell lines such as hybridoma or myeloma cell lines, such as SP2 / 0 (American Type Culture Collection (ATCC), Manassas, VA, CRL-1581), NS0 (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No. 85110503), FO (ATCC CRL-1646), and Ag653 (ATCC CRL-1580) murine cell lines. An exemplary human myeloma cell line is U266 (ATCC CRL-TIB-196). Other useful cell lines include those derived from Chinese Hamster Ovary (CHO) cells, such as CHO-K1SV (Lonza Biologics, Walkersville, MD), CHO-K1 (ATCC CRL-61), or DG44.

[0538] The present disclosure provides recombinant host cells containing any of the expression vectors of the present disclosure. Nucleic acids encoding any of the PSMA-binding proteins or fragments thereof can be used to transform suitable mammalian host cells. Host cell transformation, culture, antibody expression, and purification are carried out using well-known methods.

[0539] Cell lines can be selected based on high-level expression of the PSMA antibody of interest and minimal contamination from host cell proteins. Mammalian cell lines available as host cells for expression are well known in the art and include, but are not limited to, Chinese Hamster Ovary (CHO) cells, such as CHO-K1SV (Lonza Biologics, Walkersville, MD), CHO-K1 (ATCC CRL-61), or CHO DG44, and Baby Hamster Kidney (BHK) cell lines. These cell lines can be used to produce any of the anti-PSMA antibodies or antibody fragments of the present disclosure by culturing the cells under conditions suitable for antibody expression and purifying the antibody from the host cells or the medium surrounding the host cells.

[0540] The present disclosure also provides methods for producing the anti-PSMA binding proteins of the present disclosure, comprising culturing host cells of the present disclosure under conditions in which the anti-PSMA binding protein is expressed, and recovering the anti-PSMA antibody binding protein produced by the host cells using methods well known in the art. The protein of interest can be substantially pure, e.g., at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or at least about 98% to 99% pure, or more, and can be free from contaminants such as cellular debris, macromolecules, etc. other than the protein of interest.

[0541] Radioconjugates and antibody drug conjugates The present disclosure also provides antibody drug conjugates (ADCs) and radioconjugates comprising the anti-PSMA antibodies of the present disclosure. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure may be conjugated with a pharmaceutically active or diagnostic moiety to form an "antibody drug conjugate" (ADC) or a "radioconjugate." The ADCs or radioconjugates of the present disclosure may be used to deliver a cytotoxin or other payload to a target location.

[0542] As used herein, the term "antibody drug conjugate" is used broadly to refer to an antibody or antigen-binding fragment thereof conjugated to (e.g., covalently associated with) a second molecule, such as any pharmaceutically active moiety, therapeutic moiety, toxin, or drug.

[0543] As used herein, the term "targeting ligand" refers to any molecule that provides enhanced affinity for a selected target, e.g., an antigen, cell, cell type, tissue, organ, body region, or compartment (e.g., a cell, tissue, or organ compartment). Targeting ligands include, but are not limited to, antibodies or antigen-binding fragments thereof, aptamers, polypeptides, and scaffold proteins. In some embodiments, the targeting ligand is a polypeptide. In some embodiments, the targeting ligand is an antibody or antigen-binding fragment thereof, an engineered domain, or a scaffold protein. A targeting ligand can function as a shuttle to deliver a payload to a specific site defined by the target recognized by the targeting ligand. For example, a targeting ligand that targets a receptor will deliver its payload to a site characterized by the abundance of that receptor. In the present disclosure, the targeting ligand is an anti-PSMA antibody or fragment thereof conjugated to a pharmaceutically active moiety and capable of delivering a payload to a site characterized by the abundance of PSMA.

[0544] As used herein, the term "payload" refers to any naturally occurring or synthetically produced molecule, including small molecules or chemical entities that can be chemically synthesized, and larger molecules or biological entities that must be produced by fermentation of host cells and that confer novel functionality to targeting ligands specific for binding to targets or antigens. Examples of payloads include, but are not limited to, drugs, toxins, cytokines, markers, oligonucleotides, antisense, small interfering RNA (siRNA), etc., for the production of site-specific antibody-drug conjugates (ADCs). Payloads can also be radioactive metal complexes or radioactive metal ions, as described below.

[0545] As used herein, the terms "drug" and "warhead" may be used interchangeably and refer to a biologically active or detectable molecule or compound, including anticancer drugs as described below. A "payload" may include a drug or warhead in combination with an optional linker compound. The warhead on the conjugate may include peptides, proteins, prodrugs metabolized to active agents in vivo, polymers, nucleic acid molecules, small molecules, binders, mimetics, synthetic drugs, inorganic molecules, organic molecules, and radioisotopes. In some embodiments, the disclosed ADC or radioconjugates direct the attached payload to a target site in a relatively unreactive and nontoxic state before releasing and activating the payload. This targeted release of the payload is preferably achieved through stable conjugation of the payload via residue-specific or site-specific conjugation as described below, and a relatively homogeneous composition of the ADC or radioconjugate preparation, which minimizes over-conjugated toxic species.

[0546] In some embodiments, the present disclosure includes a payload of a therapeutic moiety (e.g., a cytotoxin) or other payload, such as a diagnostic agent. The selected payload can be covalently or non-covalently linked to the antibody and can exhibit various stoichiometric molar ratios, depending at least in part on the method used to affect conjugation.

