Anti-PSMA radioconjugates and uses thereof

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.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 237,663, filed August 27, 2021, U.S. Provisional Application No. 63 / 277,245, filed November 9, 2022, and U.S. Provisional Application No. 63 / 339,784, filed May 9, 2022, entitled "ANTI-PSMA ANTIBODIES AND USES THEREOF," the disclosures of each of which are incorporated herein by reference in their entireties.

[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. This XML copy was created on July 11, 2022, is named JBI6621USNP2_SL.xml, and is 282,897 bytes in size.

[0003] FIELD OF THEINVENTION 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 same to treat cancer. [Background technology]

[0004] Prostate cancer is the second most common cancer and the sixth most common cause of cancer-related deaths in men worldwide. Globally, approximately 1.1 million new cases and 300,000 deaths are reported annually, constituting 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 cancer cases are found at localized or regional 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 that is 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). Expression of PSMA in cancer tissue correlates with the stage of the disease 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 aggressiveness, thus strongly supporting PSMA as a good 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 by hormone therapy, treatment options are limited. This clearly indicates the need for improved treatment and effective therapies for PSMA-expressing advanced prostate cancer. Despite this clear need, developing improved treatments for prostate cancer remains challenging. As of August 27, 2021, there have been approximately 100 clinical trials for prostate cancer evaluating at least one PSMA inhibitor and / or targeting folate hydrolase 1. However, only about 15% of these trials had a positive outcome / primary endpoint met. Approximately 23% of the trials were discontinued, temporarily terminated, or had a negative outcome / primary endpoint not met. Another approximately 29% of trials were completed but classified as having unknown or indeterminate outcomes. Summary of the Invention [Problem to be solved by the invention]

[0007] Although an estimated 33% of clinical trials have currently been initiated, planned, or are underway, there remains an unmet patient need for novel prostate cancer treatments given the low success rates for this devastating disease. [Means for solving the problem]

[0008] 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), SISSSSYISYADAVKG (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; y. 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), 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 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 84 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 86 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 88 and a 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 a HC of SEQ ID NO: 90 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 92 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 94 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 96 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 98 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 100 and a 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 Disclosed is an isolated antibody or antigen-binding fragment thereof comprising a HC of SEQ ID NO: 102 and a LC of SEQ ID NO: 103, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0026] The 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 a first antigen-binding domain binds to a first epitope on PSMA and a 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; the second antigen binding domain is in scFv format 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 scFv format 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 deletion / 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 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 a polynucleotide encoding an isolated antibody or antigen-binding fragment thereof of the present disclosure.

[0038] Optionally, a 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, a polynucleotide encoding an 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 a 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 vectors comprising the polynucleotides of the present disclosure.

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

[0042] The present disclosure also provides a radioconjugate 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 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 disclosure also provides a radioconjugate, 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 a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:53.

[0047] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises a HC of SEQ ID NO:84 and a LC of SEQ ID NO:85.

[0048] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises a HC of SEQ ID NO:88 and a LC of SEQ ID NO:89.

[0049] The 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 results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

[0050] The disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment thereof comprises an HC of SEQ ID NO: 90 and an LC of SEQ ID NO: 89, 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 results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

[0051] 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 deletion / 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.

[0052] In some embodiments, the mutation that results in reduced binding of the antibody, or antigen-binding fragment thereof, to FcγR is L234A_L235A_D265S.

[0053] The 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.

[0054] The disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment thereof comprises an HC of SEQ ID NO: 90 and an LC of SEQ ID NO: 89, 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.

[0055] 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.

[0056] In some embodiments, the mutations that modulate the half-life of the antibody or antigen-binding fragment thereof are M252Y / S254T / T256E mutations.

[0057] 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 compound comprises a chelator complexed with a radioactive metal ion selected from the group consisting of Xe.

[0058] In some embodiments, the radioactive metal ion is 225 It is Ac.

[0059] In some embodiments, the radioactive metal ion is 111 In.

[0060] In some embodiments, the radioactive metal ion is 134 It's Xe.

[0061] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (II) or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (III) or a pharma- ceutically acceptable salt thereof.

[0064] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (IV) or a pharma- ceutically acceptable salt thereof.

[0065] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of formula (V) or a pharma- ceutically acceptable salt thereof.

[0066] In some embodiments, the radioconjugate of the present disclosure comprises: (a) A radioactive metal ion for use as an imaging agent coordinated to a chelator moiety, the radioactive metal ion being 111 a radioactive metal ion, wherein In is In and the chelator is p-SCN-Bn-DOTA (S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid) of formula IV; and (b) an anti-PSMA antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: (i) 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, 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, and / or (ii) a heavy chain variable region (VH) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, and / or a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53.

[0067] In some embodiments, the radioconjugate of the present disclosure comprises: (a) A radioactive metal ion for use as an imaging agent coordinated to a chelator moiety, the radioactive metal ion being 111 a radioactive metal ion, wherein In is In and the chelator is p-SCN-Bn-DOTA (S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid) of formula IV; and (b) an anti-PSMA antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: (i) 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, 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, and / or (ii) a heavy chain variable region (VH) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 54, and / or a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 55.

[0068] In some embodiments, the present disclosure provides a radioimmunoconjugate having the following structure:

[0069] [ka] (also referred to herein as TOPA-[C7]-phenylthiourea-PSMA antibody conjugate), In the formula, M + Actinium 225 ( 225 Ac), The mAb has binding specificity for PSMA, e.g. (i) the mAb is a PSMB1154 antibody comprising a heavy chain (HC) variable region comprising the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and a light chain (LC) variable region comprising the amino acid sequences of SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9; and / or (ii) the mAb comprises a heavy chain variable region (VH) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, and / or a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53.

[0070] In some embodiments, the present disclosure provides a radioimmunoconjugate having the following structure:

[0071] [ka] (also referred to herein as TOPA-[C7]-phenylthiourea-PSMA antibody conjugate), In the formula, M + Actinium 225 ( 225 Ac), The mAb has binding specificity for PSMA, e.g. (i) the mAb is a PSMB1183 antibody comprising a heavy chain (HC) variable region comprising the amino acid sequences of SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, and a light chain (LC) variable region comprising the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15; and / or (ii) the mAb comprises a heavy chain variable region (VH) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 54, and / or a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 55.

[0072] 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 pharma- ceutically acceptable carrier.

[0073] The present disclosure also provides a method of treating a 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.

[0074] In some embodiments, the subject has prostate cancer.

[0075] In some embodiments, the subject has renal cancer.

[0076] The present disclosure also provides methods of detecting PSMA in a sample using the radioconjugates of the present disclosure.

[0077] 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0078] Various publications, articles and patents are cited or described in the "Background" and throughout the specification, 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.

[0079] 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 certain 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.

[0080] Unless otherwise stated, any explanation of possible mechanisms or modes of action, or reasons for improvements, are 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 of any such proposed mechanisms or modes of action, or reasons for improvements.

