Anti-PSMA antibodies and their uses

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 237,663, filed on August 27, 2021, entitled “ANTI-PSMA ANTIBODIES AND USESTHEREOF,” the disclosures of each of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The XML copy, created on July 11, 2022, is named JBI6621USNP1_SL.xml and is 282,897 bytes in size. Technical Field

[0005] Provided herein are antibodies or antigen-binding fragments thereof, polynucleotides, vectors, host cells, radioconjugates, antibody drug conjugates that bind to prostate specific membrane antigen (PSMA), and methods of using the same to treat cancer. Background Art

[0006] Prostate cancer is the second most common cancer in men worldwide and the sixth leading cause of cancer-related death. Globally, there are approximately 1.1 million new cases and 300,000 deaths each year, accounting for 4% of all cancer deaths. An estimated 1 in 6 men will be diagnosed with the disease in his lifetime. In the United States, over 90% of prostate cancers are diagnosed at the localized or localized stage. In these early stages, the 5-year survival rate approaches 100%. However, when the cancer has metastasized, the 5-year survival rate drops to 28%, and effective treatments for advanced prostate cancer remain unresolved.

[0007] Prostate-specific membrane antigen (PSMA) is a type II membrane protein that is highly expressed in prostate intraepithelial neoplasia (PIN), a condition in which some prostate cells begin to look and behave abnormally, as well as in primary and metastatic prostate cancer (Bostwick DG et al., Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: A study of 184 cases. Cancer 1998; 82(11): 2256–2261). PSMA expression in cancer tissue correlates with disease stage and Gleason score (Kawakami M et al., Enhanced expression of prostate-specific membrane antigen gene in prostate cancer as revealed by in situ hybridization. Cancer Res 1997; 57(12): 2321–2324). PSMA expression is also high 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). In surgically treated prostate cancer, high levels of PSMA expression are associated with recurrence of early prostate-specific antigen (PSA)-positive prostate cancer.PSMA expression levels correlate with disease aggressiveness, strongly supporting PSMA as an excellent target for prostate cancer characterization and subsequent treatment.

[0008] Current treatments for prostate cancer include surgery, radiation therapy, and hormone therapy. Despite lowering testosterone levels through hormone therapy, prostate cancer continues to grow, and treatment options are limited. This highlights the need for more improved treatments and effective therapies for advanced prostate cancer that expresses PSMA. Summary of the Invention

[0009] Provided herein is an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the following amino acid sequence:

[0010] 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;

[0011] 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;

[0012] 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;

[0013] 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);

[0014] 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);

[0015] 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);

[0016] 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);

[0017] 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);

[0018] 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;

[0019] 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;

[0020] 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;

[0021] 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;

[0022] 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;

[0023] 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;

[0024] 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;

[0025] 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;

[0026] 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;

[0027] 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;

[0028] s. Separately, 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);

[0029] t. Separately, 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);

[0030] u. Separately, 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);

[0031] v. Separately, 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);

[0032] w. Separately, 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);

[0033] 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;

[0034] 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;

[0035] 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;

[0036] 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;

[0037] 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;

[0038] 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;

[0039] 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;

[0040] 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;

[0041] 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;

[0042] 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;

[0043] 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;

[0044] 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

[0045] 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.

[0046] Also disclosed is an isolated antibody or antigen-binding fragment thereof, comprising the following heavy chain variable region (VH) and light chain variable region (VL):

[0047] SEQ ID NOs: 52 and 53, respectively;

[0048] SEQ ID NOs: 54 and 55, respectively;

[0049] SEQ ID NOs: 56 and 57, respectively;

[0050] SEQ ID NOs: 58 and 59, respectively;

[0051] SEQ ID NOs: 60 and 61, respectively;

[0052] SEQ ID NOs: 62 and 63, respectively;

[0053] SEQ ID NOs: 64 and 65, respectively;

[0054] SEQ ID NOs: 66 and 67, respectively; or

[0055] SEQ ID NOs: 278 and 279, respectively, and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0056] 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.

[0057] 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.

[0058] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284 and 288.

[0059] The present disclosure also provides an isolated 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.

[0060] The present disclosure also provides an isolated 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.

[0061] The present disclosure also provides an isolated 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.

[0062] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0063] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0064] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0065] The HC of SEQ ID NO: 84 and the LC of SEQ ID NO: 85; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0066] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0067] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0068] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0069] The HC of SEQ ID NO: 86 and the LC of SEQ ID NO: 85; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0070] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0071] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively;

[0072] VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55; and / or

[0073] The HC of SEQ ID NO: 88 and the LC of SEQ ID NO: 89; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0074] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0075] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively;

[0076] VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55; and / or

[0077] The HC of SEQ ID NO:90 and the LC of SEQ ID NO:89; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0078] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0079] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20 and 21, respectively;

[0080] VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57; and / or

[0081] The HC of SEQ ID NO: 92 and the LC of SEQ ID NO: 93; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0082] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0083] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26 and 27, respectively;

[0084] VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59; and / or

[0085] The HC of SEQ ID NO: 94 and the LC of SEQ ID NO: 95; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0086] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0087] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32 and 33, respectively;

[0088] VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61; and / or

[0089] The HC of SEQ ID NO: 96 and the LC of SEQ ID NO: 97; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0090] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0091] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38 and 39, respectively;

[0092] VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63; and / or

[0093] The HC of SEQ ID NO: 98 and the LC of SEQ ID NO: 99; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0094] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0095] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44 and 45, respectively;

[0096] VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65; and / or

[0097] The HC of SEQ ID NO: 100 and the LC of SEQ ID NO: 101; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0098] Also disclosed is an isolated antibody or antigen-binding fragment thereof comprising:

[0099] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50 and 51, respectively;

[0100] VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67; and / or

[0101] The HC of SEQ ID NO: 102 and the LC of SEQ ID NO: 103; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0102] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof that binds 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.

[0103] In some embodiments, a biparatopic antibody comprises two antigen binding domains, wherein:

[0104] The first antigen binding domain is a Fab or Fab fragment comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, LCDR3 of SEQ ID NO: 9, VH of SEQ ID NO: 52, VL of SEQ ID NO: 53, HC of SEQ ID NO: 268, and LC of SEQ ID NO: 269; and the second antigen binding domain is in the form of a scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, HC of SEQ ID NO: 282; or

[0105] 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: 284, and LC of SEQ ID NO: 269; and the second antigen binding domain is in the form of a scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, and HC of SEQ ID NO: 288.

[0106] In some embodiments, the disclosed isolated antibodies or antigen-binding fragments thereof are of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0107] In some embodiments, the isolated antibody or antigen-binding fragment is of the IgG1 isotype.

[0108] 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 the 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).

[0109] 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, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236-deficient 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.

[0110] In some embodiments, the mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to FcγR is L234A_L235A_D265S.

[0111] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0112] 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 of the fragment or the constant region comprises at least one mutation that modulates the half-life of the antibody.

[0113] 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, wherein the residue numbering is according to the EU index.

[0114] In some embodiments, the mutation that modulates the half-life of the antibody or antigen-binding fragment thereof is an M252Y / S254T / T256E mutation.

[0115] The present disclosure also provides a polynucleotide encoding the isolated antibody or antigen-binding fragment thereof of the present disclosure.

[0116] Optionally, the polynucleotide encoding the isolated antibody or antigen-binding fragment thereof that binds PSMA comprises the polynucleotide sequence of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

[0117] Optionally, the polynucleotide encoding the isolated antibody or antigen-binding fragment thereof that binds PSMA is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 99%, or 100%) identical to the polynucleotide sequence of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286, or 289.

[0118] The present disclosure also provides a vector comprising the polynucleotide of the present disclosure.

[0119] The present disclosure also provides a host cell comprising the polynucleotide or vector of the present disclosure.

[0120] 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, and wherein the radiometal complex comprises a radiometal ion.

[0121] The present disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to any one of the antibodies or antigen-binding fragments thereof of the present disclosure, and wherein the radiometal complex comprises a radiometal ion.

[0122] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises: a heavy chain variable domain comprising HCDR1, HCDR2 and HCDR3 of SEQ ID NOs: 4, 5 and 6, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 7, 8 and 9, respectively.

[0123] The present 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.

[0124] 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.

[0125] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises the HC of SEQ ID NO: 86 and the 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 the 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).

[0126] 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, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236-deficient 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.

[0127] In some embodiments, the mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to FcγR is L234A_L235A_D265S.

[0128] The present disclosure also provides a radioconjugate, wherein the antibody or antigen-binding fragment comprises the HC of SEQ ID NO: 86 and the 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 the fragment of the constant region comprises at least one mutation that modulates the half-life of the antibody.

[0129] 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, wherein the residue numbering is according to the EU index.

[0130] In some embodiments, the mutation that modulates the half-life of the antibody or antigen-binding fragment thereof is an M252Y / S254T / T256E mutation.

[0131] The present disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to an antibody or antigen-binding fragment thereof, wherein the radiometal complex comprises a chelator complexed with a radiometal ion selected from: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 Second, 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 Xe.

[0132] In some embodiments, the radioactive metal ion is 225 Ac.

[0133] In some embodiments, the radioactive metal ion is 111 In.

[0134] In some embodiments, the radioactive metal ion is 134 Xe.

[0135] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the radiometal complex comprises a radiometal ion chelated to a compound of Formula (III) or a pharmaceutically acceptable salt thereof.

[0138] The present invention also provides a pharmaceutical composition comprising any one of the disclosed antibodies or antigen-binding fragments thereof; or any one of the disclosed radioconjugates, and a pharmaceutically acceptable carrier.

[0139] 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 antigen-binding fragments thereof, any of the disclosed radioconjugates, or any of the disclosed pharmaceutical compositions, for a time sufficient to treat the cancer.

[0140] In some embodiments, the subject has prostate cancer.

[0141] In some embodiments, the subject has renal cancer.

[0142] The present disclosure also provides a method for detecting PSMA in a sample using the radioconjugate of the present disclosure.

[0143] The present disclosure also provides a kit 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

[0144] Various publications, articles, and patents are cited or described in the Background and throughout the specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, and the like included in this specification is intended to provide a context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0145] 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 taken in conjunction with the accompanying drawings, which form a part of this disclosure. It is understood that the disclosed antibodies, antigen-binding domains, antibody fragments, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods are not limited to those specifically described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to limit the claimed antibodies, antigen-binding domains, antibody fragments, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods.

[0146] Unless specifically stated otherwise, any description of possible mechanisms or modes of action or reasons for improvement is intended for illustrative purposes only, and the disclosed antibodies, antigen-binding fragments, polynucleotides, vectors, cells, radioconjugates, antibody-drug conjugates, compositions, kits, and methods are not bound by the correctness or incorrectness of any such suggested mechanisms or modes of action or reasons for improvement.

[0147] In this article, description relates to antibodies, their antigen-binding fragments, radioconjugates, antibody drug conjugates and methods using the antibodies, their antigen-binding fragments, radioconjugates and antibody drug conjugates. When the disclosure describes or claims the features or embodiments relevant to antigen-binding domains, radioconjugates and antibody-drug conjugates, such features or embodiments are equally applicable to methods using the antigen-binding domains, radioconjugates and antibody-drug conjugates. Similarly, when the disclosure describes or claims the features or embodiments relevant to methods using antigen-binding domains, radioconjugates and antibody-drug conjugates, such features or embodiments are equally applicable to antigen-binding domains, radioconjugates and antibody-drug conjugates. When numerical ranges are listed or established herein, the range includes all individual integers and fractions within its end value and the range, and also includes each of the narrower ranges formed by all various possible combinations of those end values ​​and internal integers and fractions, to form a subgroup of the larger numerical group within the range to the same extent, as each of those narrower ranges is clearly listed. When a numerical range is stated herein to be greater than a specified value, the range is however limited, and its upper limit is limited by a value that is operable in the context of the present invention as described herein. When a numerical range is stated herein to be less than a specified value, the lower limit of the range is however limited by a non-zero value. It is not intended that the scope of the present invention be limited to the specific values ​​recited when defining a range. All ranges are inclusive and combinable.

[0148] When "about" is used above to express a value as an approximation, it should be understood that the specific value forms another embodiment. A reference to a specific value includes at least that specific value unless the context clearly dictates otherwise.