[0547] The conjugates of the present disclosure have the formula: Ab-[LD]n or a pharmaceutically acceptable salt thereof, wherein: a) the Ab comprises an anti-PSMA antibody or antigen-binding fragment thereof disclosed herein; b) L comprises an optional linker; c) D comprises a drug moiety or a chelator; d) n is an integer from about 1 to about 20.

[0548] Those skilled in the art will appreciate that conjugates according to the foregoing formula can be made using a number of different linkers and drugs, and that the conjugation methodology will vary depending on the choice of components.

[0549] In preferred embodiments, the compatible linker confers stability to the ADC or radioconjugate in the extracellular environment, prevents aggregation of the ADC molecule or radioconjugate, and keeps the ADC and radioconjugate freely soluble in aqueous media and in a monomeric state. Prior to transport or delivery to a cell, the ADC or radioconjugate preferably remains stable and intact, i.e., the antibody remains linked to the drug moiety. Linkers are designed to be stable outside the target cell but cleave or degrade at an effective rate inside the cell. Thus, an effective linker (i) maintains the specific binding properties of the antibody, (ii) enables intracellular delivery of the conjugate or drug moiety, (iii) remains stable and intact, i.e., is not cleaved or degraded, until the conjugate is delivered or transported to its target site, and (iv) maintains the cytotoxic, cell-killing, or cytostatic activity of the drug moiety.

[0550] The stability of the ADC or radioconjugate may be measured by standard analytical techniques such as mass spectroscopy, hydrophobic interaction chromatography (HIC), HPLC, and the separation / analytical technique LC / MS.

[0551] Cytotoxic Agents and Drugs In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure are conjugated to one or more therapeutic moieties or drugs, such as anti-cancer agents, including, but not limited to, cytotoxic agents, cytostatic agents, anti-angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapeutic agents, targeted anti-cancer agents, biological response modifiers, cancer vaccines, cytokines, hormone therapy, oligonucleotides, antisense, siRNA, anti-metastatic agents, and immunotherapeutic agents.

[0552] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure are conjugated to one or more cytotoxic agents, examples of which include chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatic toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), and radioisotopes. Exemplary toxins include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as geldanamycin (Mandler et al (2000) Jour, of the Nat. Cancer Inst. 92(19):1573-1581; Mandler et al (2000) Bioorganic & Med. Chem. Letters 10:1025-1028; Mandler et al (2002) Bioconjugate Chem. 13:786-791), maytansinoids (EP 1391213; Liu et al., (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), and calicheamicin (Lode et al (1998) Cancer Res. 58:2928; Hinman et al (1993) Cancer Res. 53:3336-3342). Toxins may achieve their cytotoxic or cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or have low activity.Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, the unbound active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleuritesfordii protein, dianthin protein, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the trichothecenes.

[0553] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein are conjugated to one or more drugs. Exemplary drugs include maytansinoids (see, e.g., U.S. Pat. Nos. 5,208,020 and 5,416,060), auristatins such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see, e.g., U.S. Pat. Nos. 5,635,483, 5,780,588, and 7,498,298), dolastatins, calicheamicin, or derivatives thereof (see, e.g., U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., (1993) Cancer Res. 53:3336-3342, and Lode et al., (1998) Cancer Res 58:2925-2928), anthracyclines such as daunomycin or doxorubicin (see, e.g., Kratz et al., (2006) Current Med. Chem 13:477-523; Jeffrey et al., (2006) Bioorganic & Med Chem Letters 16:358-362; Torgov et al., (2005) Bioconj Chem 16:717-721; Nagy et al., (2000) Proc Natl Acad Sci USA 97:829-834; Dubowchik et al, Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., (2002) J Med Chem 45:4336-4343, and U.S. Pat. No. 6,630,579), methotrexate, vindesine, taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel, camptothecin (CPT) analogs such as topotecan and irinotecan (see, e.g., Slichenmyer et al., (1994) Cancer Chemother Pharmacol, 34(Suppl):S53-S570), pyrrolobenzodiazepine (PBD) derivatives (U.S. Pat. No. 10,639,373), amatoxin derivatives such as α-amanitin and β-amanitin, or duocarmycin analogs.

[0554] Radioconjugates In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure are conjugated to a radioactive metal ion to form a radioconjugate.

[0555] A "radioconjugate" (also referred to herein as a "radioimmunoconjugate" or "immunoconjugate") is an immunoconjugate in which an antibody or antigen-binding fragment thereof is labeled with a radioactive metal or conjugated to a radioactive metal complex. A "radioconjugate" specifically refers to an antibody or antigen-binding domain conjugated (linked, e.g., covalently bonded) to at least one radioactive metal complex. Stated differently, a radioconjugate refers to at least one radioactive metal complex linked, e.g., covalently bonded, to an antibody or antigen-binding domain. A radioconjugate may comprise at least one radioactive metal complex comprising a linker, where the radioactive metal complex is linked to the antibody or antigen-binding domain via the linker. As used herein, a "radioactive metal complex" refers to a complex comprising a radioactive metal ion associated with a chelator. Typically, the radioactive metal ion is bound or coordinated to the chelator by a coordinate bond. In some embodiments, the chelator is a macrocycle. The heteroatoms of the macrocyclic ring may participate in the coordination of the radiometal ion to the chelator. The chelator may be substituted with one or more substituents, and one or more substituents may also participate in the coordination of the radiometal ion to the chelator in addition to or instead of the heteroatoms of the macrocyclic ring.