[0081] Throughout this context, the description refers to antibodies, antigen-binding fragments thereof, radioconjugates, antibody-drug conjugates, and methods of using the antibodies, antigen-binding fragments thereof, radioconjugates, and antibody-drug conjugates. Where the present disclosure describes or claims features or embodiments related to antigen-binding domains, radioconjugates, and antibody-drug conjugates, such features or embodiments are equally applicable to methods of using the antigen-binding domains, radioconjugates, and antibody-drug conjugates. Similarly, where the present disclosure describes or claims features or embodiments related 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, the range includes its endpoints, and all individual integers and rational numbers within the 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 subgroup of the larger group of values ​​within the recited range, as if each of the narrower ranges were explicitly recited. When a range of numerical values ​​is recited herein as being greater than the recited value, the range is nevertheless finite, and its upper limit is defined by a value that is operable within the context of the invention described herein. When a range of numerical values ​​is recited herein as being less than the recited value, the range is nevertheless defined by a lower limit by a non-zero value. It is not intended that the scope of the invention be limited to the specific values ​​recited in defining the range. All ranges are inclusive and combinable.

[0082] When values ​​are expressed as approximations, by use of the antecedent "about," it is to be understood that the particular value forms another embodiment. Reference to a particular numerical value is intended to include at least the particular value unless the context clearly indicates otherwise.

[0083] 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 considered to be combinable with any other embodiment, and such combination is considered to be another embodiment. Conversely, different features of the invention that are described for brevity in the context of a single embodiment may be provided separately or in any subcombination. Finally, although an embodiment may be described as part of a series of steps or as part of a more general structure, each step may be considered to be an independent embodiment in itself that can be combined with the others.

[0084] Unless otherwise stated, any description of possible mechanisms or modes of operation or reasons 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 mechanisms or modes of operation or reasons for improvement.

[0085] Various terms relating to the embodiments of the present specification are used throughout the specification and claims. Unless otherwise indicated, such terms are to be given their ordinary meaning in the art. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein.

[0086] 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.

[0087] The transitional phrases "comprising," "consisting essentially of," and "consisting of" are intended to connote the 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 that do not "materially affect the basic and novel characteristics" of the claimed disclosure. Embodiments described with the phrase "comprising" (or its synonyms) are also provided as embodiments described separately with "consisting of" and "consisting essentially of." Embodiments described with the phrase "consisting essentially of" (or its synonyms) are also provided as embodiments described separately with "consisting of."

[0088] 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.

[0089] In general, a reference to a particular element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, C 14 , P 32 and S 35Compounds containing radioisotopes such as are within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0090] The term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that all normal valences are maintained and the replacement results in a stable compound. When a particular group is "substituted," the group can have one or more substituents, preferably 1-5 substituents, more preferably 1-3 substituents, and most preferably 1-2 substituents, independently selected from a list of substituents. For example, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to a non-hydrogen or non-carbon atom. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by a heteroatom with one or more bonds, including double or triple bonds. Thus, unless otherwise specified, a substituted group is substituted with one or more substituents. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogens (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SF), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like. The term "independently," when used with reference to substituents, means that when two or more such substituents are possible, such substituents can be the same or different from one another.

[0091] Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups can also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0092] As used herein, C 1 ~C 11 , C 1 ~C 8 , or C 1 ~C 6 and so forth Cm-Cn, when used before a group, refers to the group containing m to n carbon atoms.

[0093] Alkyl groups include straight-chain and branched alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbon atoms, or in some embodiments 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of straight-chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups can be substituted or unsubstituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, including, but not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0094] Cycloalkyl groups include monocyclic, bicyclic, or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring, or in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Bicyclic and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Cycloalkyl groups can be substituted or unsubstituted. Substituted cycloalkyl groups can be substituted one or more times with non-hydrogen and non-carbon groups, as defined above. However, substituted cycloalkyl groups also include rings substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-2,5-, or 2,6-disubstituted cyclohexyl groups, which can be substituted with substituents such as those listed above.

[0095] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, the cycloalkylalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, typically 4 to 10 carbon atoms. Cycloalkylalkyl groups can be substituted or unsubstituted. Substituted cycloalkylalkyl groups can be substituted at the alkyl portion, the cycloalkyl portion, or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups can be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted with the substituents listed above.

[0096] Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond is present between two carbon atoms. Alkenyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, an alkenyl can have one carbon-carbon double bond or multiple carbon-carbon double bonds, such as 2, 3, 4 or more carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, methenyl, ethenyl, propenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, for example, but not limited to, mono-, di-, or tri-substituted with the substituents listed above.

[0097] Cycloalkenyl groups include cycloalkyl groups as defined above, with at least one double bond between two carbon atoms. Cycloalkenyl groups can be monocyclic or polycyclic alkyl groups having 3 to 12, more preferably 3 to 8, carbon atoms in the ring and containing at least one double bond between two carbon atoms. Cycloalkenyl groups can be substituted or unsubstituted. In some embodiments, cycloalkenyl groups can have one, two, or three double bonds, or multiple carbon-carbon double bonds, such as two, three, four, or more carbon-carbon double bonds, but do not include aromatic compounds. Cycloalkenyl groups have 3 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

[0098] Cycloalkenylalkyl groups are alkyl groups as defined above, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups can be substituted or unsubstituted. Substituted cycloalkenylalkyl groups can be substituted at the alkyl portion, the cycloalkenyl portion, or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups can be substituted one or more times with a substituent such as those listed above.

[0099] Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond is present between two carbon atoms. Alkynyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkynyl groups have 1, 2, or 3 carbon-carbon triple bonds. Examples include, among others, -C=CH, -C=CCH 3 , -CH 2 C=CCH 3 , -C=CCH 2 CH(CH 2 CH 3 ) 2Examples of alkynyl groups include, but are not limited to, cyclooctyne, bicyclononyne (BCN), difluorinated cyclooctyne (DIFO), dibenzocyclooctyne (DIBO), keto-DIBO, biarylazacyclooctyne (BARAC), dibenzoazacyclooctyne (DIBAC), dimethoxyazacyclooctyne (DIMAC), difluorobenzocyclooctyne (DIFBO), monobenzocyclooctyne (MOBO), and tetramethoxyDIBO (TMDIBO).

[0100] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic, and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in other cases, 6-12, or even 6-10 carbon atoms in the ring portion of the group. In some embodiments, an aryl group is phenyl or naphthyl. An aryl group can be substituted or unsubstituted. The phrase "aryl group" includes groups that contain fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Representative substituted aryl groups can be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, di-, tri-, tetra-, penta-, or hexasubstituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above. Aryl moieties are well known and are described, for example, in Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13 th Edition, John Wiley & Sons, Inc., New York (1997). Aryl groups can be a single ring structure (i.e., monocyclic) or can contain multiple ring structures (i.e., polycyclic) that are fused ring structures. Preferably, the aryl group is a monocyclic aryl group.

[0101] An alkoxy group is a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with a substituent such as those listed above.

[0102] Similarly, alkylthio or thioalkoxy refers to the group -SR, where R is an alkyl attached to the parent molecule through a sulfur bridge, e.g., -S-methyl, -S-ethyl, etc. Representative examples of alkylthio include -SCH 3 , -SCH 2 CH 3 These include, but are not limited to:

[0103] As used herein, the term "halogen" refers to bromine, chlorine, fluorine, or iodine. Correspondingly, the term "halo" means fluoro, chloro, bromo, or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0104] The terms "hydroxy" and "hydroxyl" may be used interchangeably and refer to --OH.