[0149] It should be understood that certain features of the present invention, for the sake of clarity, are described in the context of separate embodiments, but may also be provided in combination in a single embodiment. That is, unless clearly incompatible or expressly excluded, each individual embodiment is considered combinable with any other embodiment, and such combination is considered another embodiment. Conversely, various features of the present invention are described in the context of individual embodiments for the sake of clarity, but may also be provided separately or in any subcombination. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each of the steps may also be considered a separate embodiment in itself, combinable with other embodiments.

[0150] Unless specifically stated otherwise, any description of possible mechanisms or modes of action or reasons for improvement is intended for illustrative purposes only, and the methods disclosed herein are not bound by the correctness or incorrectness of any such suggested mechanisms or modes of action or reasons for improvement.

[0151] Various terms related to various aspects of the specification are used throughout the specification and claims. Unless otherwise indicated, such terms are given their ordinary meaning in the art. Other specifically defined terms should be understood in a manner consistent with the definitions provided herein.

[0152] 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 so forth.

[0153] The transition terms "comprising," "consisting essentially of," and "consisting of" are intended to suggest their recognized meanings in patent parlance; that is, (i) "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, 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 equivalents) are also provided, as are those embodiments described independently with "consisting of" and "consisting essentially of." Embodiments described with the phrase "consisting essentially of" (or its equivalents) are also provided, as are those embodiments described independently with "consisting of."

[0154] As used in this specification and the appended claims, the phrase "and fragments thereof" when appended to a list includes fragments of one or more members of the associated list. A list may include Markush groups, so that, for example, the phrase "a group consisting of peptides A, B, and C and fragments thereof" specifies or lists a Markush group that includes A, B, C, a fragment of A, a fragment of B, and / or a fragment of C.

[0155] 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 herein.

[0156] PSMA-binding antibodies

[0157] The present disclosure relates to isolated antibodies and antigen-binding fragments thereof that specifically bind PSMA.

[0158] As used herein, the term "antibody" refers broadly to and includes immunoglobulin molecules, including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies), dimeric antibodies, tetrameric antibodies, multimeric antibodies or biparatopic antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules that contain an antigen-binding site with the desired specificity. The term antibody includes full-length antibodies, whole antibodies, intact antibodies, antibody fragments, antigen-binding fragments and antigen-binding domains.

[0159] Generally speaking, antibody is a protein or peptide chain that shows binding specificity for a specific antigen. Antibody structure is well known. According to the heavy chain constant domain amino acid sequence, immunoglobulin can be designated as five major classes (i.e., IgA, IgD, IgE, IgG, and IgM). IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Therefore, the antibody of the present invention can be any one of the five main classes or corresponding subclasses. Preferably, the antibody of the present invention is IgG1, IgG2, IgG3, or IgG4. Based on the amino acid sequence of its constant domain, the antibody light chain of vertebrate species can be designated as one of two completely different types, i.e., κ and λ. Therefore, the antibody of the present invention can contain κ or λ light chain constant domains. According to some embodiments, the antibody of the present invention includes heavy chain and / or light chain constant regions from rat or human antibodies. In addition to the heavy and light chain constant domains, antibodies also contain an antigen-binding region consisting of a light chain variable region and a heavy chain variable region, wherein each variable region contains three domains (i.e., complementary 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.

[0160] "Complementarity determining regions" (CDRs) are regions of antibodies that bind antigen. There are three CDRs in VH (HCDR1, HCDR2, HCDR3) and three CDRs in VL (LCDR1, LCDR2, LCDR3). CDRs can be defined using various delineations, 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). The correspondence between various delineations and variable region numbers is 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 from UCL Business PLC) can be used to delineate CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms "CDR," "HCDR1," "HCDR2," "HCDR3," "LCDR1," "LCDR2," and "LCDR3" include CDRs defined by any of the above methods (Kabat, Chothia, IMGT, or AbM). The correspondence between numbering systems, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to those skilled in the art (see, for example, Kabat, supra; Chothia, supra; Martin, supra; Lefranc et al., supra).

[0161] Table 1 .

[0162]

[0163]

[0164] The term "variable region" or "variable domain" refers to the domain of the heavy or light chain involved in antibody binding to the antigen. The variable domain of the heavy or light chain (VH and VL, respectively) contains four framework regions (FR) and three complementarity determining regions (CDR).

[0165] As used herein, the term "isolated" refers to a homogenous population of molecules (such as synthetic polynucleotides or polypeptides) that have been substantially separated and / or purified from other components of the system (such as a recombinant cell) in which the molecule was produced, as well as proteins that have been subjected to at least one purification or isolation step. "Isolated" refers to a molecule that is substantially free of other cellular material and / or chemicals, and encompasses molecules isolated to higher purities (such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity).

[0166] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds to PSMA is substantially free of antibodies that do not bind to PSMA). Additionally, an isolated antibody can be substantially free of other cellular material and / or chemicals. An "isolated antibody" encompasses antibodies that have been isolated to a higher degree of purity, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.

[0167] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the group are identical except for possible naturally occurring mutations that may be present in small amounts. The monoclonal antibodies of the present invention can be prepared by hybridoma methods, phage display technology, single lymphocyte gene cloning technology, or by recombinant DNA methods. For example, a monoclonal antibody can be produced by a hybridoma comprising B cells obtained from a transgenic non-human animal, such as a transgenic mouse or rat, having a genome comprising a human heavy chain transgene and a light chain transgene.

[0168] 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 indicated, PSMA as used herein 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. The extracellular domain spans residues -4-750 of SEQ ID NO: 336, the transmembrane domain spans residues -0-43 of SEQ ID NO: 336, and the cytoplasmic domain spans residues -1-19 of SEQ ID NO: 336.

[0169] SEQ ID NO: 336 (full-length human PSMA)

[0170] MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0171] The term "PSMA" includes any PSMA variant, isoform, and species homolog that is naturally expressed by cells (including prostate cells) or is capable of being expressed on cells transfected with a gene or cDNA encoding the polypeptide. In specific embodiments, the PSMA is human PSMA.

[0172] "Specifically binds" or "specific binding" refers to the binding of a proteinaceous molecule to an antigen or an epitope within an antigen with a greater affinity than to other antigens.

[0173] "Epitope" refers to the portion of an antigen that specifically binds to an antibody. An epitope is typically composed of chemically active (e.g., polar, nonpolar, or hydrophobic) surface groups of a portion (e.g., amino acids or polysaccharide side chains) and may have specific three-dimensional structural characteristics as well as specific charge characteristics. An epitope may be composed of continuous and / or discontinuous amino acids that form a unit of conformational space. For discontinuous epitopes, amino acids from different parts of the linear sequence of an antigen are close in 3-dimensional space due to the folding of the protein molecule.

[0174] Typically, a protein molecule binds to an antigen or an epitope within an antigen, and the equilibrium dissociation constant (K D ) is about 1×10 -7 M or lower, for example, about 5×10 -8 M or less, about 1×10 -8 M or lower, about 1×10 -9 M or lower, about 1×10 -10 M or less, about 1×10 -11 M or lower or about 1×10 -12 M or lower, usually K D It is the K of its binding to nonspecific antigens (such as BSA, casein) D At most 1 / 100.

[0175] The term "KD" refers to the D The ratio of Kd to Ka (i.e., Kd / Ka) is obtained and expressed as the dissociation constant of molar concentration (M). D The K value can be determined using methods known in the art. For example, the K value of an antibody is D This can be achieved by using surface plasmon resonance, such as by using a biosensor system (e.g. The K of the antibody is determined by using biolayer interferometry techniques such as the Octet RED96 system. D The smaller the value, the higher the affinity of the antibody for binding to the target antigen.

[0176] As used herein, "binds to PSMA" or "an antibody that specifically binds to PSMA" refers to an antibody that binds to PSMA at a concentration of 1×10 -7 M or smaller, preferably 1×10 -8 M or less, more preferably 5×10 -9 M or smaller, 1×10 -9M or smaller, 5×10 -10 M or smaller, or 1×10 -10 M or smaller K D An antibody that binds PSMA, preferably human PSMA.

[0177] The terms "isolated antibody," "antigen-binding fragment thereof," and "anti-PSMA antibody" and the like are used interchangeably and refer to an antibody that binds PSMA and comprises at least one binding domain that specifically binds PSMA.

[0178] As used herein, the term "biparatopic antibody" refers to an antibody that specifically binds to two different epitopes on the same target protein (eg, PSMA).

[0179] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments of the present disclosure are biparatopic antibodies that bind PSMA.

[0180] In some embodiments, the biparatopic antibodies of the invention comprise at least one receptor binding domain directed against a first epitope on a PSMA target protein and a second receptor binding domain directed against a second epitope on the same PSMA target protein. D and K for the second epitope D In some embodiments, the K for the first epitope D and K for the second epitope D In some embodiments, the K for the first epitope D and K for the second epitope D About 1×10 -7 M or smaller, preferably 1×10 -8 M or less, more preferably 5×10 -9 M or smaller, 1×10 -9 M or smaller, 5×10 -10 M or smaller, or 1×10 -10 M or smaller.

[0181] The anti-PSMA antibodies of the present disclosure include whole antibodies, antibody fragments that specifically bind to PSMA, and antigen-binding fragments thereof that specifically bind to PSMA.

[0182] In some embodiments, the anti-PSMA antibodies of the present disclosure include whole or full-length antibodies, Fv fragments, single-chain scFv fragments (scFv), Fab, F(ab)2, or single-chain antibodies. In some embodiments, the anti-PSMA antibodies of the present disclosure are whole or full-length antibodies.

[0183] In some embodiments, the anti-PSMA antibodies of the present disclosure are full-length antibodies, whole antibodies, and intact antibodies.

[0184] The terms "full length antibody", "whole antibody" and "intact antibody" are used interchangeably herein to refer to antibodies with a structure similar to that of natural antibodies. "Intact antibodies" are composed of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (composed of the 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, which are called complementarity determining regions (CDRs) and are interspersed with framework regions (FRs). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, based on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The light chains of antibodies from any vertebrate species can be assigned to one of two distinct types, kappa and lambda, based on the amino acid sequence of their constant domains.

[0185] In some embodiments, the anti-PSMA antibodies of the present disclosure are antibody fragments or antigen-binding domains that specifically bind to PSMA.

[0186] As used herein, the terms "antibody fragment" and "antigen-binding fragment" refer to molecules other than intact antibodies. Antigen-binding fragments can be synthetic, enzymatically obtainable, or genetically engineered polypeptides and include portions of immunoglobulins that bind to antigens, such as VH, VL, VH and VL, Fab, Fab', F(ab')2, Fd and Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (dsdiabodies), single-chain antibody molecules (scFv), single-domain antibodies (sdab), scFv dimers (divalent diabodies), multispecific antibodies formed from a portion of an antibody comprising one or more CDRs, Antibodies, camelized single domain antibodies, nanobodies, domain antibodies, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, VHH domains, minimal recognition units consisting of amino acid residues that mimic the CDRs of an antibody, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2 and / or HCDR3 and LCDR1, LCDR2 and / or LCDR3, alternative scaffolds that bind to an antigen, bivalent domain antibodies, multispecific proteins comprising antigen-binding fragments, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure.

[0187] "dAb" or "dAb fragment" refers to an antibody fragment consisting of the VH domain (Ward et al., Nature 341:544546 (1989)).

[0188] "Fab" or "Fab fragment" refers to an antibody fragment consisting of the VH domain, CH1 domain, VL domain, and CL domain.

[0189] "F(ab')2" or "F(ab')2 fragment" refers to an antibody fragment containing two Fab fragments linked by a disulfide bridge in the hinge region.

[0190] "Fd" or "Fd fragment" refers to an antibody fragment consisting of the VH domain and the CH1 domain.

[0191] "Fv" or "Fv fragment" refers to an antibody fragment consisting of the VH and VL domains from a single arm of an antibody. An Fv fragment lacks the constant regions of the Fab (CH1 and CL) region. The VH and VL in the Fv fragment are held together by non-covalent interactions.

[0192] Antigen binding fragments (such as VH and VL) can be linked together via synthetic linkers to form various types of single antibody designs, wherein the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen binding domains, such as single-chain Fv (scFv) or diabodies. In recombinant expression systems, the linker is a peptide linker and can comprise 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 length of the linker should be sufficient to allow the VH and VL to form the correct conformation relative to each other so that they maintain the desired activity (such as binding to PSMA). The length of the linker can be about 5 to 50 amino acids.