[0556] As used herein, the term "radioactive metal ion" or "radioactive metal ion" refers to one or more isotopes of an element that emit particles and / or photons. Any radioactive metal ion known to those of skill in the art in light of the present disclosure can be used in the present invention. Exemplary radioisotopes can be gamma-emitting, Auger-emitting, beta-emitting, alpha-emitting, or positron-emitting radioisotopes. Exemplary radioactive isotopes include: 3 H, 11 C. 13 C. 15 N, 18 F, 19 F, 55 Co, 57 Co, 60 Co, 61 Cu, 62Cu, 64 Cu, 67 Cu, 68 Ga, 72 As, 75 Br, 86 Y, 89 Zr, 90 Sr, 94m Tc, 99m Tc, 115 In, 123 1, 124 1, 125 I, 131 1, 211 At, 212 Bi, 213 Bi, 223 Ra, 226 Ra, 134 Ce, 225 Ac, and 227 Ac are included.

[0557] Exemplary metal atoms include metals having an atomic number greater than 20, such as calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, germanium, arsenic, selenium, bromine, krypton, rubidium, strontium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, indium, tin, antimony, tellurium, iodine, xenon, cesium, barium, lanthanum, hafnium, tantalum, tungsten, and rhenium atoms. , osmium atom, iridium atom, platinum atom, gold atom, mercury atom, thallium atom, lead atom, bismuth atom, francium atom, radium atom, actinium atom, cerium atom, praseodymium atom, neodymium atom, promethium atom, samarium atom, europium atom, gadolinium atom, terbium atom, dysprosium atom, holmium atom, erbium atom, thulium atom, ytterbium atom, lutetium atom, thorium atom, protactinium atom, uranium atom, neptunium atom, plutonium atom, americium atom, curium atom, berkelium atom, californium atom, einsteinium atom, fermium atom, mendelevium atom, nobelium atom, or lawrencium atom.

[0558] In some embodiments, the radioactive metal ion is a "therapeutic emitter," meaning a radioactive metal ion that is useful for therapeutic applications, such as damaging cells, such as cancer cells. Radiometals suitable for use as therapeutic agents are those that can reduce or inhibit the growth of cancer cells, such as prostate cancer cells, or specifically kill cancer cells. High-energy radiometals selected to target cancer cells preferably act over a short range so that the cytotoxic effect is localized to the targeted cells. In certain embodiments, the radioconjugates of the present disclosure can deliver cytotoxic payloads capable of emitting alpha and / or beta particles in the vicinity of tumors by binding to surface antigens on cancer cells and initiating cell death. Thus, radiation therapy is delivered in a more localized manner to reduce damage to non-cancerous cells.

[0559] Examples of radioactive metal ions suitable for use in generating the radioconjugates of the present disclosure include: 47 Sc, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 89 Sr, 90 Y, 99 Tc, 105 Rh, 109 Pd, 111 Ag, 111 In, 117 Sn,, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 177 Lu, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 Bi, 213Bi, 223 Ra, 225 Ac, 227 Th, and 255 Preferably, the radioactive metal ion is a "therapeutic emitter," which refers to a radioactive metal ion useful in therapeutic applications. Examples of therapeutic emitters include beta or alpha emitters, e.g., 132 La, 135 La, 134 Ce, 144 Nd, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 177 Lu, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 255 Fm, and 227 Th, 226 Th, 230 Examples include, but are not limited to, U.

[0560] In some embodiments, the radioactive metal ion used as a therapeutic agent is an alpha-emitting radioactive metal ion, such as actinium-225 ( 225 Ac). 225 The 10-day half-life of Ac is long enough to facilitate production of radioconjugates, yet short enough to match the circulating pharmacokinetics of delivery vehicles such as antibodies. 225 Of particular interest are Ac radioimmunoconjugates. 225 Ac decays in a series of steps, ultimately emitting four alpha particles, before reaching a stable isotope.

[0561] In some embodiments, radiometals may be used as imaging agents or detectable labels. Radionuclides used in radiolabeling include, but are not limited to, carbon-11, nitrogen-13, oxygen-15, fluorine-18, copper-67, gallium-67, gallium-68, krypton-81m, rubidium-82, technetium-99, indium-111, iodine-123, iodine-124, iodine-125, iodine-131, xenon-133, thallium-201, zirconium-89, copper-64, yttrium-90, technetium-99m, iodine-123, iodine-124, and iodine-125, ruthenium-177, At-211, lead-212, bismuth-212, bismuth-213, cerium-134, and actinium-225. These radionuclides and their characteristics (e.g., half-life, emission, etc.), as well as methods for making them and labeling proteins with them, are well known in the art. In some embodiments, the radiometal used as an imaging agent or detectable label is cerium-134 ( 134 Ce).

[0562] In some embodiments, the radiometal used as an imaging agent or detectable label is indium-111 ( 111 In) or xenon-134 ( 134 Xe).

[0563] In some embodiments, the radioactive metal ion is conjugated to the isolated antibody or antigen-binding fragment thereof of the present disclosure using known methods.

[0564] In some embodiments, the radioactive metal ion is conjugated to the antibody or antigen-binding fragment of the present disclosure using a linker.

[0565] In some embodiments, the radioactive metal ion is complexed with a chelating agent or chelator.