[0105] The term "carboxy" refers to --COOH.

[0106] The term "cyano" refers to --CN.

[0107] The term "nitro" refers to -NO 2Refers to...

[0108] The term "isothiocyanate" refers to --N.dbd.C.dbd.S.

[0109] The term "isocyanate" refers to --N.dbd.C.dbd.O.

[0110] The term "azide" refers to -N 3 Refers to...

[0111] The term "amino" refers to -NH 2 The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms attached to the nitrogen are replaced with an alkyl group. An alkylamine group is -NR 2 where each R is independently hydrogen or an alkyl group. For example, an alkylamine can be methylamine (-NHCH 3 ), dimethylamine (-N(CH 3 ) 2 ), -NHCH 2 CH 3 As used herein, the term "aminoalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more amino groups. Representative examples of aminoalkyl groups include -CH 2 NH 2 , -CH 2 CH 2 NH 2 , and -CH 2 CH(NH 2 )CH 3 These include, but are not limited to:

[0112] As used herein, "amide" refers to -C(O)NI 2 where each R is independently an alkyl group or hydrogen. An example of an amide is -C(O)NH 2 , -C(O)NHCH 3 , and -C(O)N(CH 3 ) 2 These include, but are not limited to:

[0113] The terms "hydroxylalkyl" and "hydroxyalkyl" are used interchangeably and refer to an alkyl group substituted with one or more hydroxyl groups. The alkyl can be a branched or straight chain aliphatic hydrocarbon. An example of a hydroxylalkyl is hydroxymethyl (-CH 2 OH), hydroxyethyl (-CH 2 CHOH), but are not limited to these.

[0114] As used herein, the term "heterocyclyl" includes stable monocyclic and polycyclic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. As used herein, the term "heteroaryl" includes stable monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Each ring of a heteroatom-containing heterocyclyl or heteroaryl group can contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring has at least one carbon atom. Heteroaryl groups that are polycyclic, e.g., bicyclic or tricyclic, must contain at least one fully aromatic ring, but other fused rings or rings can be aromatic or non-aromatic. The heterocyclyl or heteroaryl group can be attached to any available nitrogen or carbon atom of any ring of the heterocyclyl or heteroaryl group. Preferably, the term "heteroaryl" refers to 5- or 6-membered monocyclic and 9- or 10-membered bicyclic groups having at least one heteroatom (O, S, or N) in at least one of the rings, with the heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms, more preferably having 1 or 2 heteroatoms selected from O, S, and / or N. The nitrogen heteroatom of a heteroaryl can be substituted or unsubstituted. Additionally, the nitrogen and sulfur heteroatoms of a heteroaryl can be optionally oxidized (i.e., N→O and S(O)). r where r is 0, 1 or 2.

[0115] The term "ester" refers to -C(O) 2 R, where R is alkyl.

[0116] The term "carbamate" refers to -OC(O)NR 2 wherein each R is independently alkyl or hydrogen.

[0117] The term "aldehyde" refers to -C(O)H.

[0118] The term "carbonate" refers to -OC(O)OR, where R is alkyl.

[0119] The term "maleimide" has the chemical formula H 2 C 2 (CO) 2 The term "maleimide" refers to a maleimide group covalently bonded to another group or molecule. Preferably, the maleimide group is N-bonded, for example:

[0120] [ka]

[0121] The term "acyl halide" refers to -C(O)X, where X is halo (e.g., Br, Cl). Exemplary acyl halides include acyl chlorides (-C(O)Cl) and acyl bromides (-C(O)Br).

[0122] According to the convention used in the art,

[0123] [ka] is used in structural formulas herein to indicate a bond that is the point of attachment of a moiety, functional group, or substituent to a core, parent, or backbone structure, such as a compound of the invention or a targeting ligand.

[0124] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, that group may be optionally substituted with up to 3 R groups, and each occurrence of R is independently selected from the definitions of R.

[0125] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.

[0126] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0127] Antibodies that bind to PSMA The present disclosure relates to isolated antibodies and antigen-binding fragments thereof that specifically bind to PSMA.

[0128] 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, such as 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.

[0129] In general, an antibody is a protein or peptide chain that exhibits binding specificity to a specific antigen. The structure of an antibody 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 subclassified as isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Thus, an antibody of the invention can be of any of the five major classes or corresponding subclasses. Preferably, an antibody of the invention is IgG1, IgG2, IgG3, or IgG4. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda, based on the amino acid sequence of their constant domain. Thus, an antibody of the invention can contain a κ or λ light chain constant domain. According to some embodiments, an antibody of the invention comprises a heavy and / or light chain constant region 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.

[0130] A "complementarity determining region" (CDR) is a 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 may 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 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; International ImMunoGeneTics (IMGT) database, web resource, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to describe CDRs. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated in the specification. For example, the correspondence between numbering systems, including Kabat numbering and the IMGT specific numbering system, is well known to those of skill in the art (see, for example, Kabat, supra; Chothia, supra; Martin, supra; Lefranc et al., supra).

[0131] [Table 1]

[0132] The term "variable region" or "variable domain" refers to a heavy or light chain domain involved in binding of 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).

[0133] 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 the molecule is produced, such as a recombinant cell, as well as 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 that have been 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.

[0134] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen 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.

[0135] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that make up the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The 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 that contain B cells obtained from a transgenic non-human animal, e.g., a transgenic mouse or rat, and have a genome that includes a human heavy chain transgene and a light chain transgene.

[0136] 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, as used herein, PSMA refers to human PSMA. The amino acid sequence of human PSMA can be retrieved from Uniprot (Accession No. Q04609). The amino acid sequence of full-length human PSMA is shown in SEQ ID NO: 336. In SEQ ID NO: 336, the extracellular domain spans residues -4 to 750, the transmembrane domain spans residues -0 to 43, and the cytoplasmic domain spans residues -1 to 19.

[0137] SEQ ID NO: 336 (Full length human PSMA) MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0138] The term "PSMA" includes any PSMA variants, isoforms, and interspecies homologs that can be naturally expressed by cells (including prostate cells) or expressed on cells transfected with a gene or cDNA encoding the polypeptide. In certain embodiments, the PSMA is human PSMA.

[0139] "Specifically binds," "specific binding," "specifically binding," or "binds" refers to the binding of a proteinaceous molecule to an antigen or an epitope within an antigen with greater affinity than its affinity for other antigens.

[0140] "Epitope" refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of surface groupings of chemically active (such as polar, non-polar, 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.

[0141] Typically, proteinaceous molecules are about 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 non-specific antigens (e.g., BSA, casein) D is at least 100 times smaller than

[0142] The term "KD" refers to D The dissociation constant of an antibody is calculated by the ratio of its K to its Ka (i.e., K / Ka) and 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 Dcan be determined by using surface plasmon resonance techniques, for example by using a biosensor system, such as the Biacore® system, or by using biolayer interferometry techniques, for example the Octet RED96 system. D The smaller the value, the higher the affinity with which the antibody binds to the target antigen.

[0143] 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.

[0144] The terms "isolated antibody," "antigen-binding fragment thereof," and "anti-PSMA antibody" are used interchangeably and refer to an antibody that contains at least one binding domain that binds and specifically binds to PSMA.