[0193] "Single-chain Fv" or "scFv" is a fusion protein comprising at least one antibody fragment containing a light chain variable region (VL) and at least one antibody fragment containing a heavy chain variable region (VH), wherein the VL and VH are continuously connected via a polypeptide linker and can be expressed as a single chain polypeptide. The scFv can have the VL variable region and the VH variable region in either order, for example, relative to the N-terminus and C-terminus of the polypeptide, the scFv can comprise VL-linker-VH or can comprise VH-linker-VL.

[0194] In recombinant expression systems, the linker is a peptide linker and can comprise 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 length of the linker should be sufficient to allow the VH and VL to be connected in the correct conformation relative to each other so that they retain the desired activity (such as binding to PSMA).

[0195] The length of the linker may be about 5 to 50 amino acids. In some embodiments, the length of the linker is about 10 to 40 amino acids. In some embodiments, the length of the linker is about 10 to 35 amino acids. In some embodiments, the length of the linker is about 10 to 30 amino acids. In some embodiments, the length of the linker is about 10 to 25 amino acids. In some embodiments, the length of the linker is about 10 to 20 amino acids. In some embodiments, the length of the linker is about 15 to 20 amino acids. In some embodiments, the length of the linker is 6 amino acids. In some embodiments, the length of the linker is 7 amino acids. In some embodiments, the length of the linker is 8 amino acids. In some embodiments, the length of the linker is 9 amino acids. In some embodiments, the length of the linker is 10 amino acids. In some embodiments, the length of the linker is 11 amino acids. In some embodiments, the length of the linker is 12 amino acids. In some embodiments, the length of the linker is 13 amino acids. In some embodiments, the length of the linker is 14 amino acids. In some embodiments, the length of the linker is 15 amino acids. In some embodiments, the length of the linker is 16 amino acids. In some embodiments, the linker is 17 amino acids in length. In some embodiments, the linker is 18 amino acids in length. In some embodiments, the linker is 19 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 21 amino acids in length. In some embodiments, the linker is 22 amino acids in length. In some embodiments, the linker is 23 amino acids in length. In some embodiments, the linker is 24 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 26 amino acids in length. In some embodiments, the linker is 27 amino acids in length. In some embodiments, the linker is 28 amino acids in length. In some embodiments, the linker is 29 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 31 amino acids in length. In some embodiments, the linker is 32 amino acids in length. In some embodiments, the linker is 33 amino acids in length. In some embodiments, the linker is 34 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is 36 amino acids in length. In some embodiments, the length of the linker is 37 amino acids. In some embodiments, the length of the linker is 38 amino acids. In some embodiments, the length of the linker is 39 amino acids. In some embodiments, the length of the linker is 40 amino acids.Exemplary linkers that can be used are Gly-rich linkers, linkers containing Gly and Ser, linkers containing Gly and Ala, linkers containing Ala and Ser, and other flexible linkers.

[0196] Other linker sequences can include portions of the immunoglobulin hinge region, CL or CH1 derived from any immunoglobulin heavy or light chain isotype. Alternatively, a variety of non-protein polymers, including polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes or copolymers of polyethylene glycol and polypropylene glycol can be used as linkers. Exemplary linkers that can be used are shown in Table 2.

[0197] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL).

[0198] In some embodiments, the scFv comprises VL, L1, and VH from N-terminus to C-terminus (VL-L1-VH).

[0199] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:308.

[0200] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:309.

[0201] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:310.

[0202] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:311.

[0203] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:312.

[0204] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:313.

[0205] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:314.

[0206] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:315.

[0207] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:316.

[0208] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:317.

[0209] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:318.

[0210] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:319.

[0211] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:320.

[0212] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:321.

[0213] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:322.

[0214] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:323.

[0215] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:324.

[0216] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:325.

[0217] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:326.

[0218] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:327.

[0219] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:328.

[0220] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:329.

[0221] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:330.

[0222] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:331.

[0223] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:332.

[0224] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:333.

[0225] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:334.

[0226] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:335.

[0227] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:87.

[0228] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:107.

[0229] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:91.

[0230] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:111.

[0231] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:285.

[0232] In some embodiments, the L1 comprises the amino acid sequence of SEQ ID NO:287.

[0233] Table 2. Amino acid sequences of linkers .

[0234]

[0235]

[0236] Divalent / bivalent single-chain variable fragments (di-scFv, bi-scFv) can be engineered by linking two scFvs. "(scFv)2" or "tandem scFv" or "double scFv" fragments refer to fusion proteins comprising two light chain variable regions (VL) and two heavy chain variable regions (VH), wherein the two VL regions and the two VH regions are continuously connected via a polypeptide linker and can be expressed as a single-chain polypeptide. The two VL regions and the two VH regions fused by a peptide linker form a divalent molecule VL A -Connector-VH A -Connector-VL B -Connector-VH B , to form two binding sites capable of simultaneously binding to two different antigens or epitopes. (ScFv)2 can be expressed as a single-chain polypeptide.

[0237] Any of the PSMA-binding VH and VL domains identified herein can be engineered into scFv formats in the VH-linker-VL or VL-linker-VH orientations. Any of the VH and VL domains identified herein can also be used to generate sc(Fv) structures, such as VH-linker-VL-linker-VL-linker-VH, VH-linker-VL-linker-VH-linker-VL, VH-linker-VH-linker-VL-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VL, or VL-linker-VL-linker-VH-linker-VH.

[0238] "Diabodies" are bivalent dimers formed by two chains, each containing a VH domain 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 arrangement. The linker can be a glycine-rich pentamer linker (G4S (SEQ ID NO: 337)).

[0239] "VHH" refers to a single-domain antibody or nanobody composed solely of the antigen-binding domain of a heavy chain. VHH single-domain antibodies lack the light chain and heavy chain CH1 domains of conventional Fab regions. In some embodiments, the anti-PSMA antibodies of the present disclosure include Fv fragments, single-chain scFv fragments (scFv), (scFv)2, Fab, F(ab)2, diabodies, VHH, dAb, Fd, Fv, or other single-chain antibodies.

[0240] The anti-PSMA antibodies of the present invention include chimeric antibodies, humanized antibodies, or fully human antibodies that specifically bind to PSMA.

[0241] "Human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody comprises a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained by using a system of human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody comprises a heavy chain variable region and a light chain variable region "derived from" a sequence of human origin. Such exemplary systems are human immunoglobulin gene libraries displayed on phages, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Because of the differences between the systems for obtaining human antibodies and human immunoglobulin loci, the introduction of somatic mutations or the intentional introduction of substitutions into the framework or CDR or both, "human antibodies" typically comprise amino acid differences compared to immunoglobulins expressed in humans.

[0242] Ordinarily, a "human antibody" has an amino acid sequence that 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 to the amino acid sequence encoded by a human germline immunoglobulin gene or a rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise a consensus framework sequence derived from human framework sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86), or a synthetic HCDR3 incorporated into a human immunoglobulin gene library displayed on phage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0243] Transgenic animals (such as mice, rats, or chickens) that carry human immunoglobulin (Ig) loci in their genomes can be used to generate antigen-binding fragments that bind to PSMA and are described, for example, in U.S. Pat. No. 6,150,584, International Patent Publication No. WO 1999 / 45962, International Patent Publication Nos. WO 2002 / 066630, WO 2002 / 043478, and WO 1990 / 04036. The endogenous immunoglobulin loci in such animals can be disrupted or deleted, and at least one complete or partial human immunoglobulin locus can be inserted into the genome of the animal by homologous or nonhomologous recombination using a transchromosome or 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) can be enlisted to provide human antibodies against the selected antigen.

[0244] Antibodies or antigen-binding fragments that bind to PSMA and are generated by immunizing non-human animals can be humanized. Exemplary humanization techniques that include selecting a human acceptor framework include CDR grafting (U.S. Pat. No. 5,225,539), SDR grafting (U.S. Pat. No. 6,818,749), resurfacing (Padlan, (1991) Mol Immunol 28:489-499), resurfacing of specificity-determining residues (U.S. Pat. Pub. No. 2010 / 0261620), human framework reshaping (U.S. Pat. No. 8,748,356), or superhumanization (U.S. Pat. No. 7,709,226). In these methods, the CDRs or a subset of CDR residues from a parent antibody are transferred to a human framework, which can be selected based on its overall homology to the parent framework, based on similarity in CDR length or canonical structural identity, or a combination thereof.

[0245] The humanized antigen binding domain can be further optimized to improve its selectivity or affinity for the desired antigen by incorporating altered framework support residues to maintain binding affinity (back mutations) using techniques such as those described in International Patent Publication Nos. WO1090 / 007861 and WO1992 / 22653, or by introducing variations in any CDR to improve the affinity of the antigen binding domain.

[0246] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the following amino acid sequence:

[0247] 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;

[0248] 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;

[0249] 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;

[0250] d. SYGMH (SEQ ID NO:22), VISYDGSNKYYADSVKG (SEQ ID NO:23), EHYDSSGYYHGYYGMDV (SEQ ID NO:24), SGSSSNIGSNYVY (SEQ ID NO:25), SNNQRPS (SEQ IDNO:26), AARDDSLSGYV (SEQ ID NO:27);

[0251] 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;

[0252] 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;

[0253] 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;

[0254] 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;

[0255] 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;

[0256] 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;

[0257] k. GGSISSY (SEQ ID NO:130), YSSGN (SEQ ID NO:13), GRGANVGLFDY (SEQ ID NO:12), TGSNSNIGANYDVH (SEQ ID NO:13), GNINRPL (SEQ ID NO:14) and QSYDFSLSGSV (SEQ ID NO:15) respectively;

[0258] 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;

[0259] 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;

[0260] 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;

[0261] 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;

[0262] 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;

[0263] 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);

[0264] 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);

[0265] 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);

[0266] 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);

[0267] 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);

[0268] v. separately with 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);

[0269] w. separately with 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);

[0270] x. separately with 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);

[0271] y. separately with 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);

[0272] z. separately with 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);

[0273] 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;

[0274] 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;

[0275] 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;

[0276] 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;

[0277] 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;

[0278] 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;

[0279] gg. GTFFSTYG (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;

[0280] 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;

[0281] 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

[0282] 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.

[0283] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0284] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively.

[0285] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 16, 17, 18, 29, 20, and 21, respectively.

[0286] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26, and 27, respectively.

[0287] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively.

[0288] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38, and 39, respectively.

[0289] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively.

[0290] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4647, 48, 49, 50, and 51, respectively.

[0291] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof that binds PSMA, comprising HCDR1, HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276, and 277, respectively.

[0292] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof, comprising:

[0293] the heavy chain complementarity determining regions (HCDR) 1, HCDR2, and HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 52, and the light chain complementarity determining regions (LCDR) 1, LCDR2, and LCDR3 of the light chain variable region (VL) of SEQ ID NO: 53; or

[0294] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:54, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:55; or

[0295] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:56, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:57; or

[0296] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:58, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:59; or

[0297] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:60, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:61; or

[0298] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:62, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:63; or

[0299] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:64, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:65; or

[0300] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO:66, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO:67; or

[0301] HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 278, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 279.

[0302] In some embodiments, the isolated protein comprising an antigen binding domain comprises HCDR1, HCDR2, and HCDR3 of the VH of SEQ ID NO: 52, and LCDR1, LCDR2, and LCDR3 of the VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0303] In some embodiments, the isolated protein comprising an 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 wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0304] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0305] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; or

[0306] VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55; or

[0307] VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57; or

[0308] VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59; or

[0309] VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61; or

[0310] VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63; or

[0311] VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65; or

[0312] VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67; or

[0313] The VH of SEQ ID NO: 278 and the VL of SEQ ID NO: 279; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0314] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0315] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0316] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:56 and the VL of SEQ ID NO:57.

[0317] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO:58 and the VL of SEQ ID NO:59.

[0318] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61.

[0319] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:62 and the VL of SEQ ID NO:63.

[0320] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:64 and the VL of SEQ ID NO:65.

[0321] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO:66 and the VL of SEQ ID NO:67.

[0322] In some embodiments, the antibody or antigen-binding fragment that binds PSMA comprises the VH of SEQ ID NO: 278 and the VL of SEQ ID NO: 279.

[0323] In some embodiments, the present disclosure also provides an isolated antibody or antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284 and 288.

[0324] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:84.

[0325] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:85.

[0326] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:86.

[0327] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:88.

[0328] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:89.

[0329] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO:90.

[0330] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:84 and the light chain of SEQ ID NO:85.

[0331] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:86 and the light chain of SEQ ID NO:85.

[0332] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:88 and the light chain of SEQ ID NO:89.

[0333] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:90 and the light chain of SEQ ID NO:89.

[0334] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:92 and the light chain of SEQ ID NO:93.