[0566] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure are conjugated (i.e., covalently linked) to a chelator and a radiometal complex to produce a radioimmunoconjugate that is suitable for medical use in a subject, e.g., a human, such as, for example, targeted radiotherapy. In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure are conjugated (i.e., covalently linked) to a chelator and a radiometal complex to produce a radioimmunoconjugate that is suitable for detection.

[0567] As used herein, the term "chelator" or "chelant" refers to a chemical compound to which a radionuclide or radiometal can be chelated via a coordinate bond to form a radiometal complex. In some embodiments, the chelator is a macrocycle containing one or more heteroatoms, e.g., oxygen and / or nitrogen, as ring atoms.

[0568] In some embodiments, the chelator comprises a macrocyclic chelating moiety. Examples of macrocyclic chelating moieties include, but are not limited to, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA), 5-S-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-tris(acetic acid) (DO3A) or derivatives thereof. In some embodiments, the chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10,tetraacetic acid (DOTA). In other embodiments, the chelating agent is S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In further embodiments, the chelating agent is 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA). In still other embodiments, the chelating agent is 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA). In yet further embodiments, the chelator is 5-S-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-tris(acetic acid) (DO3A). In other embodiments, the chelator is DOTA, DFO, DTPA, NOTA, TETA, DTPA, or HOPO.

[0569] In some embodiments, the chelator is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, tetraxathen).

[0570] In some embodiments, the chelator is H2bp18c6 (N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6) or an H2bp18c6 derivative, as described in Thiele et al., "An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy," Angew. Chem. Int. Ed. (2017) 56, 14712-14717, and Roca-Sabio et al., "Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides," J. Am. Chem. Soc. (2009) 131, 3331-3341.

[0571] Additional chelating agents suitable for use according to the present invention are described in WO 2018 / 183906 and WO 2020 / 106886, which are incorporated herein by reference. In some embodiments, the radioconjugates of the present disclosure comprise a radioactive metal ion chelated to a chelator described in WO 2020 / 229974, which is incorporated herein by reference in its entirety. In some embodiments, the chelator is represented by Formula (I):

[0572] [ka] [In the formula, each of ring A and ring B is independently a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; Each of Z1 and Z2 independently represents (C(R 12 )2) m - or -(CH2) n -C(R 12 )(X)-(CH2) n - and R 14 , R 15 , R 16 and R 17each is independently hydrogen, alkyl, or X; Alternatively, R 14 and R 15 and / or R 16 and R 17 together with the carbon atoms to which they are attached form a 5- or 6-membered cycloalkyl ring which may be substituted by X; each X is independently -L1-R4; R4 is a nucleophilic or electrophilic moiety, or R4 comprises a targeting ligand; L1 is absent or is a linker, or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the radioconjugate of the present disclosure has formula (II):

[0574] [ka] [In the formula, R1 is hydrogen and R2 is -L1-R4; Alternatively, R1 is -L1-R4 and R2 is hydrogen; R3 is hydrogen; or R2 and R3 together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl, which 5- or 6-membered cycloalkyl is optionally substituted with -L1-R4; L1 is absent or a linker, R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand] or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, L is absent. When L is absent, R is directly bonded to the compound (e.g., via a covalent bond).

[0576] In some embodiments, the radioconjugate has formula (III):

[0577] [ka] [In the formula, L1 is absent or a linker, R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand] or a pharmaceutically acceptable salt thereof.

[0578] The chelators of the present disclosure can be produced by any method known in the art in light of the present disclosure, for example, the pendant aromatic / heteroaromatic group can be attached to the macrocyclic ring moiety by methods known in the art, such as those exemplified and described below.

[0579] In some embodiments, the present disclosure also provides a chelator, preferably a chelator to which a radiometal ion can be chelated via a coordinate bond.

[0580] As used herein, "antibody-chelator complex" or "conjugate intermediate" refers to a precursor of a radioconjugate comprising an antibody or antigen-binding domain conjugated (linked, e.g., covalently bonded) to a chelator that does not contain a radioactive metal. The conjugate intermediate may include a linker, and the chelator is linked to the antibody or antigen-binding domain via the linker. After the radioactive metal is chelated to the chelator of the conjugate intermediate, it becomes a radioconjugate. For example, "DOTA-mAb" refers to a conjugate intermediate comprising DOTA conjugated to an antibody.

[0581] Any of the chelators described herein may include a radioactive metal ion. In some embodiments, the radioactive metal ion is an alpha-emitting radioactive metal ion. In some embodiments, the radioactive metal is 225 In some embodiments, the radioactive metal ion is a gamma-emitting radioactive metal ion. In some embodiments, the radioactive metal is 111In some embodiments, the radiometal is 134 The chelators of the present disclosure are capable of chelating radioactive metal ions, especially radioactive metal ions, with any specific activity, regardless of metal impurities. 225 It can tightly chelate Ac, thus forming a stable radiometal complex with high chelation stability in vivo and in vitro.

[0582] The radiometal complexes can be prepared by any method known in the art in light of the present disclosure. For example, a chelator of the present invention can be mixed with a radiometal ion and the mixture can be incubated to form the radiometal complex. In an exemplary embodiment, the chelator is 225 It was mixed with a solution of Ac(NO3)3 and bound to the chelator via a coordinate bond. 225 The chelators of the present invention form radioactive complexes with radiometals, especially Ac. 225 Thus, in certain embodiments, the chelating agent of the present invention is used in a ratio of 1:1000, 1:500, 1:400, 1:300, 1:200, 1:100, 1:50, 1:10, or 1:5, preferably 1:5 to 1:200, more preferably 1:5 to 1:100, of the chelating agent of the present invention to chelate Ac. 225 The concentration ratio with Ac ions is 225 The radioactive complex may be characterized by instant thin layer chromatography (e.g., iTLC-SG), HPLC, LC-MS, etc.