[0145] 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.

[0146] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments of the disclosure are biparatopic antibodies that bind to PSMA.

[0147] In some embodiments, a biparatopic antibody of the present disclosure comprises at least one receptor binding domain to a first epitope on a PSMA target protein and a second receptor binding domain to 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 about 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.

[0148] The anti-PSMA antibodies of the disclosure include whole antibodies, antibody fragments that specifically bind to PSMA, and antigen-binding fragments thereof that specifically bind to PSMA.

[0149] In some embodiments, the anti-PSMA antibodies of the disclosure are prepared as 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 disclosure are whole or full-length antibodies.

[0150] In some embodiments, the anti-PSMA antibodies of the disclosure are full-length antibodies, whole antibodies, and intact antibodies.

[0151] The terms "full-length antibody", "whole antibody" and "intact antibody" are used interchangeably herein and 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) interconnected by disulfide bonds, as well as 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), 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.

[0152] In some embodiments, the anti-PSMA antibodies of the disclosure are antibody fragments or antigen-binding domains that specifically bind to PSMA.

[0153] 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 obtained, or genetically engineered polypeptides, and include portions of immunoglobulins that bind to antigens, such as VH, VL, VH and VL, Fab, Fab', F(ab') 2 , Fd and Fv fragments, disulfide stabilized Fv fragments (dsFv), (dsFv) 2 , bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabody (ds diabody), single-chain antibody molecule (scFv), single domain antibody (sdab), scFv dimer (bivalent diabody), multispecific antibodies formed from portions of antibodies containing one or more CDRs, camelized single domain antibodies, nanobodies, domain antibodies, domain antibodies consisting of one VH domain or one VL domain "includes: a polypeptide comprising an antibody, a nucleotide sequence comprising an IgG1 domain, an IgG2 domain, a polypeptide ...

[0154] A "dAb" or "dAb fragment" refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544 546 (1989)).

[0155] "Fab" or "Fab fragment" refers to an antibody fragment composed of the VH, CH1, VL, and CL domains.

[0156] "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.

[0157] "Fd" or "Fd fragment" refers to an antibody fragment composed of the VH and CH1 domains.

[0158] "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.

[0159] Antigen-binding fragments (such as VH and VL) can be linked together via synthetic linkers to form various types of single-chain antibody designs, where the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding domains, such as 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 a length that is appropriate 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 about 5 to 50 amino acids in length.

[0160] 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 linked contiguously 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-terminus and C-terminus of the polypeptide, and an scFv can comprise a VL-linker-VH or a VH-linker-VL.

[0161] 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 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 retain the desired activity, such as binding to PSMA.

[0162] The linker can be about 5-50 amino acids long. In some embodiments, the linker is about 10-40 amino acids long. In some embodiments, the linker is about 10-35 amino acids long. In some embodiments, the linker is about 10-30 amino acids long. In some embodiments, the linker is about 10-25 amino acids long. In some embodiments, the linker is about 10-20 amino acids long. In some embodiments, the linker is about 15-20 amino acids long. In some embodiments, the linker is 6 amino acids long. In some embodiments, the linker is 7 amino acids long. In some embodiments, the linker is 8 amino acids long. In some embodiments, the linker is 9 amino acids long. In some embodiments, the linker is 10 amino acids long. In some embodiments, the linker is 11 amino acids long. In some embodiments, the linker is 12 amino acids long. In some embodiments, the linker is 13 amino acids long. In some embodiments, the linker is 14 amino acids long. In some embodiments, the linker is 15 amino acids long. In some embodiments, the linker is 16 amino acids long. In some embodiments, the linker is 17 amino acids long. In some embodiments, the linker is 18 amino acids long. In some embodiments, the linker is 19 amino acids long. In some embodiments, the linker is 20 amino acids long. In some embodiments, the linker is 21 amino acids long. In some embodiments, the linker is 22 amino acids long. In some embodiments, the linker is 23 amino acids long. In some embodiments, the linker is 24 amino acids long. In some embodiments, the linker is 25 amino acids long. In some embodiments, the linker is 26 amino acids long. In some embodiments, the linker is 27 amino acids long. In some embodiments, the linker is 28 amino acids long. In some embodiments, the linker is 29 amino acids long.In some embodiments, the linker is 30 amino acids long. In some embodiments, the linker is 31 amino acids long. In some embodiments, the linker is 32 amino acids long. In some embodiments, the linker is 33 amino acids long. In some embodiments, the linker is 34 amino acids long. In some embodiments, the linker is 35 amino acids long. In some embodiments, the linker is 36 amino acids long. In some embodiments, the linker is 37 amino acids long. In some embodiments, the linker is 38 amino acids long. In some embodiments, the linker is 39 amino acids long. In some embodiments, the linker is 40 amino acids long. Exemplary linkers that may be used are Gly-rich linkers, Gly and Ser-containing linkers, Gly and Ala-containing linkers, Ala and Ser-containing linkers, and other flexible linkers.

[0163] Other linker sequences may include portions of the immunoglobulin hinge region, CL or CH1, derived from immunoglobulin heavy or light chain isotypes. 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.

[0164] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL).

[0165] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VL, an L1, and a VH (VL-L1-VH).

[0166] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:308.

[0167] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:309.

[0168] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:310.

[0169] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:311.

[0170] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:312.

[0171] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:313.

[0172] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:314.

[0173] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:315.

[0174] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:316.

[0175] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:317.

[0176] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:318.

[0177] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:319.

[0178] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:320.

[0179] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:321.

[0180] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:322.

[0181] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:323.

[0182] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:324.

[0183] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:325.

[0184] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:326.

[0185] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:327.

[0186] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:328.

[0187] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:329.

[0188] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:330.

[0189] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:331.

[0190] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:332.

[0191] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:333.

[0192] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:334.

[0193] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:335.

[0194] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:87.

[0195] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:107.

[0196] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:91.

[0197] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:111.

[0198] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:285.

[0199] In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:287.

[0200] [Table 2]

[0201] Divalent or bivalent single chain variable fragments (di-scFv, bi-scFv) can be engineered by linking two scFvs. 2 " or "tandem scFv" or "bis-scFv" fragment refers to a fusion protein 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 contiguously linked via a polypeptide linker and can be expressed as a single polypeptide chain. The two VLs and the two VHs 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 bind two different antigens or epitopes simultaneously.

[0202] Any of the VH and VL domains identified herein that bind PSMA can be engineered into an scFv format in either a VH-linker-VL or VL-linker-VH orientation. Any of the VH and VL domains identified herein can be engineered into an sc(Fv) format 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-VL-linker-VH, or VL-linker-VL-linker-VH-linker-VH. 2 It can be used to generate structures.

[0203] 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)).

[0204] "VHH" refers to a single domain antibody or nanobody that is exclusively composed 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 are Fv fragments, single chain scFv fragments (scFv), (scFv) 2 , Fab, F(ab) 2 , diabodies, VHH, dAb, Fd, Fv, or other single chain antibodies.

[0205] The anti-PSMA antibodies of the present disclosure include chimeric, humanized, or fully human antibodies that specifically bind to PSMA.