[0335] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:94 and the light chain of SEQ ID NO:95.

[0336] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:96 and the light chain of SEQ ID NO:97.

[0337] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO:98 and the light chain of SEQ ID NO:99.

[0338] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO: 100 and the light chain of SEQ ID NO: 101.

[0339] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the heavy chain of SEQ ID NO: 102 and the light chain of SEQ ID NO: 103.

[0340] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0341] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0342] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0343] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0344] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0345] The HC of SEQ ID NO: 84 and the LC of SEQ ID NO: 85; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0346] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0347] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0348] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0349] The HC of SEQ ID NO: 86 and the LC of SEQ ID NO: 85; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0350] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0351] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively;

[0352] VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55; and / or

[0353] The HC of SEQ ID NO: 88 and the LC of SEQ ID NO: 89; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0354] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0355] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively;

[0356] VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55; and / or

[0357] The HC of SEQ ID NO:90 and the LC of SEQ ID NO:89; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0358] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0359] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20 and 21, respectively;

[0360] VH of SEQ ID NO: 56 and VL of SEQ ID NO: 57; and / or

[0361] The HC of SEQ ID NO: 92 and the LC of SEQ ID NO: 93; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0362] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0363] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26 and 27, respectively;

[0364] VH of SEQ ID NO: 58 and VL of SEQ ID NO: 59; and / or

[0365] The HC of SEQ ID NO: 94 and the LC of SEQ ID NO: 95; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0366] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0367] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32 and 33, respectively;

[0368] VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61; and / or

[0369] The HC of SEQ ID NO: 96 and the LC of SEQ ID NO: 97; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0370] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising

[0371] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38 and 39, respectively;

[0372] VH of SEQ ID NO: 62 and VL of SEQ ID NO: 63; and / or

[0373] The HC of SEQ ID NO: 98 and the LC of SEQ ID NO: 99; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0374] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0375] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44 and 45, respectively;

[0376] VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65; and / or

[0377] The HC of SEQ ID NO: 100 and the LC of SEQ ID NO: 101; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0378] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0379] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50 and 51, respectively;

[0380] VH of SEQ ID NO: 66 and VL of SEQ ID NO: 67; and / or

[0381] The HC of SEQ ID NO: 102 and the LC of SEQ ID NO: 103; and wherein the antibody or antigen-binding fragment thereof binds PSMA.

[0382] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope of PSMA and the second binding domain binds to a different epitope on PSMA.

[0383] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising a CDR1 sequence having an amino acid sequence of SEQ ID NO: 4, a CDR2 sequence having an amino acid sequence of SEQ ID NO: 5, and a CDR3 sequence having an amino acid sequence of SEQ ID NO: 6; a light chain variable region comprising a CDR1 sequence having an amino acid sequence of SEQ ID NO: 7, a CDR2 sequence having an amino acid sequence of SEQ ID NO: 8, and a CDR3 sequence having an amino acid sequence of SEQ ID NO: 9; and a heavy chain variable region comprising a CDR1 sequence having an amino acid sequence of SEQ ID NO: 272, a CDR2 sequence having an amino acid sequence of SEQ ID NO: 273, and a CDR3 sequence having an amino acid sequence of SEQ ID NO: 274; and a light chain variable region comprising a CDR1 sequence having an amino acid sequence of SEQ ID NO: 275, a CDR2 sequence having an amino acid sequence of SEQ ID NO: 276, and a CDR3 sequence having an amino acid sequence of SEQ ID NO: 277. NO: 277; and wherein the antibody or antigen-binding fragment thereof binds to PSMA, optionally binds to two different epitopes on PSMA.

[0384] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and the second binding domain binds to a different epitope on PSMA, and wherein:

[0385] The first antigen binding domain is a Fab or Fab fragment comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, LCDR3 of SEQ ID NO: 9, VH of SEQ ID NO: 52, VL of SEQ ID NO: 53, HC of SEQ ID NO: 268, and LC of SEQ ID NO: 269; and

[0386] The second antigen binding domain is in the form of a scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, and HC of SEQ ID NO: 282.

[0387] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and the second binding domain binds to a different epitope on PSMA, and wherein:

[0388] 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:284, and LC of SEQ ID NO:269; and

[0389] The second antigen binding domain is in the form of a scFv comprising HCDR1 of SEQ ID NO: 272, HCDR2 of SEQ ID NO: 273, HCDR3 of SEQ ID NO: 274, LCDR1 of SEQ ID NO: 275, LCDR2 of SEQ ID NO: 276, LCDR3 of SEQ ID NO: 277, VH of SEQ ID NO: 278, VL of SEQ ID NO: 279, and HC of SEQ ID NO: 288.

[0390] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein the first antigen-binding domain binds an epitope of PSMA and comprises a heavy chain of SEQ ID NO: 268 and a light chain of SEQ ID NO: 269, and the second binding domain binds a different epitope on PSMA and comprises a heavy chain of SEQ ID NO: 282.

[0391] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and comprises a heavy chain of SEQ ID NO: 284 and a light chain of SEQ ID NO: 269, and the second binding domain binds to a different epitope on PSMA and comprises a heavy chain of SEQ ID NO: 288.

[0392] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0393] a first binding domain that binds a first epitope on PSMA, and wherein the first binding domain comprises:

[0394] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0395] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0396] HC of SEQ ID NO: 268 and LC of SEQ ID NO: 269;

[0397] a second binding domain that binds a second epitope on PSMA, and wherein the second binding domain comprises:

[0398] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276 and 277, respectively;

[0399] VH of SEQ ID NO: 278 and VL of SEQ ID NO: 279; and / or

[0400] HC of SEQ ID NO:282.

[0401] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising:

[0402] a first binding domain that binds a first epitope on PSMA, and wherein the first binding domain comprises:

[0403] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively;

[0404] VH of SEQ ID NO: 52 and VL of SEQ ID NO: 53; and / or

[0405] HC of SEQ ID NO: 284 and LC of SEQ ID NO: 269;

[0406] a second binding domain that binds a second epitope on PSMA, and wherein the second binding domain comprises:

[0407] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276 and 277, respectively;

[0408] VH of SEQ ID NO: 278 and VL of SEQ ID NO: 279; and / or

[0409] HC of SEQ ID NO:288.

[0410] Homologous antibodies and their antigen-binding fragments

[0411] Derivatives, homologous antigen-binding domains, functional equivalents, or variants of the antibodies or antigen-binding fragments thereof are also the 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 an amino acid sequence substantially identical to the amino acid sequence of the variable domain or hypervariable domain 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 to the sequence of the antibodies or antigen-binding fragments thereof that bind to PSMA and are functionally similar to unmodified anti-PSMA antibodies to retain binding to PSMA or retain at least one activity of the unmodified antibody.

[0412] The terms "antibody derivative," "cognate antigen binding domain," "functional equivalent," or "variant" refer to an antibody that comprises 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. Where several amino acids have been added, substituted, or deleted, any combination of additions, substitutions, or deletions is contemplated, provided that the resulting antibody still possesses at least the favorable properties of the antibodies of the present disclosure.

[0413] In some embodiments, the present disclosure provides amino acid sequence modifications of 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 level, effector function, glycosylation (e.g., fucosylation), reduced immunogenicity or solubility. Therefore, in addition to the antibodies and antigen-binding fragments described herein, antibody variants may also 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.

[0414] In some embodiments, the antibody and its Fab provided herein are chemically modified, for example, by covalently attaching any type of molecule to the antibody. Antibody derivatives can include, for example, antibodies chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protection / blocking groups, proteolytic cleavage, connection with cellular ligands or other proteins. Any of many chemical modifications can be carried out by known techniques, including but not limited to specific chemical cleavage, acetylation, preparation, metabolic synthesis of tunicamycin, etc. In addition, the antibody can contain one or more atypical amino acids.

[0415] Variants may also include substitutions, deletions or insertions of one or more codons encoding an antibody or polypeptide that result in changes in the amino acid sequence compared to a native sequence antibody or polypeptide. Amino acid substitutions may be the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties.

[0416] The sequences of the present disclosure may comprise amino acid sequences that are at least 80% identical or homologous to the sequences of the above-mentioned antibodies or antigen-binding fragments thereof. In some embodiments, the sequence identity to the PSMA-binding antigen-binding domain of the present disclosure may be about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Variants of the PSMA-binding antigen-binding domain comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 amino acid substitutions in the PSMA-binding antigen-binding domain are within the scope of the present disclosure, provided that they retain or have improved functional properties when compared to the parent antigen-binding domain. Functional equivalents or variants of the PSMA-binding antigen-binding domain include one or more deletions and / or additions of one or more amino acid residues. Such additions, substitutions, or deletions can be located at any position in the molecule. Where several amino acids have been added, substituted, or deleted, any combination of additions, substitutions, or deletions is contemplated, provided that the resulting antibody still possesses at least the favorable properties of the antibodies of the present disclosure.

[0417] In the context of two or more nucleic acid or polypeptide sequences (e.g., anti-PSMA antibodies and polynucleotides encoding them), the terms "identical" or "percent identity" refer to two or more sequences or subsequences that are identical or have a specified percentage of identical 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. The percent (%) identity of an amino acid sequence relative 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 × 100), taking into account the number of gaps and the length of each gap, parameters 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 in the art using publicly available software such as BLAS, BLAST-2, ALIGN, Megalin (DNASTAR), or the GAP program available in the GCG software package.

[0418] The polypeptide is typically substantially identical to the second polypeptide, e.g., where the two peptides differ only by conservative substitutions. The antibodies of the present disclosure also include those whose binding characteristics, functions, or physical properties have been improved by directed mutagenesis. In some embodiments, the variant antigen-binding domain that binds to PSMA comprises one or two conservative substitutions in any CDR region while retaining the desired functional properties of the parent antigen-binding fragment that binds to PSMA.

[0419] In a specific embodiment, substitution is a conservative amino acid substitution made at one or more predicted non-essential amino acid residues. "Conservative modifications" refer to amino acid modifications that do 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. "Conservative amino acid substitutions" are substitutions 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 having the following side chains: 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). Furthermore, any native residue in the polypeptide may 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).

[0420] Standard techniques known to those skilled in the art can be used to introduce mutations in the nucleotide sequences encoding the molecules provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis resulting in amino acid substitutions.

[0421] 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 can be determined.

[0422] Amino acid sequence insertions include amino and / or carboxyl terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertion variants of antibody molecules include fusions of the N- or C-terminus of an antibody to an enzyme (e.g., for antibody-directed enzyme prodrug therapy) or a polypeptide to extend the serum half-life of the antibody.

[0423] In some embodiments, the 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.

[0424] In some embodiments, the 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.

[0425] In some embodiments, the 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.

[0426] In some embodiments, the 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.

[0427] In some embodiments, the 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.

[0428] In some embodiments, the 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.

[0429] In some embodiments, the 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: 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.

[0430] In some embodiments, the 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.

[0431] In some embodiments, the 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.

[0432] In some embodiments, the 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.

[0433] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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.

[0434] In some embodiments, the 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 95% identical to the VL of SEQ ID NO:53.

[0435] In some embodiments, the 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.

[0436] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO:52 and a VL that is at least 95% identical to the VL of SEQ ID NO:53.

[0437] In some embodiments, the 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.

[0438] In some embodiments, the 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.

[0439] In some embodiments, the 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.

[0440] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.

[0441] 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, 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.

[0442] 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, 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.

[0443] 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 95% identical to the VL of SEQ ID NO: 53, 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.

[0444] 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, 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.

[0445] 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, 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.

[0446] 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, 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.

[0447] 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, 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.

[0448] 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, 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.

[0449] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0450] In some embodiments, the present 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; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0451] 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; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0452] In some embodiments, the 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.

[0453] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO:85.

[0454] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0455] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0456] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0457] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0458] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0459] 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; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0460] In some embodiments, the 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.

[0461] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 85.

[0462] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0463] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0464] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0465] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0466] In some embodiments, the present 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: 88, and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0467] In some embodiments, the present 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: 89, and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0468] 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; and wherein the antibody or antigen-binding fragment thereof binds to PSMA.

[0469] In some embodiments, the 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.

[0470] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 89.

[0471] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0472] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0473] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0474] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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.

[0475] 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.

[0476] 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, 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.

[0477] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0478] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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, 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.

[0479] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0480] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0481] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0482] The present disclosure also provides an isolated antibody or antigen-binding fragment thereof, which comprises 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 the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 4, 5, 6, 7, 8 and 9, respectively.