[0583] Linker In some embodiments, the (ADCs) of the present disclosure comprise a linker that connects the anti-PSMA antibodies and antigen-binding fragments thereof of the present disclosure to a drug moiety or chelator.

[0584] Numerous linker compounds can be used to conjugate the antibodies of the present disclosure to the relevant drug or chelator. Preferably, the linker covalently bonds a reactive residue (preferably cysteine ​​or lysine) and the selected drug compound. Thus, any linker that can be used to react with a selected antibody residue and provide a relatively stable conjugate (site-specific or otherwise) of the present invention is compatible with the teachings herein.

[0585] As used herein, the term "linker" refers to a chemical moiety that links a chelator or drug to an antibody or antigen-binding domain. Any suitable linker known to one of skill in the art in light of the present disclosure can be used to conjugate the antibody of the present disclosure to the relevant drug. Preferably, the linker covalently bonds to a reactive residue of the antibody. Thus, any linker that can be used to react with a selected antibody residue and provide a relatively stable conjugate (site-specific or otherwise) of the present disclosure is compatible with the teachings herein. Ideally, the linker is designed to largely release the drug once it is delivered to the tumor site, substantially reducing undesirable nonspecific toxicity by minimizing exposure of non-targeted cells and tissues to the cytotoxic drug, thereby providing an enhanced therapeutic index.

[0586] The linker may contain, for example, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl moiety, a substituted or unsubstituted aryl or heteroaryl, a polyethylene glycol (PEG) linker, a peptide linker, a sugar-based linker, or a cleavable linker, e.g., a disulfide linkage or a protease cleavage site, e.g., valine-citrulline-p-aminobenzyl (PAB).

[0587] The linker may be composed of one or more linker moieties. Exemplary linker components include 6-maleimidocaproyl ("MC"), maleimidopropanoyl ("MP"), valine-citrulline ("val-cit"), alanine-phenylalanine ("alaphe"), p-aminobenzyloxycarbonyl ("PAB"), N-succinimidyl 4-(2-pyridylthio)pentanoate ("SPP"), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate ("SMCC"), and N-succinimidyl (4-iodo-acetyl)aminobenzoate ("Succinimidyl (4-iodo-acetyl)aminobenzoate, "SIAB." In one embodiment, the linker is valinecitrulline-p-aminobenzyloxycaronyl ("vc-PAB"). In some embodiments, the linker may comprise an amino acid residue. Exemplary amino acid linker components include a dipeptide, tripeptide, tetrapeptide, or pentapeptide. Exemplary dipeptides include valine-citrulline (vc or val-cit) and alanine-phenylalanine (af or ala-phe). Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). Amino acid residues that comprise the amino acid linker component include naturally occurring as well as minor amino acids and non-naturally occurring amino acid analogs such as citrulline.Amino acid linker components can be designed and optimized in their selectivity for enzymatic cleavage by specific enzymes, for example, tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases.

[0588] In some embodiments, the chelator or chelator-linker comprises a nucleophilic or electrophilic moiety. Reaction of the nucleophilic or electrophilic group of the chelator or chelator-linker with an antibody or antigen-binding domain comprising a corresponding reaction partner allows the antibody or antigen-binding domain to be covalently linked to the chelator-linker.

[0589] A number of compatible linkers can be advantageously attached to the nucleophilic reduced cysteines and lysines. Conjugation reactions involving reduced cysteines and lysines include, but are not limited to, thiol-maleimide, thiol-halogeno(acyl halide), thiol-ene, thiol-yne, thiol-vinylsulfone, thiol-bisulfone, thiol-thiosulfonate, thiol-pyridyl disulfide, and thiol-parafluoro reactions.

[0590] Exemplary linker structures suitable for use in the present disclosure also include:

[0591] [ka] These include, but are not limited to:

[0592] In the formula, m is an integer of 0 to 12.

[0593] In preferred embodiments, a compatible linker confers stability to the ADC in the extracellular environment, prevents aggregation of the ADC molecule, and keeps the ADC freely soluble in aqueous media and in a monomeric state. Prior to transport or delivery to a cell, the ADC preferably remains stable and intact, i.e., the antibody remains linked to the drug moiety. Linkers are designed to be stable outside the target cell but cleave or degrade at an effective rate inside the cell. Thus, an effective linker (i) maintains the specific binding properties of the antibody, (ii) enables intracellular delivery of the conjugate or drug moiety, (iii) remains stable and intact, i.e., is not cleaved or degraded, until the conjugate is delivered or transported to its target site, and (iv) maintains the cytotoxic, cell-killing, or cytostatic activity of the drug moiety. ADC stability can be measured by standard analytical techniques, such as mass spectroscopy, hydrophobic interaction chromatography (HIC), HPLC, and the separation / analysis technique LC / MS.

[0594] Conjugation It will be appreciated that several different well-known reactions can be used to attach the drug moiety, chelator, and / or linker to the antibody of choice.