[0206] "Human antibody" refers to an antibody that is optimized to minimize immune responses when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If the 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 that are "derived" from sequences of human origin when the variable regions of the human antibody are derived from a system that uses human germline immunoglobulin 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. "Human antibodies" typically contain amino acid differences when compared to immunoglobulins expressed in humans, due to differences in the system used to obtain the human antibodies and human immunoglobulin loci, the deliberate introduction of somatic mutations or substitutions into the framework or CDRs, or both.

[0207] 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 a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a "human antibody" may contain a consensus framework sequence derived from human framework sequence analysis as described, for example, in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a library of human immunoglobulin genes displayed on phage as described, for example, 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."

[0208] Transgenic animals, such as mice, rats, or chickens carrying human immunoglobulin (Ig) loci in their genome, can be used to generate antigen-binding fragments that bind 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 selected antigens.

[0209] Antibodies or antigen-binding fragments thereof that bind to PSMA produced by immunizing non-human animals can be humanized. Exemplary humanization techniques that involve the selection of a human acceptor framework include CDR grafting (US Pat. No. 5,225,539), SDR grafting (US Pat. No. 6,818,749), resurfacing (Padlan, (1991) Mol Immunol 28:489-499), specificity determining residue resurfacing (US Patent Application Publication No. 2010 / 0261620), human framework adaptation (US Pat. No. 8,748,356), or superhumanization (US Pat. No. 7,709,226). In these methods, the CDRs or a subset of CDR residues of a parent antibody are grafted onto a human framework that can be selected based on overall homology to the parent framework, based on similarity in CDR length or identity of canonical structure, or a combination thereof.

[0210] 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.

[0211] In some embodiments, the disclosure provides 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 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), SISSSSYISYADAVKG (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; y. 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), 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] In some embodiments, the isolated protein comprising the antigen-binding domain comprises HCDR1, HCDR2, and HCDR3 of VH of SEQ ID NO: 52, and LCDR1, LCDR2, and LCDR3 of VL of SEQ ID NO: 53, and the antibody or antigen-binding fragment thereof binds to PSMA.

[0223] 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.

[0224] 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.

[0225] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:52 and a VL of SEQ ID NO:53.

[0226] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:54 and a VL of SEQ ID NO:55.

[0227] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:56 and a VL of SEQ ID NO:57.

[0228] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:58 and a VL of SEQ ID NO:59.

[0229] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:60 and a VL of SEQ ID NO:61.

[0230] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:62 and a VL of SEQ ID NO:63.

[0231] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:64 and a VL of SEQ ID NO:65.

[0232] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:66 and a VL of SEQ ID NO:67.

[0233] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO:278 and a VL of SEQ ID NO:279.

[0234] 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.

[0235] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:84.

[0236] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:85.

[0237] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:86.

[0238] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:88.

[0239] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:89.

[0240] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:90.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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 a HC of SEQ ID NO: 84 and a LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0254] 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 a HC of SEQ ID NO: 86 and a LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0255] 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 a HC of SEQ ID NO: 88 and a LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0256] 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 a HC of SEQ ID NO: 90 and a LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0257] 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 a HC of SEQ ID NO: 92 and a LC of SEQ ID NO: 93, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0258] 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 a HC of SEQ ID NO: 94 and a LC of SEQ ID NO: 95, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0259] 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 a HC of SEQ ID NO: 96 and a LC of SEQ ID NO: 97, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0260] 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 a HC of SEQ ID NO: 98 and a LC of SEQ ID NO: 99, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0261] 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 a HC of SEQ ID NO: 100 and a LC of SEQ ID NO: 101, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0262] 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 a HC of SEQ ID NO: 102 and a LC of SEQ ID NO: 103, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0263] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, where a first antigen-binding domain binds to an epitope of PSMA and a second binding domain binds to a different epitope on PSMA.

[0264] The 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 light chain variable region comprising 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, a CDR3 sequence having the amino acid sequence of SEQ ID NO:9, in combination with 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, 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, 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.

[0265] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, a first antigen-binding domain that binds to an epitope of PSMA and a second binding domain that 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: 268, and an LC of SEQ ID NO: 269; The second antigen binding domain is in scFv format 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.

[0266] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, a first antigen-binding domain that binds to an epitope of PSMA and a second binding domain that 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 scFv format 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: 288.

[0267] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, 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.

[0268] In some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, 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.

[0269] 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, the second binding domain comprising: 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.

[0270] 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, the second binding domain comprising: 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.

[0271] 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 subject of the present disclosure. The 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 substantially identical amino acid sequences to the amino acid sequences of the variable or hypervariable domains of the antibodies of the present disclosure, or polypeptides having conservative substitutions. The 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 antibodies to retain binding to PSMA or retain at least one of the activities of the unmodified antibody.

[0272] 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 may be considered, provided that the resulting antibody still has at least the advantageous properties of the antibodies of the present disclosure.

[0273] 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 adding mutations, substitutions, deletions, and / or additions of one or more amino acid residues to the antibodies and antigen-binding fragments described herein.

[0274] 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, and the like. 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, and the like. In addition, the antibody can include one or more non-classical amino acids.

[0275] 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.

[0276] The sequences of the present disclosure may include amino acid sequences 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 antigen-binding domain that binds PSMA, including 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 antigen-binding domain that binds PSMA, are within the scope of the present disclosure, so long as they retain or have improved functional properties when compared to the parent antigen-binding domain. Functional equivalents or variants of the antigen-binding domain that binds PSMA 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 can be considered, provided that the resulting antibody still has at least the advantageous properties of the antibody of the present disclosure.

[0277] 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 measured 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 to the 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 x 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.

[0278] 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 direct mutation. In some embodiments, a variant antigen-binding domain that binds 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 PSMA.

[0279] In certain embodiments, the substitutions are conservative amino acid substitutions made at one or more predicted non-essential amino acid residues. "Conservative modification" or "conservative substitution" refers to an amino acid modification that does not significantly affect or change 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).

[0280] 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.

[0281] 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.

[0282] 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 extends the serum half-life of the antibody.

[0283] 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.

[0284] 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.

[0285] 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: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.

[0286] 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: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.

[0287] 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: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.

[0288] 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: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.

[0289] 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: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.

[0290] 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: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.

[0291] 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: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.

[0292] 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.

[0293] 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 the VL of SEQ ID NO:53.

[0294] 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.

[0295] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0296] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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 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.

[0303] 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.

[0304] 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 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.

[0305] 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 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] In some embodiments, the 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.

[0310] In some embodiments, the 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.

[0311] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] In some embodiments, the 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.

[0319] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0320] In some embodiments, an 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] In some embodiments, the 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.

[0327] In some embodiments, the 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.

[0328] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0329] 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.

[0330] In some embodiments, an 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, 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.

[0336] In some embodiments, an 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.

[0337] In some embodiments, an 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 comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0338] In some embodiments, an 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, 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.

[0339] In some embodiments, an 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, 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.

[0340] In some embodiments, an 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, 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.

[0341] In some embodiments, an 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, 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.

[0342] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, 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.

[0343] In some embodiments, an 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.

[0344] In some embodiments, an 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 comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0345] In some embodiments, an 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, 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.

[0346] In some embodiments, an 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, 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.