[0483] 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, 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.

[0484] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0485] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0486] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0487] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0488] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0489] 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.

[0490] 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, 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.

[0491] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.

[0492] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0493] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0494] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0495] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, 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.

[0496] 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 the VH of SEQ ID NO: 52 and the VL of SEQ ID NO: 53.

[0497] 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO:52 and a VL of SEQ ID NO:53.

[0498] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO:85, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0499] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0500] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0501] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0502] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0503] 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 the VH of SEQ ID NO: 52 and the VL of SEQ ID NO: 53.

[0504] 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.

[0505] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO:85, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0506] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0507] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0508] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0509] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:52 and the VL of SEQ ID NO:53.

[0510] In some embodiments, the 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.

[0511] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises 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.

[0512] In some embodiments, the 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.

[0513] In some embodiments, the 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.

[0514] In some embodiments, the antibody or antigen-binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO:54 and a VL that is at least 95% identical to the VL of SEQ ID NO:55.

[0515] In some embodiments, the 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.

[0516] In some embodiments, the 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.

[0517] In some embodiments, the 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.

[0518] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0519] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0520] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0521] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0522] 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, wherein 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.

[0523] 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, wherein 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.

[0524] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0525] 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, wherein 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.

[0526] 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, wherein the antibody or antigen-binding fragment comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14, and 15, respectively.

[0527] 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 the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55.

[0528] 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, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.

[0529] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO:89, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0530] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0531] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0532] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0533] In some embodiments, the antibody or antigen-binding fragment thereof that binds 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO:54 and the VL of SEQ ID NO:55.

[0534] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and the second binding domain binds to a different epitope on PSMA, and wherein:

[0535] 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; and

[0536] 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.

[0537] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and the second binding domain binds to a different epitope on PSMA, and wherein:

[0538] 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; and

[0539] 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.

[0540] In some embodiments, the antibody or antigen-binding fragment thereof that binds to PSMA comprises two antigen-binding domains, wherein the first antigen-binding domain binds to one epitope on PSMA and the second binding domain binds to a different epitope on PSMA, and wherein:

[0541] 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; and

[0542] 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.

[0543] Half-life extension and Fc engineering

[0544] In addition to the modifications described above, the anti-PSMA antibodies or antigen-binding fragments thereof, and their functional equivalents, of the present disclosure can be conjugated to other antibodies, proteins, antigen-binding fragments, or alternative scaffolds that can be used to adjust, alter, improve, or modulate the characteristics of the antibodies as desired.

[0545] For example, antibodies with increased in vivo half-life can be generated by linking a half-life extending moiety (such as albumin, albumin variants, albumin binding proteins and / or domains, transferrin and fragments and analogs thereof, immunoglobulins (Ig) or fragments thereof (such as Fc regions) to the antibodies, antigen-binding fragments of the present disclosure. Additional half-life extending moieties include, for example, polyethylene glycol (PEG) molecules, such as PEG5000 or PEG20,000; fatty acids and fatty acid esters of varying chain lengths, such as laurate, myristate, stearate, arachidate, behenate, oleate, arachidonic acid, suberic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, etc., polylysine, octane, carbohydrates (dextran, cellulose, oligosaccharides or polysaccharides) to obtain the desired properties. These moieties can be fused directly to the antibodies, or antigen-binding fragments thereof, of the present disclosure and can be produced by standard cloning and expression techniques.

[0546] The half-life extending moiety can be attached to the antibody or antibody fragment or derivative with or without a multifunctional linker by conjugation to the N-terminus or C-terminus of the antibody or antibody fragment or through the ε-amino group present on the lysine residue. Alternatively, well-known chemical coupling methods can be used to attach these moieties to the recombinantly produced antibodies or antigen-binding fragments of the present disclosure.

[0547] A polyethylene glycol moiety can be conjugated to the antibodies or antigen-binding fragments of the disclosure, for example, by incorporating a cysteine ​​residue into the C-terminus of the PSMA-binding antibodies or antigen-binding fragments of the disclosure or by engineering a cysteine ​​into a residue position facing away from the PSMA-binding site and attaching a polyethylene glycol group to the cysteine ​​using well-known methods.

[0548] In some embodiments, the half-life extending moiety is albumin.

[0549] In some embodiments, the half-life extending moiety is an albumin binding domain.

[0550] In some embodiments, the half-life extending moiety is transferrin.

[0551] In some embodiments, the half-life extending moiety is polyethylene glycol.

[0552] In some embodiments, the half-life extending moiety is an Ig constant region or a fragment of an Ig constant region.

[0553] In some embodiments, the half-life extending moiety is Ig.

[0554] In some embodiments, the half-life extending moiety is a fragment of Ig.

[0555] In some embodiments, the half-life extending moiety is an Ig constant region.

[0556] In some embodiments, the half-life extending moiety is a fragment of an Ig constant region.

[0557] In some embodiments, the half-life extending moiety is an Fc region.

[0558] The Ig constant region or fragment of an Ig constant region (such as an Fc region) present in the antibodies or antigen-binding fragments thereof of the present disclosure can be of any allotype or isotype, ie, IgGl, IgG2, IgG3, IgG4, IgM, IgA, and IgE.

[0559] In some embodiments, the Ig constant region or fragment of the Ig constant region is of the IgG1 isotype.

[0560] In some embodiments, the Ig constant region or fragment of the Ig constant region is of the IgG2 isotype.

[0561] In some embodiments, the Ig constant region or fragment of the Ig constant region is of the IgG3 isotype.

[0562] In some embodiments, the Ig constant region or fragment of the Ig constant region is of the IgG4 isotype.

[0563] It is expected that allotypes have no effect on the effector functions of the properties of Ig constant regions, such as binding or Fc mediation. The immunogenicity of therapeutic proteins comprising Ig constant regions or their fragments is associated with increased risk of infusion reactions and reduced therapeutic response duration (Baert et al., (2003) N Engl J Med 348:602-08). The degree to which therapeutic proteins comprising Ig constant regions or their fragments induce immune responses in hosts can be determined in part by the allotypes of the Ig constant regions (Stickler et al., (2011) Genes and Immunity 12:213-21). Ig constant region allotypes are related to the amino acid sequence variations at specific positions in the constant region sequences of antibodies.

[0564] 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 antibody or antigen-binding fragment effector functions (such as ADCC, ADCP and / or ADCP and / or pharmacokinetic properties). This can be achieved by introducing mutations into Fc that modulate the binding of the mutated Fc to activating FcγRs (FcγRI, FcγRIIa, FcγRIII), inhibitory FcγRIIb and / or FcRn.

[0565] 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 comprises at least one mutation in the Ig constant region or in the fragment of the Ig constant region.

[0566] In some embodiments, at least one mutation is in the Fc region.

[0567] In some embodiments, a PSMA-binding antibody or antigen-binding fragment thereof conjugated to an Ig constant region or a fragment of an Ig constant region comprises at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen mutations in the Fc region.

[0568] Neonatal Fc receptor (FcRn) plays an important role in the cellular trafficking and serum half-life of IgG. In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an Ig constant region or a fragment of an Ig constant region that comprises 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.

[0569] 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.

[0570] Fc positions 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 mutations T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A, and H435R. Exemplary single mutations or combined mutations that can be generated to increase half-life are 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 of the present disclosure, and their functional equivalents, is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, wherein residue numbering is according to the EU index.

[0571] 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 comprises the M252Y / S254T / T256E mutations.

[0572] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure and their functional equivalents are conjugated to an Ig constant region or a fragment of an Ig constant region comprising at least one mutation in the Fc region that reduces binding of the protein to activating Fc gamma receptors (FcγR) and / or reduces Fc effector function (such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP)).

[0573] Fc positions that can be mutated to reduce protein binding 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 can be made, alone or in combination, are mutations K214T, E233P, L234V, L234A, G236 deletion, 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 that produce proteins with reduced ADCC are mutations L234A / L235A on IgG1, mutations L234A / L235A / D265S on IgG1, mutations V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, mutations F234A / L235A on IgG4, mutations S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, mutations V234A / G237A on IgG2, mutations K214T / E233P / L234V / L235A / G236-deficient on IgG1. Loss / A327G / P331A / D365E / L358M on IgG2, mutations H268Q / V309L / A330S / P331S on IgG2, mutations S267E / L328F on IgG1, mutations L234F / L235E / D265A on IgG1, mutations L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, mutations S228P / F234A / L235A / G237A / P238S on IgG4, and mutations S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4. A hybrid IgG2 / 4 Fc domain may also be used, eg, an Fc having residues 117-260 from IgG2 and residues 261-447 from IgG4.

[0574] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA is conjugated to an IgG1 heavy chain constant region or a fragment of an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises at least one mutation that results in reduced binding of the antibody to an FcγR. In some embodiments, the at least one mutation that results in reduced binding of the antibody to an FcγR is selected from the group consisting of: F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236-deletion / A327G / 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.

[0575] In some embodiments, the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises the following mutations: L234A_L235A_D265S.

[0576] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0577] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure and their functional equivalents are conjugated to an Ig constant region or a fragment of an Ig constant region comprising at least one mutation in the Fc region that enhances binding of the protein to an Fcγ receptor (FcγR) and / or enhances Fc effector functions (such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and / or phagocytosis (ADCP)).

[0578] 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, alone or in combination, are G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T, and P396L. Exemplary combinatorial mutations that produce 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.

[0579] Fc positions that can be mutated to enhance CDC include positions 267, 268, 324, 326, 333, 345, and 430. Exemplary mutations that can be made individually or in combination are S267E, F1268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F, and E430T. Exemplary combination mutations that produce proteins with increased CDC are K326A / E333A, K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T, and S267E / H268F / S324T.

[0580] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8 and 9, respectively, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0581] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the VH of SEQ ID NO: 52 and the VL of SEQ ID NO: 53, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0582] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VH of SEQ ID NO: 52 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52, at least 85%, at least 90%, at least 95%, or at least 99% identical to the VL of SEQ ID NO: 53, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0583] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 53, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0584] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises a VH of SEQ ID NO: 52 and a VL that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 99%) identical to a VL of SEQ ID NO: 53, wherein the antibody or antigen-binding fragment 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0585] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 52, and the VL of SEQ ID NO: 53, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0586] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 52, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0587] 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, wherein the antibody or antigen-binding fragment comprises a VH that is at least 99% identical to the VL of SEQ ID NO: 54, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0588] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 52, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0589] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 10, 11, 12, 13, 14 and 15, respectively, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0590] In some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0591] 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, wherein the antibody or antigen-binding fragment 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. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0592] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 55, respectively. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0593] 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, wherein the antibody or antigen-binding fragment 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, NO: 10, 11, 12, 13, 14 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0594] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 54, respectively, and the VL of SEQ ID NO: 55. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0595] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 54, respectively. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0596] 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, wherein the antibody or antigen-binding fragment comprises a VH that is at least 99% identical to the VL of SEQ ID NO: 56, respectively. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0597] 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, wherein the antibody or antigen-binding fragment comprises the VH of SEQ ID NO: 54, respectively. NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0598] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds PSMA, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0599] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds PSMA, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0600] 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 fragment thereof that is at least 80% identical (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. ID NO: 85 LC 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 IgG1 (e.g., IgG1λ), and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0601] 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0602] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0603] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0604] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0605] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0606] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0607] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds PSMA, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0608] In some embodiments, the present 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, and wherein the antibody or antigen-binding fragment thereof binds PSMA, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0609] 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 fragment thereof that is at least 80% identical (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. ID NO: 85 LC 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 IgG1 (e.g., IgG1λ), and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0610] 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0611] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0612] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0613] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0614] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0615] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0616] 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 fragment thereof that is at least 80% identical (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. ID NO: 89 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 the antibody or antigen-binding fragment, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0617] 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0618] In some embodiments, an antibody or antigen-binding fragment thereof that binds PSMA comprises 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%, or at least 99%) identical to the LC of SEQ ID NO: 89, and wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0619] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0620] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0621] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0622] In some embodiments, an antibody or antigen-binding fragment thereof that binds 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 wherein the antibody or antigen-binding fragment is an IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0623] 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 the HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0624] 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 the HC of SEQ ID NO: 84, respectively. NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0625] 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 a HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0626] 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 the HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0627] 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 the HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0628] 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 the HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0629] 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 the HC of SEQ ID NO: 84, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0630] 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 the HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0631] 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 the HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0632] 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 a HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0633] 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 a HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0634] 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 a HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0635] 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 a HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0636] 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 the HC of SEQ ID NO: 86, 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, NO: 4, 5, 6, 7, 8 and 9 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0637] 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0638] 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 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0639] 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: 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0640] 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: 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0641] 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: 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0642] 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: 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0643] 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: 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 the HC of SEQ ID NO: 88, 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, NO: 10, 11, 12, 13, 14 and 15 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0644] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0645] 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 of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0646] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises 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 the VH of SEQ ID NO: 52 and the VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0647] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0648] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0649] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0650] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0651] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0652] 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 of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0653] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises 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 the VH of SEQ ID NO: 52 and the VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0654] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0655] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0656] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0657] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0658] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0659] 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 of SEQ ID NO: 85, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0660] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises 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 the VH of SEQ ID NO: 52 and the VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0661] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0662] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0663] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0664] 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 a VH of SEQ ID NO: 52 and a VH of SEQ ID NO: 53. NO:53 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0665] 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 a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0666] 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 of SEQ ID NO: 89, wherein the antibody or antigen-binding fragment comprises a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0667] In some embodiments, an antibody or antigen-binding fragment thereof that binds to PSMA comprises 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 the VH of SEQ ID NO: 54 and the VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0668] 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: 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 a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0669] 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: 85 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 a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0670] 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: 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 a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0671] 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: 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 a VH of SEQ ID NO: 54 and a VH of SEQ ID NO: 55. NO:55 VL, and wherein the antibody or antigen-binding fragment is IgG1 (e.g., IgG1λ), optionally wherein the first Ig constant region or a fragment of the first Ig constant region and / or the second Ig constant region or a fragment of the second Ig constant region comprises L234A_L235A_D265S and / or M252Y / S254T / T256E mutations, such as wherein the first Ig constant region or a fragment of the first Ig constant region and the second Ig constant region or a fragment of the second Ig constant region comprise L234A_L235A_D265S and / or M252Y / S254T / T256E mutations.