[0595] According to certain embodiments, the drug moiety, chelator, or chelator-linker comprises a nucleophilic or electrophilic moiety. Reaction of the nucleophilic or electrophilic group of the chelator or chelator-linker with an antibody or antigen-binding domain containing the corresponding reactive partner allows the antibody or antigen-binding domain to be covalently linked to the drug moiety, chelator, or chelator-linker. Examples of nucleophilic groups include, but are not limited to, azides, amines, and thiols. Examples of electrophilic groups include, but are not limited to, amine-reactive groups, thiol-reactive groups, alkynyls, and cycloalkynyls. Amine-reactive groups preferably react with primary amines, including those present at the N-terminus of each polypeptide chain and in the side chains of lysine residues. Examples of amine-reactive groups include, but are not limited to, N-hydroxy succinimide (NHS), substituted NHS (such as sulfo-NHS), isothiocyanate (-NCS), isocyanate (-NCO), ester, carboxylic acid, acyl halide, amide, alkylamide, and tetrafluorophenyl ester and perfluorophenyl ester. Thiol-reactive groups react with thiols or sulfhydryls, preferably with thiols present in the side chains of cysteine ​​residues in polypeptides. Examples of thiol-reactive groups include, but are not limited to, Michael acceptors (e.g., maleimides), haloacetyls, acyl halides, activated disulfides, and phenyloxadiazole sulfones.

[0596] Residue-specific conjugation In some embodiments, conjugation of a drug moiety, chelator, and / or linker to an antibody or antigen-binding fragment thereof of the present disclosure can be achieved by residue-specific methods (random conjugation), such as acylation of amines on lysine residues and alkylation of thiols on cysteine ​​residues. Examples of residue-specific methods for conjugation that can be used include conjugation of a drug moiety, chelator, linker, and / or radiometal complex to a lysine residue of an antibody using, for example, an activated ester or isothiocyanate group; conjugation of a drug moiety, chelator, linker, and / or radiometal complex to a cysteine ​​residue of an antibody using, for example, a maleimide, haloacetyl derivative, acyl halide, activated disulfide group, or methylsulfonylphenyloxadiazole group; Examples include, but are not limited to, conjugation of a drug moiety, chelator, linker, and / or radiometal complex to a tyrosine residue of an antibody using a drug moiety, chelator, linker, or radiometal complex comprising, for example, 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-dione (PTAD); and conjugation of a drug moiety, chelator, linker, and / or radiometal complex to a methionine residue of an antibody using, for example, a drug moiety, chelator, linker, or radiometal complex comprising, for example, an oxaziridine derivative.

[0597] Residue-specific methods for conjugation to proteins are well established and most commonly involve either lysine side chains using activated esters or isothiocyanates, or cysteine ​​side chains with maleimides, haloacetyl derivatives, or activated disulfides (Brinkley Bioconjugate Chem 1992:2). Because most proteins have multiple lysine and cysteine ​​residues, heterogeneous mixtures of products with different numbers of conjugate molecules at various amino acid positions are typically obtained using such methods. Additional methods have been established, including tyrosine-specific conjugation (Ban et al. Bioconjugate Chemistry 2013:520), methionine-specific methods (Lin et al. Science 2017(355)597), and approaches focusing on additional cysteines (Toda et al. Angew Chemie 2013:12592).

[0598] In some embodiments, the PSMA antibodies or antibody fragments thereof of the present disclosure may be conjugated to any of the radiometal complexes described herein via one or more lysine residues of the antibody.

[0599] In some embodiments, the ADCs or radioconjugates of the present disclosure can be generated via conjugation of a drug moiety, chelator, linker, or radiometal complex to solvent-exposed amino groups of lysine residues present in a selected antibody. Conjugation reactions involving lysine include, but are not limited to, isothiocyanates, NHS-esters, sulfonyl fluorides, fluorosulfates, dichlorotriazines, activated esters, activated sulfonamides, vinylsulfonamides, imidoesters, isothiocyanates, salicylaldehydes, iminoboronates, and α,β-unsaturated carbonyls.

[0600] In some embodiments, the ADCs or radioconjugates of the present disclosure can be produced via reactions that utilize the sulfhydryl groups of cysteine ​​residues present in a selected antibody. Particularly preferred embodiments involve the conjugation of antibodies containing one or more free cysteines. Conjugation reactions involving reduced cysteines include, but are not limited to, thiol-maleimide, thiol-halogeno(acyl halide), thiol-ene, thiol-yne, thiol-vinylsulfone, thiol-bisulfone, thiol-thiosulfonate, thiol-pyridyl disulfide, and thiol-parafluororeactions.

[0601] In some embodiments, antibodies can be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) prior to conjugation. In some embodiments, reactive thiol groups can be introduced into a selected antibody (or fragment thereof) by introducing one, two, three, four, or more free cysteine ​​residues. In some embodiments, conjugation methodologies can involve complete or partial reduction of each intra- or inter-chain antibody disulfide bond to provide a conjugation site. In some embodiments, free cysteines can be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP). Each free cysteine ​​thus theoretically presents a reactive thiol nucleophile.

[0602] Because most proteins have multiple lysine, threonine, methionine, and cysteine ​​residues, a heterogeneous mixture of products with different numbers of conjugate molecules at various amino acid positions is typically obtained using residue-specific conjugation methods.

[0603] Site-specific conjugation More recently, site-selective and site-specific conjugation methods have been established for monoclonal antibodies and other proteins (Agarwal, P. and C.R. Bertozzi, Bioconjug Chem, 2015. 26(2):...