[0347] In some embodiments, an 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, 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.

[0348] In some embodiments, an 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, 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.

[0349] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, 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.

[0350] In some embodiments, an 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.

[0351] In some embodiments, an 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.

[0352] In some embodiments, an 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, 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.

[0353] In some embodiments, an 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, 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.

[0354] In some embodiments, an 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, 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.

[0355] In some embodiments, an 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, 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.

[0356] The present disclosure also provides an isolated antibody comprising a 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 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0357] In some embodiments, an antibody that binds 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 a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0358] In some embodiments, an 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 comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0359] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0360] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0361] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0362] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0363] The present disclosure also provides an isolated antibody comprising a 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 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0364] In some embodiments, an antibody that binds 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 a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0365] In some embodiments, an 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 comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0366] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0367] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0368] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0369] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0370] 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.

[0371] 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 the VL of SEQ ID NO:55.

[0372] 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.

[0373] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0374] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0375] 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.

[0376] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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 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.

[0381] 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.

[0382] 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.

[0383] 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 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] The present disclosure also provides an isolated antibody comprising a 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 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0388] In some embodiments, an antibody that binds 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 a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0389] In some embodiments, an 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.

[0390] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0391] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0392] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0393] In some embodiments, an 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, and the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0394] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, a first antigen-binding domain that binds to an epitope of PSMA and a second binding domain that 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.

[0395] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, a first antigen-binding domain that binds to an epitope of PSMA and a second binding domain that 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.

[0396] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, a first antigen-binding domain that binds to an epitope of PSMA and a second binding domain that 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.

[0397] Half-life extending moieties and Fc engineering In addition to the modifications described above, the anti-PSMA antibodies of the present disclosure or antigen-binding fragments thereof 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 mitigate antibody characteristics as desired.

[0398] For example, antibodies with increased in vivo half-life 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 Fc regions, to the antibodies, antigen-binding fragments of the present disclosure. Additional half-life extending moieties include polyethylene glycol (PEG) molecules, such as PEG 5000 or PEG 20,000, fatty acids and fatty acid esters of different chain lengths, such as 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 may be fused directly to the antibodies or antigen-binding fragments of the present disclosure or may be generated by standard cloning and expression techniques.

[0399] The half-life extending moiety may 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.

[0400] 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.

[0401] In some embodiments, the half-life extending moiety is albumin.

[0402] In some embodiments, the half-life extending moiety is an albumin binding domain.

[0403] In some embodiments, the half-life extending moiety is transferrin.

[0404] In some embodiments, the half-life extending moiety is polyethylene glycol.

[0405] In some embodiments, the half-life extending moiety is an Ig constant region or a fragment of an Ig constant region.

[0406] In some embodiments, the half-life extending moiety is Ig.

[0407] In some embodiments, the half-life extending moiety is a fragment of Ig.

[0408] In some embodiments, the half-life extending moiety is an Ig constant region.

[0409] In some embodiments, the half-life extending moiety is a fragment of an Ig constant region.

[0410] In some embodiments, the half-life extending moiety is an Fc region.

[0411] 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 disclosure can be of any allotype or isotype, i.e., IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE.

[0412] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG1 isotype.

[0413] In some embodiments, the Ig constant region or fragment of an Ig constant region is an IgG2 isotype.

[0414] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG3 isotype.

[0415] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG4 isotype.

[0416] Allotypes are not expected to affect the properties of Ig constant regions, such as binding or Fc-mediated effector functions. 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 extent to which therapeutic proteins containing fragment Ig constant regions induce an immune response in the host may be determined in part by the allotype of the Ig constant region (Stickler et al., (2011) Genes and Immunity 12:213-21). Ig constant region allotypes are associated with amino acid sequence variations at specific positions in the antibody constant region sequence.

[0417] The antibodies or antigen-binding fragments thereof of the present disclosure, and their functional equivalents, 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), FcγRIIb, and / or FcRn.

[0418] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0419] In some embodiments, at least one mutation is in the Fc region.

[0420] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0421] The neonatal Fc receptor (FcRn) plays a central role in cellular trafficking and serum half-life of IgG. In some embodiments, an antibody or antigen-binding fragment thereof that binds 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.

[0422] 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.

[0423] 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, alone or in combination, that may be made to increase the half-life of an antibody 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.

[0424] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region that includes the M252Y / S254T / T256E mutations.

[0425] In some embodiments, the antibodies or antigen-binding fragments of the disclosure, and functional equivalents thereof, are conjugated to an Ig constant region or to 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).

[0426] Fc positions that may 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 ... These 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. A hybrid IgG2 / 4 Fc domain may also be used, such as an Fc having residues 117-260 from IgG2 and residues 261-447 from IgG4.

[0427] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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 / 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.

[0428] 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 mutations: L234A_L235A_D265S.

[0429] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0430] 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 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).

[0431] 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.

[0432] Fc positions that may be mutated to enhance CDC include positions 267, 268, 324, 326, 333, 345, and 430. Exemplary mutations that may 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.

[0433] 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., IgG1 lambda), 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] 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 IgG1 lambda), 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] 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.

[0436] 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 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 comprises 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.

[0437] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 comprises 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.

[0438] 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, 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.

[0439] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0440] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0441] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0442] 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., IgG1 lambda), 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] 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 IgG1 lambda), 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] 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 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.

[0445] 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 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 comprises 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.

[0446] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, respectively, and the antibody or antigen-binding fragment comprises 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.

[0447] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0448] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0449] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0450] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0451] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence that is 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 comprises the 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 comprises the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0452] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence that is 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 comprises the 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 comprises the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0453] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., 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.

[0454] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 is an IgG1 (e.g., an IgG1 lambda), 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] In some embodiments, an 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 IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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.

[0457] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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.

[0458] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0460] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence that is 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 fragment of the second Ig constant region, comprise the 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0461] In some embodiments, the disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising an amino acid sequence that is 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 comprises the 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 comprises the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0462] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., 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.

[0463] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 is an IgG1 (e.g., an IgG1 lambda), 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.

[0464] In some embodiments, an 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 IgG1 lambda), 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.

[0465] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] In some embodiments, an 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0469] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment is an IgG1 (e.g., 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.

[0470] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 is an IgG1 (e.g., an IgG1 lambda), 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.

[0471] In some embodiments, an 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 IgG1 lambda), 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.

[0472] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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] In some embodiments, an 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, and the antibody or antigen-binding fragment is an IgG1 (e.g., an IgG1 lambda), 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 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0476] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, 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.

[0477] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 LCDR1 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., IgG1 lambda) 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.

[0478] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR1 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., IgG1 lambda) 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.

[0479] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0480] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0481] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0482] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0483] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, 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.

[0484] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 LCDR1 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., IgG1 lambda) 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.

[0485] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR1 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., IgG1 lambda) 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.

[0486] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0487] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0488] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0489] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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.

[0490] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and 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.

[0491] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, and the antibody or antigen-binding fragment is 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.

[0492] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 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, wherein the antibody or antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively. and LCDR3, and the antibody or antigen-binding fragment is 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.

[0493] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 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.

[0494] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 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.

[0495] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 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.

[0496] The disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising a 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 a 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 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.

[0497] 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 an 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.