[0672] polynucleotides

[0673] Also provided are polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure and their functional equivalents. The present disclosure provides an isolated polynucleotide encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof of the present disclosure.

[0674] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:52.

[0675] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:54.

[0676] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:56.

[0677] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:58.

[0678] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:60.

[0679] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:62.

[0680] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO:64.

[0681] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO: 66.

[0682] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO: 278.

[0683] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:53.

[0684] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:55.

[0685] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:57.

[0686] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO:59.

[0687] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 61.

[0688] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 63.

[0689] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 65.

[0690] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 67.

[0691] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 279.

[0692] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:84.

[0693] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:86.

[0694] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:88.

[0695] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:90.

[0696] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:92.

[0697] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:94.

[0698] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:96.

[0699] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO:98.

[0700] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 100.

[0701] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 102.

[0702] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 268.

[0703] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 282.

[0704] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 284.

[0705] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 288.

[0706] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:85.

[0707] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:89.

[0708] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:93.

[0709] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:95.

[0710] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:97.

[0711] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO:99.

[0712] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 101.

[0713] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 103.

[0714] In some embodiments, the present disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 269.

[0715] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 52 and 53.

[0716] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 84 and 85.

[0717] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 86 and 85.

[0718] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 54 and 55.

[0719] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 88 and 89.

[0720] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequences of SEQ ID NOs: 52, 53, 278, and 279.

[0721] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequence of SEQ ID NOs: 268, 269, and 282.

[0722] In some embodiments, the present disclosure provides an isolated polynucleotide sequence encoding the polypeptide sequence of SEQ ID NOs: 284, 269, and 288.

[0723] In some embodiments, the present 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.

[0724] Polynucleotides encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure include polynucleotides having nucleic acid sequences that are substantially identical to the nucleic acid sequences 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 when 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.

[0725] Modified nucleotides can be used to generate the polynucleotides disclosed herein. Exemplary modified nucleotides are 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, β-D-mannosyl quercetin, 5″-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N 6 -Isopentenyl adenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queuosine, β-D-galactosylqueuosine, inosine, N 6-isopentenyl adenine, 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-oxyacetate, 3-(3-amino-3-N-2-carboxypropyl)uracil, and 2,6-diaminopurine.

[0726] Vectors containing polynucleotides encoding anti-PSMA antibodies

[0727] Also provided are vectors comprising DNA encoding the anti-PSMA antibodies or antigen-binding fragments of the present disclosure. The disclosed vectors can be used, for example, to produce any of the anti-PSMA antibodies or antigen-binding fragments thereof disclosed above. Standard molecular biology methods can be used to incorporate a polynucleotide encoding any of the anti-PSMA antibodies or antigen-binding fragments thereof disclosed herein into a vector.

[0728] In some embodiments, the present disclosure provides an expression vector comprising a 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 polynucleotides of the present invention into a given organism or genetic background by any means. The vectors of the present disclosure can be expression vectors for efficient synthesis of PSMA antibody polypeptides and expression of the PSMA antibody polypeptides of the present disclosure in prokaryotic and eukaryotic systems, including but not limited to yeast and mammalian cell culture.

[0729] Exemplary vectors that can be used are bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBsKS, 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.), the pBluescript series (Stratagene, LaJolla, Calif.), the pET series (Novagen, Madison, Wis.), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), and the pEX series (Clontech, Palo Alto, Calif.). Phage 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, such as a retroviral vector, such as a gamma retroviral vector.

[0730] The vectors 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 control sequences in the expression vector that ensure expression of the PSMA-binding protein. Such regulatory elements may include a transcriptional promoter, a sequence encoding a suitable mRNA ribosome binding site, and sequences that control the termination of transcription and translation. The expression vector may also contain 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' flanking non-transcribed sequences, 5' or 3' non-translated sequences (such as essential ribosome binding sites), a polyadenylation site, splice donor and acceptor sites, or a transcription termination sequence. An origin of replication that confers replication capability in the host may also be incorporated.

[0731] Vectors of the present disclosure may also contain one or more internal ribosome entry sites (IRES). The inclusion of an IRES sequence in the fusion vector may be beneficial for enhancing the expression of some proteins. In some embodiments, the vector system will include one or more polyadenylation sites (e.g., SV40), which may be upstream or downstream of any of the above-mentioned nucleic acid sequences. Vector components may be connected continuously, or arranged in a manner that provides optimal spacing for expressing a gene product (i.e., by introducing "spacer" nucleotides between the ORFs), or positioned in another manner. Regulatory elements such as the IRES motif may also be arranged to provide optimal spacing for expression.

[0732] The vectors disclosed herein may be circular or linear. They may be prepared to contain a replication system that functions in prokaryotic or eukaryotic host cells. The replication system may be derived from, for example, ColE1, SV40, 2μ plasmid, lambda, bovine papilloma virus, and the like.

[0733] The recombinant expression vector can be designed for transient expression, for stable expression, or for both. Moreover, the recombinant expression vector can be prepared for constitutive expression or for inducible expression.

[0734] The vector can also include a selection marker well known in the art. Selection markers include positive and negative selection markers. Marker genes include biocide resistance (for example, resistance to antibiotics, heavy metals, etc.), complementary effects of prototrophy provided in auxotrophic hosts, etc. Exemplary marker genes include antibiotic resistance genes (for example, neomycin resistance gene, hygromycin resistance gene, kanamycin resistance gene, tetracycline resistance gene, penicillin resistance gene, histidinol resistance gene, histidinol x resistance gene), glutamine synthase gene, HSV-TK, HSV-TK derivatives for ganciclovir selection, or bacterial purine nucleoside phosphorylase genes (Gadi et al., 7 Gene Ther. 1738-1743 (2000)) for 6-methylpurine selection. The nucleic acid sequence encoding the selection marker or cloning site can be upstream or downstream of the nucleic acid sequence encoding the polypeptide of interest or the cloning site.

[0735] host cells

[0736] The present disclosure also provides a host cell comprising any one of the vectors of the present disclosure. "Host cell" refers to a cell into which a vector has been introduced. It should be understood that the term host cell is intended to refer not only to a specific host cell, but also to the progeny of such cells, and also to the stable cell line produced by a specific host cell. Because certain modifications may occur in the offspring due to mutations or due to environmental influences, such progeny may be different from the parent cell, but are still included in the scope of the term "host cell" as used herein. Such host cells can be eukaryotic cells, prokaryotic cells, plant cells or archaeal cells. Examples of prokaryotic host cells are Escherichia coli, Bacilli (such as Bacillus subtilis and other Enterobacteriaceae (such as Salmonella, Serratia)) and various Pseudomonas species. Other microorganisms such as yeast can also be used for expression. Saccharomyces (e.g., Saccharomyces cerevisiae) and Pichia pastoris are examples of suitable yeast host cells. Exemplary eukaryotic cells can be 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), NSO (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No. 85110503), FO (ATCC CRL-1646), and Ag653 (ATCC CRL-1580) mouse 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.

[0737] The present disclosure provides host cells containing any of the vectors disclosed herein. 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 accomplished using well-known methods.

[0738] Cell lines can be selected based on high-level expression of the PSMA antibody of interest and minimal contamination from host cell proteins. Mammalian cell lines useful as host cells for expression are well known in the art and include, but are not limited to, cells from Chinese hamster ovary (CHO), such as CHO-K1SV (Lonza Biologics, Walkersville, MD), CHO-K1 (ATCC CRL-61), or CHO DG44, and baby hamster kidney (BHK) cells. These cell lines can be used to produce any of the anti-PSMA antibodies or antibody fragments of the present disclosure by culturing the cells under conditions suitable for antibody expression and purifying the antibody from the host cells or the culture medium surrounding the host cells.

[0739] The present disclosure also provides a method for producing an anti-PSMA-binding protein of the present disclosure, the method comprising culturing a host cell of the present disclosure under conditions that express a PSMA-binding protein, and recovering the anti-PSMA antibody-binding protein produced by the host cell using methods well known in the art. The subject protein can be substantially pure, for example, at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or at least about 98% to 99% pure, or more pure, for example, free of contaminants other than the subject protein, such as cell debris, macromolecules, etc.

[0740] Radioconjugates and antibody-drug conjugates

[0741] 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 can be conjugated to a pharmaceutically active moiety or a diagnostic moiety to form an "antibody drug conjugate" (ADC) or a "radioconjugate." The ADCs or radioconjugates of the present disclosure can be used to deliver cytotoxins or other payloads to a target location.

[0742] As used herein, the term "antibody drug conjugate" is used broadly and refers to an antibody or antigen-binding fragment thereof conjugated (e.g., covalently bound) to a second molecule, such as any pharmaceutically active moiety, therapeutic moiety, toxin, or drug.

[0743] As used herein, the term "targeting ligand" refers to any molecule that provides enhanced affinity for 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, nucleic acid 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. Targeting ligands can be used as shuttle agents 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 the receptor. In the present disclosure, a targeting ligand is an anti-PSMA antibody or fragment thereof conjugated to a pharmaceutically active moiety and capable of delivering a payload to a site characterized by the abundance of PSMA.

[0744] 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 need to be produced by fermentation of host cells and confer specific new functionality for binding to a target or antigen to a targeting ligand. Examples of payable loads include, but are not limited to, drugs, toxins, cytokines, markers, oligonucleotides, antisense, small interfering RNA oligonucleotides (siRNA), etc., which are used to produce site-specifically conjugated antibody drug conjugates (ADCs). Payloads can also be radioactive metal complexes or radioactive metal ions as described below.

[0745] As used herein, the terms "drug" or "warhead" are used interchangeably and will refer to a biologically active or detectable molecule or compound, including an anticancer agent as described below. A "payload" may comprise a drug or warhead in combination with an optional linker compound. The warhead on the conjugate may include peptides, proteins, prodrugs that are metabolized in vivo to active agents, polymers, nucleic acid molecules, small molecules, binding agents, mimetics, synthetic drugs, inorganic molecules, organic molecules, and radioisotopes. In some embodiments, the disclosed ADC or radioconjugate will direct the bound payload to the target site in a relatively non-reactive, non-toxic state prior to release and activation of the payload. This targeted release of the payload is preferably achieved by stable conjugation of the payload via residue-specific or site-specific conjugation as described below and a relatively uniform composition of the ADC or radioconjugate formulation that minimizes over-conjugated toxic species.

[0746] In some embodiments, the present disclosure comprises 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 exhibit different stoichiometric molar ratios, depending at least in part on the method used to effect conjugation.