Claims

1. 1. An isolated antibody or antigen-binding fragment comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are: a. RYGMH (SEQ ID NO: 4), LISYDGSNRYYADSVKG (SEQ ID NO: 5), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; b. SYYWN (SEQ ID NO: 10), RIYSSGNTDYNPSLKS (SEQ ID NO: 11), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; c. GYGMH (SEQ ID NO: 16), VISYDGSNRYYADSVKG (SEQ ID NO: 17), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; d. SYGMH (SEQ ID NO: 22), VISYDGSNKYYADSVKG (SEQ ID NO: 23), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), AARDDSLSGYV (SEQ ID NO: 27), respectively. e. SYDMH (SEQ ID NO: 28), VISFDGSNKYYVDSVKG (SEQ ID NO: 29), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; f. TYGMH (SEQ ID NO: 34), FISYDGSNKYYADSVKG (SEQ ID NO: 35), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; g. IYSMN (SEQ ID NO: 40), SISSSSSYIFYADSVKG (SEQ ID NO: 41), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; h. SYSLN (SEQ ID NO: 46), SISSSSSYISYADAVKG (SEQ ID NO: 47), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; i. SYYWS (SEQ ID NO: 272), RIYSSGSTNYNPSLKS (SEQ ID NO: 273), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; j. GFTLSRY (SEQ ID NO: 124), SYDGSN (SEQ ID NO: 125), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; k. GGSISSY (SEQ ID NO: 130), YSSGN (SEQ ID NO: 131), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; 1. VRTFSGY (SEQ ID NO: 136), SYDGSN (SEQ ID NO: 125), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; m. GFTFTSY (SEQ ID NO: 142), SYDGSN (SEQ ID NO: 125), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; n. GFTFSSY (SEQ ID NO: 148), SFDGSN (SEQ ID NO: 149), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; GFTFSTY (SEQ ID NO: 154), SYDGSN (SEQ ID NO: 125), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; p. GFTLSIY (SEQ ID NO: 160), SSSSSY (SEQ ID NO: 161), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; q. GFTFSSY (SEQ ID NO: 166), SSSSSY (SEQ ID NO: 167), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; r. GGSIISY (SEQ ID NO: 290), YSSGS (SEQ ID NO: 291), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; GFTLSRYGMH (SEQ ID NO: 172), LISYDGSNRY (SEQ ID NO: 173), ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHVV (SEQ ID NO: 9), respectively; t. GGSISSYYWN (SEQ ID NO: 178), RIYSSGNTD (SEQ ID NO: 179), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; u. VRTFSGYGMH (SEQ ID NO: 184), VISYDGSNRY (SEQ ID NO: 185), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; v. GFTFTSYGMH (SEQ ID NO: 190), VISYDGSNKY (SEQ ID NO: 191), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO: 27), respectively; w. GFTFSSYDMH (SEQ ID NO: 196), VISFDGSNKY (SEQ ID NO: 197), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; x. GFTFSTYGMH (SEQ ID NO: 202), FISYDGSNKY (SEQ ID NO: 203), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; GFTLSIYSMN (SEQ ID NO: 208), SISSSSSSYIF (SEQ ID NO: 209), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; z. GFTFSSYSLN (SEQ ID NO: 214), SISSSSSSYIS (SEQ ID NO: 215), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWL (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSF (SEQ ID NO: 51), respectively; aa. GGSIISYYWS (SEQ ID NO: 296), RIYSSGSTN (SEQ ID NO: 297), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO: 275), SSNQRPS (SEQ ID NO: 276), and AAWDDSLNGVV (SEQ ID NO: 277), respectively; bb. GFTLSRYG (SEQ ID NO: 220), ISYDGSNR (SEQ ID NO: 221), ARERESSGWFEGYFDY (SEQ ID NO: 222), NIGSKS (SEQ ID NO: 223), DNS, and QVWDSSSDHVV (SEQ ID NO: 9), respectively; cc. GGSISSYY (SEQ ID NO: 226), IYSSGNT (SEQ ID NO: 227), ARGRGANVGLFDY (SEQ ID NO: 228), NSNIGANYD (SEQ ID NO: 229), GNI, and QSYDFSLSGSV (SEQ ID NO: 15), respectively; dd. VRTFSGYG (SEQ ID NO: 232), ISYDGSNR (SEQ ID NO: 233), ARDGNWGSLDLYFDL (SEQ ID NO: 234), SSNIGADYD (SEQ ID NO: 235), VNN, and QSYDNTLSGVV (SEQ ID NO: 21), respectively; ee. GFTFTSYG (SEQ ID NO: 238), ISYDGSNK (SEQ ID NO: 239), AREHYDSSGYYHGYYGMDV (SEQ ID NO: 240), SSNIGSNY (SEQ ID NO: 241), SNN, and AARDDSLSGYV (SEQ ID NO: 27), respectively; ff. GFTFSSYD (SEQ ID NO: 244), ISFDGSNK (SEQ ID NO: 245), ARTYYDILTGYSHYSYGMDV (SEQ ID NO: 246), QGISNY (SEQ ID NO: 247), ATS, and QKYNSAPFT (SEQ ID NO: 33), respectively; gg. GFTFSTYG (SEQ ID NO: 250), ISYDGSNK (SEQ ID NO: 251), AGRDNLRFLEWFMDV (SEQ ID NO: 252), QSVRSN (SEQ ID NO: 253), GAS, and HQYNDWPPYT (SEQ ID NO: 39), respectively; hh. GFTLSIYS (SEQ ID NO: 256), ISSSSSSYI (SEQ ID NO: 257), ARSSYGADY (SEQ ID NO: 258), QDITNF (SEQ ID NO: 259), TAS, and QKYNSAPLT (SEQ ID NO: 45), respectively; ii. GFTFSSYS (SEQ ID NO: 262), ISSSSSSYI (SEQ ID NO: 263), ARDRGFLEDYYYYYGMDV (SEQ ID NO: 264), QGISNW (SEQ ID NO: 265), VAS, and QQAYSFPLT (SEQ ID NO: 51), respectively; and jj. An isolated antibody or antigen-binding fragment comprising an amino acid sequence selected from the group consisting of GGSIISYY (SEQ ID NO: 302), IYSSGST (SEQ ID NO: 303), AKVGVWPGAFDI (SEQ ID NO: 304), SSNIGSNT (SEQ ID NO: 305), SSN, and AAWDDSLNGVV (SEQ ID NO: 277), respectively.