[0498] 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 the 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0499] 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., an IgG1λ), and optionally a first 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.

[0500] 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 an 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.

[0501] 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 an 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.

[0502] 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 the antibody or antigen-binding fragment comprises an 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.

[0503] 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 an 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.

[0504] 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 an 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.

[0505] 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 the 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0506] 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., an IgG1λ), and optionally a first 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.

[0507] 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 an 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.

[0508] 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 an 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.

[0509] 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 an 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.

[0510] 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 an 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.

[0511] 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 an 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.

[0512] 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 the 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0513] 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., an IgG1λ), and optionally a first 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.

[0514] 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 an 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.

[0515] 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 an 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.

[0516] 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 an 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.

[0517] 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 an 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.

[0518] 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 an 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.

[0519] 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 the 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 the L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0520] 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 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.

[0521] 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 an 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.

[0522] 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 the antibody or antigen-binding fragment comprises an 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.

[0523] 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 an 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.

[0524] 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 an 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.

[0525] Polynucleotides Polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the disclosure and functional equivalents thereof are also provided. The disclosure provides isolated polynucleotides encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof of the disclosure.

[0526] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:52.

[0527] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:54.

[0528] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:56.

[0529] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:58.

[0530] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:60.

[0531] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:62.

[0532] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:64.

[0533] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:66.

[0534] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:278.

[0535] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:53.

[0536] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:55.

[0537] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:57.

[0538] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:59.

[0539] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:61.

[0540] In some embodiments, the disclosure includes an isolated polynucleotide encoding the VL of SEQ ID NO:63.

[0541] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:65.

[0542] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:67.

[0543] In some embodiments, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:279.

[0544] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:84.

[0545] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:86.

[0546] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:88.

[0547] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:90.

[0548] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:92.

[0549] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:94.

[0550] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:96.

[0551] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:98.

[0552] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:100.

[0553] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:102.

[0554] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:268.

[0555] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:282.

[0556] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:284.

[0557] In some embodiments, the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:288.

[0558] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:85.

[0559] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:89.

[0560] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:93.

[0561] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:95.

[0562] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:97.

[0563] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:99.

[0564] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:101.

[0565] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:103.

[0566] In some embodiments, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:269.

[0567] In some embodiments, the disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:52 and 53.

[0568] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:84 and 85.

[0569] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:86 and 85.

[0570] In some embodiments, the disclosure provides isolated polynucleotide sequences that encode the polypeptide sequences of SEQ ID NOs:54 and 55.

[0571] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:88 and 89.

[0572] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:52, 53, 278, and 279.

[0573] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:268, 269, and 282.

[0574] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding the polypeptide sequences of SEQ ID NOs:284, 269, and 288.

[0575] 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.

[0576] Polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure include polynucleotides having a nucleic acid sequence that is substantially identical to the nucleic acid sequence 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.

[0577] 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-oxyacetate (v), wybutoxosine, pseudouracil, queuosine, beta-D-galactosylqueuosine, 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.

[0578] Vectors Containing Polynucleotides Encoding Anti-PSMA Antibodies Also provided is a vector comprising DNA encoding the anti-PSMA antibody or antigen-binding fragment of the present disclosure. The disclosed vector can be used, for example, to generate any of the anti-PSMA antibodies or antigen-binding fragments thereof disclosed above. A polynucleotide encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure can be incorporated into a vector using standard molecular biology methods.

[0579] In some embodiments, the present disclosure provides an expression vector comprising the polynucleotide of the present invention. Such vectors can be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon-based vectors, or any other vector suitable for introducing the synthetic polynucleotide of the present invention into a given organism or genetic background by any means. The vector of the present disclosure can be an expression vector for efficient synthesis of PSMA antibody polypeptide, and expression of the PSMA antibody polypeptide of the present disclosure in prokaryotic and eukaryotic systems, including but not limited to yeast and mammalian cell culture.

[0580] 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, e.g., a retroviral vector, e.g., a gamma retroviral vector.

[0581] The vector of the present disclosure may contain promoter and enhancer sequences. The polynucleotide encoding the PSMA-binding protein of the present disclosure may be operably linked to a control sequence in an expression vector that ensures the 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 that controls the termination of transcription and translation. The expression vector may also include one or more non-transcriptional elements, such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' adjacent non-transcriptional sequences, 5' or 3' non-translation 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.

[0582] The vectors of the present disclosure may also contain one or more Internal Ribosome Entry Sites (IRES). The 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, or may be positioned to provide optimal spacing for expression of the gene product (i.e., by introducing "spacer" nucleotides between ORFs), or may be otherwise positioned. Regulatory elements, such as IRES motifs, may also be positioned to provide optimal spacing for expression.

[0583] 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, for example, from ColE1, SV40, 2μ plasmid, lambda, bovine papilloma virus, and the like.

[0584] Recombinant expression vectors can be designed for either transient expression, stable expression, or both, and can be made for constitutive or inducible expression.

[0585] Vectors may also contain selection markers well known in the art. Selection markers include positive and negative selection markers. Marker genes include biocide resistance (e.g., resistance to antibiotics, heavy metals, etc.), complementation to provide 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, 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 selection marker may be upstream or downstream of the nucleic acid sequence or cloning site encoding the polypeptide of interest.

[0586] 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, either due to 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 cells. Examples of prokaryotic host cells are bacilli such as Escherichia coli, Bacillus subtilis, and other Enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species. Other microbes, 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 (ATTC 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.

[0587] 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 performed using well-known methods.

[0588] The cell line may 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 derived cells. These cell lines may 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 expression of the antibody and purifying the antibody from the host cells or the medium surrounding the host cells.

[0589] The present disclosure also provides a method of producing an anti-PSMA binding protein of the present disclosure, comprising culturing a host cell 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 cell using methods well known in the art. The protein of interest may be substantially pure, e.g., at least about 80%-85% pure, at least about 85%-90% pure, at least about 90%-95% pure, or at least about 98%-99% pure or more, and may be free of contaminants, such as cellular debris, macromolecules other than the protein of interest, etc.

[0590] 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 pharma- ceutically 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.

[0591] 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 pharma- ceutical active moiety, therapeutic moiety, toxin, or drug.

[0592] As used herein, the term "targeting ligand" refers to any molecule that provides enhanced affinity to a selected target, such as 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. The targeting ligand may act 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 delivers 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 that is conjugated to a pharmacoactive moiety and can deliver a payload to a site characterized by the abundance of PSMA.

[0593] As used herein, the term "payload" refers to any naturally occurring or synthetically produced molecule, including small molecular weight molecules or chemical entities that can be chemically synthesized, and larger molecules or biological entities that must be produced by fermentation of a host cell and that confer novel functionality to a targeting ligand specific for binding to a target or antigen. Examples of payloads include, but are not limited to, drugs, toxins, cytokines, markers, oligonucleotides, antisense, small interfering RNA oligonucleotides (siRNAs), etc., for the production of site-specifically conjugated antibody drug conjugates (ADCs). The payload can also be a radioactive metal complex or a radioactive metal ion, as described below.