[0747] The conjugates of the present disclosure can be represented by the following formula:

[0748] Ab-[LD]n or a pharmaceutically acceptable salt thereof, wherein:

[0749] a) Ab comprises an anti-PSMA antibody or antigen-binding fragment thereof disclosed herein;

[0750] b) L comprises an optional linker;

[0751] c) D comprises a drug moiety or a chelating agent; and

[0752] d) n is an integer from about 1 to about 20;

[0753] Those skilled in the art will appreciate that conjugates according to the foregoing formula can be prepared using a number of different linkers and drugs, and that the conjugation methodology will vary depending on the choice of components.

[0754] In preferred embodiments, compatible linkers will impart stability to the ADC or radioconjugate in the extracellular environment, prevent aggregation of the ADC molecules or radioconjugate, and maintain the ADC and radioconjugate freely soluble and in a monomeric state in aqueous media. Prior to transport or delivery into the cell, the ADC or radioconjugate is preferably stable and remains intact, i.e., the antibody remains attached to the drug moiety. Although linkers are stable outside the target cell, they are designed to be cleaved or degraded at an effective rate within the cell. Thus, an effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular delivery of the conjugate or drug moiety; (iii) remain stable and intact, i.e., not cleaved or degraded, until the conjugate is delivered or transported to its target site; and (iv) maintain the cytotoxic, cell-killing, or cytostatic effect of the drug moiety.

[0755] The stability of the ADC or radioconjugate can be measured by standard analytical techniques such as mass spectrometry, hydrophobic interaction chromatography (HIC), HPLC, and separation / analysis techniques LC / MS.

[0756] Cytotoxic agents and drugs

[0757] In some embodiments, an anti-PSMA antibody or antigen-binding fragment thereof of the present disclosure is 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 therapeutics, oligonucleotides, antisense, siRNA, anti-metastatic agents, and immunotherapeutic agents.

[0758] In some embodiments, an anti-PSMA antibody or antigen-binding fragment thereof of the present disclosure is conjugated to one or more cytotoxic agents. Exemplary 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 radioactive isotopes. Exemplary toxins include, but are not limited to, 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 can achieve their cytotoxic and cytostatic effects through mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active. Enzymatically active toxins and fragments thereof that can be used include diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, α-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, jatropha toxin, crotonin, sapaonaria officinalis inhibitor, gelonin, mytotoxin, restrictocin, phenomycin, enomycin, and trichothecenes.

[0759] In some embodiments, the anti-PSMA antibodies or antigen-binding fragments thereof provided herein are conjugated to one or more drugs. Exemplary drugs include matancinols (see, e.g., U.S. Pat. Nos. 5,208,020 and 5,416,06); auristatins, such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see, e.g., U.S. Pat. Nos. 5,635,483 and 5,780,588 and 7,498,298), dolastatin, calicheamicin or derivatives thereof (see, e.g., U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001 and 5,877,296; Hinman et al., (1993) Cancer Res 53:3336-3342; and Lode et al., (1998) Cancer Res 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, taxane (such as docetaxel, paclitaxel, larotaxel, tecitaxel and ortataxel), camptothecin (CPT) analogs (such as topotecan and irinotecan) (see, e.g., Slichenmyer et al., (1994) Cancer Chemother Pharmacol, 34(Suppl):S 53-S 570), pyrrolobenzodiazepine (PBD) derivatives (U.S. Pat. No. 10,639,373), amanitin derivatives (such as α-amanitin and β-amanitin), or duocarmycin analogs.

[0760] Radioconjugates

[0761] In some embodiments, an anti-PSMA antibody or antigen-binding fragment thereof of the present disclosure is conjugated to a radioactive metal ion to form a radioconjugate.

[0762] 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" particularly refers to an antibody or antigen-binding domain that is conjugated (connected, e.g., covalently bound) to at least one radioactive metal complex. In other words, a radioconjugate refers to at least one radiometal complex that is joined (e.g., covalently bound) to an antibody or antigen-binding domain. A radioconjugate may include at least one radiometal complex comprising a linker, wherein the radiometal complex is joined to the antibody or antigen-binding domain via a linker. As used herein, a "radiometallic complex" refers to a complex comprising a radiometal ion associated with a chelating agent. Typically, the radiometal ion is bound or coordinated to the chelating agent via coordinate bonding. In some embodiments, the chelating agent is a macrocyclic compound. Heteroatoms of the macrocycle may participate in the coordinate bonding of the radiometal ion to the chelating agent. The chelating agent may be substituted with one or more substituents, and the one or more substituents may also participate in coordinate bonding of the radiometal ion to the chelating agent in addition to or in addition to the heteroatoms of the macrocycle.

[0763] As used herein, the term "radiometal ion" or "radioactive metal ion" refers to one or more isotopes of an element that emits particles and / or photons. In light of the present disclosure, any radioactive metal ion known to those skilled in the art may be used in the present invention. Exemplary radioisotopes may be gamma-emitting, Auger-emitting, beta-emitting, alpha-emitting, or positron-emitting radioisotopes. Exemplary radioisotopes include 3 H. 11 C. 13 C. 15 N. 18 F. 19 F. 55 Co、 57 Co、 60 Co、 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 72 As、 75 Br, 86 Y. 89 Zr, 90 Sr. 94m Tc, 99m Tc, 115 In, 123 1.124 1. 125 I. 131 1. 211 At 212 Bi, 213 Bi, 223 Ra, 226 Ra, 134 Ce, 225 Ac and 227 Ac.

[0764] Exemplary metal atoms are metals with an atomic number greater than 20, such as calcium atom, scandium atom, titanium atom, vanadium atom, chromium atom, manganese atom, iron atom, cobalt atom, nickel atom, copper atom, zinc atom, gallium atom, germanium atom, arsenic atom, selenium atom, bromine atom, krypton atom, rubidium atom, strontium atom, yttrium atom, zirconium atom, niobium atom, molybdenum atom, technetium atom, ruthenium atom, rhodium atom, palladium atom, silver atom, cadmium atom, indium atom, tin atom, antimony atom, tellurium atom, iodine atom, xenon atom, cesium atom, barium atom, lanthanum atom , hafnium atom, tantalum atom, tungsten atom, rhenium atom, osmium atom, iridium atom, platinum atom, gold atom, mercury atom, thallium atom, lead atom, bismuth atom, francium atom, radium atom, actinium atom, cerium atom, praseodymium atom, neodymium atom, promethium atom, samarium atom, europium atom, gadolinium atom, terbium atom, dysprosium atom, holmium atom, erbium atom, thulium atom, ytterbium atom, lutetium atom, thorium atom, protactinium atom, uranium atom, neptunium atom, plutonium atom, americium atom, curium atom, berkelium atom, californium atom, einsteinium atom, fermium atom, mendelevium atom, nobelium atom, or lawrencium atom.

[0765] In some embodiments, the radioactive metal ion is a "therapeutic emitter," meaning a radioactive metal ion that can be used in therapeutic applications to damage cells (such as cancer cells). Suitable radioactive metals for use as therapeutic agents are radioactive metals that can reduce or inhibit the growth of cancer cells (such as prostate cancer cells) or specifically kill cancer cells (such as prostate cancer cells). High-energy radioactive metals selected for targeting cancer cells preferably act within a short range so that the cytotoxic effect is localized to the targeted cells. In certain embodiments, the radioconjugates of the present disclosure can deliver a cytotoxic payload that has the ability to emit alpha and / or beta particles near the tumor by binding to cancer cell surface antigens and inducing cell death. Therefore, radiotherapy is delivered in a more localized manner to reduce damage to non-cancerous cells.

[0766] Examples of radiometal ions suitable for use in producing the radioconjugates of the present disclosure include, but are not limited to: 47 Sc, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga,86 Y. 89 Zr, 89 Sr. 90 Y. 99 Tc, 105 Rh, 109 Pd, 111 Ag, 111 In, 117 Sn, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Second, 177 Lu, 186 Re、 188 Re、 194 Ir, 198 Au, 199 Au, 211 At 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th and 255 Fm. Preferably, the radioactive metal ion is a "therapeutic emitter," meaning a radioactive metal ion that can be used for therapeutic applications. Examples of therapeutic emitters include, but are not limited to, beta emitters or alpha emitters, such as 132 La, 135 La, 134 Ce, 144 Nd, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Second, 177 Lu, 186 Re、 188 Re、 194 Ir, 198 Au, 199 Au, 211 At 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 255 Fm and 227 Th, 226Th, 230 U.

[0767] In some embodiments, the radioactive metal ion used as a therapeutic agent is an alpha-emitting radioactive metal ion, such as actinium-225 ( 225 Ac). 225 The 10-day half-life of Ac is long enough to facilitate radioconjugate production, but short enough to match the circulating pharmacokinetics of delivery vehicles such as antibodies. 225 Ac radioimmunoconjugates are of particular interest. 225 Ac decays in a series of steps that ultimately emit four alpha particles before reaching a stable isotope.

[0768] In some embodiments, radioactive metals can be used as imaging agents or detectable labels. Radionuclides used for radiolabeling include, but are not limited to, carbon-11, nitrogen-13, oxygen-15, fluorine-18, copper-67, gallium-67, gallium-68, krypton-81m, rubidium-82, technetium-99, indium-111, iodine-123, iodine-124, iodine-125, iodine-131, xenon-133, thallium-201, zirconium-89, copper-64, yttrium-90, technetium-99m, iodine-123, iodine-124 and iodine-125, lutetium-177, At-211, lead-212, bismuth-212, bismuth-213, cesium-134, and actinium-225. These radionuclides and their characteristics (e.g., half-life, emission, etc.) are well known in the art, as are methods for preparing them and using them to label proteins. In some embodiments, the radioactive metal used as an imaging agent or detectable label is cerium-134 ( 134 Ce).

[0769] In some embodiments, the radioactive metal used as an imaging agent or detectable label is Indium 111 ( 111 In) or Xenon 134( 134 Xe).

[0770] In some embodiments, radioactive metal ions are conjugated to the isolated antibodies or antigen-binding fragments thereof of the present disclosure using known methods.

[0771] In some embodiments, radioactive metal ions are conjugated to the antibodies or antigen-binding fragments of the disclosure using a linker.

[0772] In some embodiments, the radiometal ion is complexed with a chelating agent (chelator).

[0773] In some embodiments, an anti-PSMA antibody or antigen-binding fragment thereof of the present disclosure is conjugated (i.e., covalently linked) to a chelator and a radioactive metal complex to produce a radioimmunoconjugate suitable for medical applications such as targeted radiation therapy, for example, in a subject (e.g., a human). In some embodiments, an anti-PSMA antibody or antigen-binding fragment thereof of the present disclosure is conjugated (i.e., covalently linked) to a chelator and a radioactive metal complex to produce a radioimmunoconjugate suitable for detection.

[0774] As used herein, the term "chelator" or "chelant" refers to a compound to which a radionuclide or radiometal can be chelated via coordinate bonding to form a radiometal complex. In some embodiments, the chelator is a macrocycle containing one or more heteroatoms (e.g., oxygen and / or nitrogen) as ring atoms.

[0775] In some embodiments, the chelating agent comprises a macrocyclic chelating moiety. Examples of macrocyclic chelating moieties include, but are not limited to, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA), 5-S-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-tris(acetic acid) (DO3A), or derivatives thereof. In some aspects, the chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In other aspects, the chelating agent is S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). In other aspects, the chelating agent is 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA). In other aspects, the chelating agent is 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA). In another aspect, the chelating agent is 5-S-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-tris(acetic acid) (DO3A). In other aspects, the chelating agent is DOTA, DFO, DTPA, NOTA, TETA, DTPA, or HOPO.

[0776] In some embodiments, the chelating agent is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; tetraxaten).

[0777] In some embodiments, the chelator is H2bp18c6 (N,N'-bis[(6-carboxy-2-pyridinyl)methyl]-4,13-diaza-18-crown-6) or a H2bp18c6 derivative, as described in Thiele et al. "An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy" Angew. Chem. Int. Ed. (2017) 56, 14712-14717, and Roca-Sabio et al. "Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides" J. Am. Chem. Soc. (2009) 131, 3331-3341.