2. a. SEQ ID NOs: 52 and 53, respectively; b. SEQ ID NOs: 54 and 55, respectively; c. SEQ ID NOs: 56 and 57, respectively; d. SEQ ID NOs: 58 and 59, respectively; e. SEQ ID NOs: 60 and 61, respectively; f. SEQ ID NOs: 62 and 63, respectively; g. SEQ ID NOs: 64 and 65, respectively; h. SEQ ID NOs: 66 and 67, respectively; and i. The isolated antibody or antigen-binding fragment of claim 1, comprising a heavy chain variable region (VH) and a light chain variable region (VL) selected from SEQ ID NOs: 278 and 279, respectively.

3. a heavy chain amino acid sequence selected from SEQ ID NOs: 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 268, 282, 284, and 288; and a light chain amino acid sequence selected from SEQ ID NOs: 85, 89, 93, 95, 97, 99, 101, 103, and 269.

4. 2. The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment is an IgG1, IgG2, IgG3, or IgG4 isotype.

5. 5. The isolated antibody or antigen-binding fragment of claim 4, wherein the antibody or antigen-binding fragment is of the IgG1 isotype.

6. 2. The isolated antibody or antigen-binding fragment of claim 1, further comprising an Ig constant region, wherein the Ig constant region comprises at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

7. The at least one mutation that results in reduced binding of the protein to the FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L 7. The isolated antibody or antigen-binding fragment of claim 6, wherein the antibody or antigen-binding fragment is selected from the group consisting of: S267E / L328F, S234F / L235E / D265A, S234A / L235A / G237A / P238S, S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236deletion / G237A / P238S, and wherein residue numbering is according to the EU index.

8. 8. The isolated antibody or antigen-binding fragment of claim 7, wherein the mutations that result in reduced binding of the antibody or antigen-binding fragment to the FcγR are L234A, L235A, and D265S.

9. 2. The isolated antibody or antigen-binding fragment of claim 1, further comprising an Ig constant region, wherein the IgG constant region comprises at least one mutation that modulates the half-life of the antibody.

10. 10. The isolated antibody or antigen-binding fragment of claim 9, wherein the at least one mutation that modulates the half-life of the antibody is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, wherein residue numbering is according to the EU index.

11. 10. The isolated antibody or antigen-binding fragment of claim 9, wherein the mutations that modulate the half-life of the antibody or antigen-binding fragment thereof are M252Y, S254T, and T256E mutations.

12. A polynucleotide encoding the isolated antibody or antigen-binding fragment of claim 1.

13. The polynucleotide of claim 12, wherein the polynucleotide sequence is selected from SEQ ID NOs: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 116, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

14. A vector comprising the polynucleotide sequence of claim 12 or 13.

15. A host cell comprising the vector of claim 14.

16. An antibody-drug conjugate comprising the antibody or antigen-binding fragment of claim 1.

17. the antibody or antigen-binding fragment: a. a heavy chain variable region (VH) comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 4, a VH CDR2 having the amino acid sequence of SEQ ID NO: 5, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 6, and a light chain variable region (VL) comprising a VL CDR1 having the amino acid sequence of SEQ ID NO: 7, a VL CDR2 having the amino acid sequence of SEQ ID NO: 8, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 9; or b) The antibody drug conjugate of claim 16, comprising a heavy chain variable region (VH) comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 10, a VH CDR2 having the amino acid sequence of SEQ ID NO: 11, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 12, and a light chain variable region (VL) comprising a VL CDR1 having the amino acid sequence of SEQ ID NO: 13, a VL CDR2 having the amino acid sequence of SEQ ID NO: 14, and a VL CDR3 having the amino acid sequence of SEQ ID NO:

15.

18. 10. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.

19. 17. A pharmaceutical composition for use in a method for treating a PSMA-expressing cancer in a subject in need thereof, said pharmaceutical composition comprising the antibody-drug conjugate of claim 16, said use comprising administering a therapeutically effective amount of said antibody-drug conjugate.

20. 20. The pharmaceutical composition of claim 19, wherein the PSMA-expressing cancer is prostate cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the prostate cancer is metastatic castration-resistant cancer (mCRPC).

22. A kit comprising the isolated antibody or antigen-binding fragment of claim 1.