[0594] As used herein, the terms "drug" or "warhead" may be used interchangeably and refer to a biologically active or detectable molecule or compound, including anti-cancer 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 that are metabolized to active agents in vivo, polymers, nucleic acid molecules, small molecules, binding agents, mimetics, synthetic drugs, inorganic molecules, organic molecules, and radioisotopes. In some embodiments, the disclosed ADC or radioconjugates direct the bound payload to a target site in a relatively unreactive and non-toxic 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 homogenous composition of the ADC or radioconjugate preparation that minimizes over-conjugated toxic species.

[0595] 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 a variety of stoichiometric molar ratios, depending at least in part on the method used to affect conjugation.

[0596] The conjugates of the present disclosure have the formula: Ab-[LD]n or a pharma- ceutical acceptable salt thereof, wherein: a) 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.

[0597] Those skilled in the art will appreciate that conjugates according to the foregoing formula may be made using a number of different linkers and drugs, and that the conjugation methodology will vary depending on the choice of components.

[0598] Linker In some embodiments, the (ADC) and radioconjugates of the disclosure comprise a linker that connects the anti-PSMA antibodies and antigen-binding fragments thereof of the disclosure to a drug moiety or chelator.

[0599] As used herein, the term "linker" refers to a chemical moiety that connects a compound (such as a chelator or drug) to a nucleophilic moiety, electrophilic moiety, targeting ligand, or antibody or its antigen-binding domain. Any suitable linker known to one of skill in the art in view of the present disclosure can be used to conjugate the antibody of the present disclosure to the relevant drug or chelator. Preferably, the linker is covalently attached 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 of the present disclosure (site-specific or otherwise) is compatible with the teachings of the present specification. Ideally, the linker is designed to largely release the drug once it is delivered to the tumor site, substantially reducing undesirable non-specific toxicity by minimizing exposure of non-targeted cells and tissues to the cytotoxic drug, thereby providing an enhanced therapeutic index.

[0600] The linker can include, 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, such as a disulfide bond or a protease cleavage site, e.g., valine-citrulline-p-aminobenzyloxycarbonyl (PAB). The linker can be composed of one or more linker components. Exemplary linker moieties 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 ("Succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate ("Succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate"). carboxylate, "SMCC," and N-Succinimidyl(4-iodo-acetyl)aminobenzoate, "SIAB."

[0601] In some embodiments, the linker is valine-citrulline-p-aminobenzyloxycarbonyl ("vc-PAB"). In some embodiments, the linker may comprise an amino acid residue. Exemplary amino acid linker moieties include dipeptides, tripeptides, tetrapeptides, or pentapeptides. Exemplary dipeptides include valine-citrulline (vc or val-cit), 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 moiety include naturally occurring as well as minor amino acids and non-naturally occurring amino acid analogs such as citrulline. Amino acid linker moieties 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.

[0602] Exemplary linker structures suitable for use in the present disclosure also include, but are not limited to, the following:

[0603] [ka] In the formula, m is an integer of 0 to 12.

[0604] In a preferred embodiment, 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. The 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) allows 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 effect of the drug moiety.

[0605] 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.

[0606] 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, hormonal therapy, oligonucleotides, antisense, siRNA, anti-metastatic agents, and immunotherapeutic agents.

[0607] 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 cytotoxic agents include chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active 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 poorly active.Enzymatically active toxins and fragments thereof that may 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 proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and the trichothecenes.

[0608] 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 5,416,06), auristatins such as the monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see, e.g., U.S. Pat. Nos. 5,635,483, and 7,498,298), dolastatins, calicheamicins, 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.

[0609] Radioactive metal ions 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.

[0610] 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" refers specifically to an antibody or antigen-binding domain conjugated (linked, e.g., bound via a covalent bond) to at least one radioactive metal complex. Stated differently, a radioconjugate refers to at least one radioactive metal complex linked, e.g., bound via a covalent bond, to an antibody or antigen-binding domain. A radioconjugate may include 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 macrocycle may participate in the coordination of a radiometal ion to the chelator. The chelator may be substituted with one or more substituents, which may also participate in the coordination of a radiometal ion to the chelator in addition to or instead of the heteroatoms of the macrocycle.

[0611] As used herein, the term "radioactive metal ion" or "radioactive metal ion...

Claims

1. A radioimmunoconjugate of the formula: 【Chemical 1】 During the ceremony, M ＋ is a radioactive metal ion, and M ＋ is actinium 225 ( ２２５ Ac), indium-111 (111In), radium-223 ( ２３３ Ra), Bismuth 213 ( ２１３ Bi), lead 212 ( ２１２ Pb(II) and / or ２１２ Pb(IV)), terbium-149 ( １４９ Tb), terbium 152 ( １５２ Tb), terbium 155 ( １５５ Tb), Fermium 255 ( ２５５ Fm), Thorium 227 ( ２２７ Th), thorium 226 ( ２２６ Th ４＋ ), Astatine 211 ( ２１１ At), cerium 134 ( １３４ Ce), neodymium 144 ( １４４ Nd), Lanthanum 132 ( １３２ La), Lanthanum 135 ( １３５ La), and uranium-230 ( ２３０ U), and mAb is an antibody or antigen-binding fragment that binds to PSMA; radioimmunoconjugate.

2. the antibody or antigen-binding fragment comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the 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: 130), 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. The radioimmunoconjugate of claim 1, each 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).

3. the antibody or antigen-binding fragment thereof 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 radioimmunoconjugate 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.

4. the antibody or antigen-binding fragment having 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.

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

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

7. 2. The radioimmunoconjugate of claim 1, wherein the antibody or antigen-binding fragment further comprises an Ig constant region, and 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).

8. 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 / 8. The radioimmunoconjugate of claim 7, wherein the residue numbering is according to the EU index and the residues are selected from the group consisting of 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.

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

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

11. 11. The radioimmunoconjugate of claim 10, 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, where residue numbering is according to the EU index.

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

13. A radioimmunoconjugate of the formula: 【Chemistry 2】 During the ceremony, M ＋ teeth, ２２５ Ac or １１１ In; mAb is an antibody or antigen-binding fragment that binds to PSMA; 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. A radioimmunoconjugate 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.

14. A radioimmunoconjugate of the formula: 【Chemistry 3】 During the ceremony, M ＋ teeth, ２２５ Ac or １１１ In; mAb is an antibody or antigen-binding fragment that binds to PSMA; 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. A radioimmunoconjugate 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.

15. A pharmaceutical composition comprising the radioimmunoconjugate of claim 1 and a pharmaceutically acceptable carrier.

16. 16. The pharmaceutical composition of claim 15, which is used to treat a PSMA-expressing cancer in a subject in need thereof.

17. 17. The pharmaceutical composition of claim 16, wherein the PSMA-expressing cancer is prostate cancer.

18. 18. The pharmaceutical composition of claim 17, wherein the prostate cancer is metastatic castration-resistant cancer (mCRPC).

19. A method for detecting a PSMA-expressing cancer in a subject, comprising contacting a sample from the subject with the radioimmunoconjugate of claim 1.

20. 20. The method of claim 19, wherein the subject sample is derived from urine, blood, serum, plasma, saliva, ascites, circulating cells, and circulating tumor cells.

21. A kit comprising the radioimmunoconjugate of claim 1, a reagent, and instructions for using the radioimmunoconjugate.

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