[0778] Additional chelating agents suitable for use according to the present invention are described in WO2018 / 183906 and WO2020 / 106886, which are incorporated herein by reference. In some embodiments, the radioconjugates of the present disclosure comprise a radioactive metal ion chelated with a chelating agent described in WO2020 / 229974, which is incorporated herein by reference in its entirety. In some embodiments, the chelating agent has the structure of formula (I):

[0779]

[0780] or a pharmaceutically acceptable salt thereof, wherein:

[0781] Each of Ring A and Ring B is independently a 6-10 membered aryl group or a 5-10 membered heteroaryl group

[0782] Z1 and Z2 are each independently -(C(R 12 )2) m – or – (CH2) n -C(R 12 )(X)-(CH2) n -;

[0783] R 14 、R 15 、R 16 and R 17 are each independently hydrogen, alkyl or X,

[0784] or alternatively R14 and R 15 and / or R 16 and R 17 taken together with the carbon atom to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X;

[0785] Each X is independently -L1-R4;

[0786] R4 is a nucleophilic moiety, an electrophilic moiety, or R4 comprises a targeting ligand;

[0787] And L1 does not exist or is a linker.

[0788] In some embodiments, the radioconjugates of the present disclosure comprise a radiometal ion chelated to a compound of formula (II):

[0789]

[0790] or a pharmaceutically acceptable salt thereof, wherein:

[0791] R1 is hydrogen and R2 is -L1-R4;

[0792] Alternatively, R1 is -L1-R4 and R2 is hydrogen;

[0793] R3 is hydrogen;

[0794] Alternatively, R2 and R3 are taken together with the carbon atom to which they are attached to form a 5- or 6-membered cycloalkyl group, wherein the 5- or 6-membered cycloalkyl group is optionally substituted with -L1-R4;

[0795] L1 is absent or is a linker; and

[0796] R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand.

[0797] In some embodiments, L1 is absent. When L1 is absent, R4 is directly bound (eg, via a covalent linkage) to the compound.

[0798] In some embodiments, the radioconjugate comprises a radiometal ion chelated to a compound of formula (III):

[0799]

[0800] or a pharmaceutically acceptable salt thereof, wherein:

[0801] L1 is absent or is a linker; and

[0802] R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand.

[0803] In accordance with the present disclosure, the chelators of the present disclosure can be produced by any method known in the art. For example, pendant aromatic / heteroaromatic groups can be attached to the macrocyclic moiety by methods known in the art, such as those exemplified and described below.

[0804] In some embodiments, the present disclosure also provides a chelating agent, preferably a chelating agent that can chelate radioactive metal ions via coordinate bonding.

[0805] As used herein, "antibody-chelator complex" or "conjugate intermediate" refers to a precursor of a radioconjugate comprising an antibody or antigen-binding domain conjugated (joined, e.g., via a covalent bond) to a chelator that does not contain a radioactive metal. The conjugate intermediate may comprise a linker, wherein the chelator is joined to the antibody or antigen-binding domain via the linker. After the radiometal is chelated to the chelator of the conjugate intermediate, it becomes a radioconjugate. For example, "DOTA-mAb" refers to a conjugate intermediate comprising DOTA conjugated to an antibody.

[0806] Any of the chelating agents described herein may comprise a radioactive metal ion. In some embodiments, the radioactive metal ion is an alpha emitting radioactive metal ion. In some embodiments, the radioactive metal is 225 Ac. In some embodiments, the radioactive metal ion is a gamma-emitting radioactive metal ion. In some embodiments, the radioactive metal is 111 In. In some embodiments, the radiometal is 134 The chelating agents disclosed herein can bind to radioactive metal ions (specifically Ce) with any specific activity without regard to metal impurities. 225 Ac) robustly chelates, thereby forming radiometal complexes that have high chelation stability and are stable in vivo and in vitro.

[0807] According to the present disclosure, radioactive metal complexes can be produced by any method known in the art. For example, the chelating agent of the present invention can be mixed with the radioactive metal ion and the mixture can be incubated to allow the formation of the radioactive metal complex. In an exemplary embodiment, the chelating agent can be mixed with the radioactive metal ion. 225 The solution of Ac(NO3)3 is mixed to form a radioactive complex comprising the chelating agent bound to the chelating agent via a coordinate bond. 225 The chelating agent of the present invention effectively chelates radioactive metals, specifically 225 Ac. Thus, in certain embodiments, the chelating agents of the present invention are 225 The solution of Ac ions is chelated with 225The concentration ratio of Ac ions is 1:1000, 1:500, 1:400, 1:300, 1:200, 1:100, 1:50, 1:10 or 1:5, preferably 1:5 to 1:200, more preferably 1:5 to 1:100. The radioactive complex can be characterized by instant thin layer chromatography (e.g., iTLC-SG), HPLC, LC-MS, etc.

[0808] connector

[0809] In some embodiments, the (ADCs) of the present disclosure comprise a linker connecting the anti-PSMA antibodies and antigen-binding fragments thereof of the present disclosure to a drug moiety or a chelator.

[0810] Many linker compounds can be used to conjugate the antibodies of the present disclosure to related drugs or chelating agents. Preferably, the linker will covalently bind to the reactive residue (preferably cysteine ​​or lysine) and the selected drug compound. Therefore, any linker that reacts with the selected antibody residue and can be used to provide a relatively stable conjugate (site-specific or other) of the present invention is compatible with the teachings herein.

[0811] As used herein, the term "linker" refers to a chemical moiety that joins a chelating agent or drug to an antibody or antigen-binding domain. According to the present disclosure, any suitable linker known to those skilled in the art can be used to conjugate the antibody of the present disclosure to a related drug. Preferably, the linker will be covalently bound to the reactive residues of the antibody. Therefore, any linker that reacts with the selected antibody residue and can be used to provide a relatively stable conjugate (site-specific or other) of the present disclosure is compatible with the teachings of this article. Ideally, the linker is designed to release the drug in large quantities once the drug has been delivered to the tumor site, significantly reducing undesirable nonspecific toxicity by minimizing the exposure of non-targeted cells and tissues to cytotoxic drugs, thereby providing an enhanced therapeutic index.

[0812] The linker can comprise, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl moiety, a substituted or unsubstituted aryl or heteroaryl group, a polyethylene glycol (PEG) linker, a peptide linker, a sugar-based linker, or a cleavable linker, such as a disulfide linkage or a protease cleavage site, such as valine-citrulline-p-aminobenzyl (PAB).

[0813] The linker can be composed of one or more linker components. Exemplary linker components include 6-maleimidocaproyl ("MC"), maleimidopropionyl ("MP"), valine-citrulline ("val-cit"), alanine-phenylalanine ("alaphe"), p-aminobenzyloxycarbonyl ("PAB"), N-succinimidyl 4-(2-pyridylthio) pentanoate ("SPP"), N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate ("SMCC"), and N-succinimidyl (4-iodoacetyl) aminobenzoate ("SIAB"). In one embodiment, the linker is valine citrulline-p-aminobenzyloxycarbonyl ("vc-PAB"). In some embodiments, the linker may comprise an amino acid residue. Exemplary amino acid linker components 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). The amino acid residues comprising the amino acid linker component include those that occur naturally, as well as minor amino acids and non-naturally occurring amino acid analogs, such as citrulline. The amino acid linker component can be designed and optimized for its selectivity for enzymatic cleavage by a specific enzyme (e.g., tumor-associated proteases, cathepsins B, C and D, or plasmin protease).

[0814] According to some embodiments, the chelator or chelator-linker comprises a nucleophilic portion or an electrophilic portion. The reaction of the nucleophilic group or electrophilic group of the chelator or chelator-linker with the antibody or antigen-binding domain comprising the corresponding reaction partner allows the antibody or antigen-binding domain to be covalently bonded to the chelator-linker.

[0815] Many compatible linkers can advantageously bind to nucleophilic reduced cysteine ​​and lysine. Conjugation reactions involving reduced cysteine ​​and lysine include, but are not limited to, thiol-maleimide, thiol-halide (acyl halide), thiol-ene, thiol-alkyne, thiol-vinyl sulfone, thiol-bissulfone, thiol-thiosulfonate, thiol-pyridyl disulfide, and thiol-p-fluorine reactions.

[0816] Exemplary linker structures suitable for use in the present disclosure also include, but are not limited to:

[0817]

[0818] And wherein m is an integer from 0 to 12.

[0819] In preferred embodiments, compatible linkers will confer stability to the ADC in the extracellular environment, prevent aggregation of ADC molecules, and maintain the ADC in an aqueous medium, freely soluble, and in a monomeric state. Prior to transport or delivery into the cell, the ADC is preferably stable and remains intact, i.e., the antibody remains attached to the drug moiety. Although linkers are stable outside the target cell, they are designed to be cleaved or degraded at an effective rate within the cell. Thus, an effective linker will: (i) maintain the specif...

Claims

1. An isolated antibody or antigen-binding fragment thereof that binds to prostate-specific membrane antigen (PSMA), wherein the antibody or antigen-binding fragment thereof comprises RYGMH (SEQ ID NO: 4), HCDR2 as shown in the amino acid sequence of LISYDGSNRYYADSVKG (SEQ ID NO: 5), and HCDR3 as shown in the amino acid sequence of ERESSGWFEGYFDY (SEQ ID NO: 6), and the light chain complementary determining region 1 (LCDR1) as shown in the amino acid sequence of GGNNIGSKSVH (SEQ ID NO: 7), LCDR2 as shown in the amino acid sequence of DNSDRPS (SEQ ID NO: 8), and LCDR3 as shown in the amino acid sequence of QVWDSSSDHVV (SEQ ID NO: 9).

2. The isolated antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain as shown in the amino acid sequence of SEQ ID NO: 84 and a light chain as shown in the amino acid sequence of SEQ ID NO:

85.

3. The isolated antibody or antigen-binding fragment thereof according to claim 1, wherein said antibody or said antigen-binding fragment thereof is of IgG1, IgG2, IgG3 or IgG4 isotype.

4. The isolated antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody or antigen-binding fragment thereof is of the IgG1 isotype.

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

6. The isolated antibody or antigen-binding fragment thereof according to claim 5, wherein the at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to the FcγR is selected from the group consisting of: F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, S228 P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236-missing / A327G / P331A / D365E / L358M, H 268Q / 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. 7 . The isolated antibody or antigen-binding fragment thereof according to claim 6 , wherein the at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to the FcγR is L234A / L235A / D265S.

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

9. The isolated antibody or antigen-binding fragment thereof of claim 8, wherein the at least one mutation that modulates the half-life of the antibody or antigen-binding fragment thereof is selected from the group consisting of: H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, wherein residue numbering is according to the EU index.

10. The isolated antibody or antigen-binding fragment thereof according to claim 9, wherein the at least one mutation that modulates the half-life of the antibody or antigen-binding fragment thereof is M252Y / S254T / T256E. 11 . A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof according to claim 1 and a pharmaceutically acceptable carrier.

12. A kit comprising the isolated antibody or antigen-binding fragment thereof according to claim 1.

13. An isolated antibody or antigen-binding fragment thereof that binds to prostate-specific membrane antigen (PSMA), comprising a heavy chain variable region (VH) as shown in the amino acid sequence of SEQ ID NO: 52 and a light chain variable region (VL) as shown in the amino acid sequence of SEQ ID NO:

53.

14. The isolated antibody or antigen-binding fragment thereof according to claim 13, wherein the antibody or antigen-binding fragment thereof is of IgG1, IgG2, IgG3 or IgG4 isotype.

15. The isolated antibody or antigen-binding fragment thereof according to claim 14, wherein the antibody or antigen-binding fragment thereof is of the IgG1 isotype.

16. The isolated antibody or antigen-binding fragment thereof of claim 13, further comprising an Ig constant region, wherein the Ig constant region comprises at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to an Fcγ receptor (FcγR).

17. The isolated antibody or antigen-binding fragment thereof according to claim 16, wherein the at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to the FcγR is selected from the group consisting of: F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, 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.

18. The isolated antibody or antigen-binding fragment thereof of claim 17, wherein the at least one mutation that results in reduced binding of the antibody or antigen-binding fragment thereof to the FcγR is L234A / L235A / D265S.

19. The isolated antibody or antigen-binding fragment thereof of claim 13, further comprising an Ig constant region, wherein the IgG constant region comprises at least one mutation that modulates the half-life of the antibody or antigen-binding fragment thereof.

20. The isolated antibody or antigen-binding fragment thereof according to claim 19, wherein the at least one mutation that modulates the half-life of the antibody or antigen-binding fragment thereof 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.

21. The isolated antibody or antigen-binding fragment thereof according to claim 20, wherein at least one mutation that modulates the half-life of the antibody or antigen-binding fragment thereof is M252Y / S254T / T256E.

22. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof according to claim 13 and a pharmaceutically acceptable carrier.

23. A kit comprising the isolated antibody or antigen-binding fragment thereof according to claim 13.

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