WO2023026235A1 - Anti-psma antibodies and uses thereof - Google Patents

Anti-psma antibodies and uses thereof Download PDF

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Publication number
WO2023026235A1
WO2023026235A1 PCT/IB2022/057978 IB2022057978W WO2023026235A1 WO 2023026235 A1 WO2023026235 A1 WO 2023026235A1 IB 2022057978 W IB2022057978 W IB 2022057978W WO 2023026235 A1 WO2023026235 A1 WO 2023026235A1
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Prior art keywords
seq
antibody
constant region
antigen binding
binding fragment
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English (en)
French (fr)
Inventor
Shalom Goldberg
Donna KLEIN
Neeraj Kohli
Theresa MCDEVITT
Steven J. Orcutt
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Janssen Biotech Inc
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Janssen Biotech Inc
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Priority to IL311070A priority Critical patent/IL311070A/en
Priority to CN202280072247.7A priority patent/CN118176213B/zh
Priority to AU2022333321A priority patent/AU2022333321A1/en
Priority to CA3230346A priority patent/CA3230346A1/en
Priority to PE2024000311A priority patent/PE20240727A1/es
Priority to KR1020247009640A priority patent/KR20240049342A/ko
Priority to EP22860756.0A priority patent/EP4392454A4/en
Priority to MX2024002476A priority patent/MX2024002476A/es
Application filed by Janssen Biotech Inc filed Critical Janssen Biotech Inc
Priority to JP2024512988A priority patent/JP2024535712A/ja
Publication of WO2023026235A1 publication Critical patent/WO2023026235A1/en
Priority to JOJO/P/2024/0041A priority patent/JOP20240041A1/ar
Priority to CONC2024/0002244A priority patent/CO2024002244A2/es
Priority to DO2024000036A priority patent/DOP2024000036A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A—HUMAN NECESSITIES
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    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1072—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate
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    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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Definitions

  • PSMA prostate specific membrane antigen
  • Prostate cancer is the second most common cancer in men worldwide, and the sixth leading cause of cancer-related death. Globally, there are approximately 1,100,000 new cases and 300,000 mortalities every year, comprising 4 percent of all cancer deaths. It is estimated that 1 in every 6 men will be diagnosed with the disease during his lifetime. In the U.S., more than 90% of prostate cancers are found in local or regional stages. At these early stages, the 5- year survival rate nears 100%. When the cancer has metastasized, however, the 5-year survival rate drops to 28%, and there remains a need for effective treatments for advanced-stage prostate cancer.
  • Prostate specific membrane antigen is a type II membrane protein that is highly expressed in prostatic intraepithelial neoplasia (PIN), a condition in which some prostate cells have begun to look and behave abnormally, and in primary and metastatic prostate cancers (Bostwick DG, et al, Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: A study of 184 cases. Cancer 1998;82 (11):2256-2261). Expression of PSMA in cancer tissues correlates with the stage of disease and Gleason score (Kawakami M, et al. Enhanced expression of prostate-specific membrane antigen gene in prostate cancer as revealed by in situ hybridization.
  • PSMA expression is also higher in prostate cancer cells from hormone-refractory patients (Wright GL et al., Upregulation of prostate-specific membrane antigen after androgendeprivation 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).
  • PSMA expression is correlated with early prostate-specific antigen (PSA) recurrence in surgically treated prostate cancer.
  • PSMA expression levels correlate with the aggressiveness of the disease, and thereby strongly support PSMA as an excellent target for prostate cancer characterization and subsequent therapy.
  • an isolated antibody or antigen binding fragment thereof that binds to PSMA comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences of: 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 QVWDSSSDHW (SEQ ID NO: 9), respectively;
  • 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
  • QSYDFSLSGSV SEQ ID NO: 15
  • GYGMH (SEQ ID NO: 16), VISYDGSNRYYADSVKG (SEQ ID NO: 17), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; d.
  • SYGMH (SEQ ID NO: 22), VISYDGSNKYYADSVKG (SEQ ID NO: 23), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), AARDDSLSGYV (SEQ ID NO: 27), respectively; e.
  • SYDMH SEQ ID NO: 28
  • VISFDGSNKYYVDSVKG SEQ ID NO: 29
  • TYYDILTGYSHYSYGMDV SEQ ID NO: 30
  • RASQGISNYLA SEQ ID NO: 31
  • ATSTLQS SEQ ID NO: 32
  • QKYNSAPFT SEQ ID NO: 33
  • TYGMH (SEQ ID NO: 34), FISYDGSNKYYADSVKG (SEQ ID NO: 35), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; g. IYSMN (SEQ ID NO: 40), SISSSSSYIFYADSVKG (SEQ ID NO: 41), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; h.
  • SYSLN (SEQ ID NO: 46), SISSSSSYISYADAVKG (SEQ ID NO: 47), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; i.
  • SYYWS SEQ ID NO: 272
  • RIYSSGSTNYNPSLKS SEQ ID NO: 273
  • VGVWPGAFDI SEQ ID NO: 274
  • SGSSSNIGSNTVN SEQ ID NO: 275
  • SSNQRPS SEQ ID NO: 276
  • AAWDDSLNGW SEQ ID NO: 277
  • 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
  • QVWDSSSDHW SEQ ID NO: 9
  • GGSISSY (SEQ ID NO: 130), YSSGN (SEQ ID NO: 131), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; l.
  • VRTFSGY (SEQ ID NO: 136), SYDGSN (SEQ ID NO: 125), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGW (SEQ ID NO: 21), respectively; m.
  • GFTFTSY (SEQ ID NO: 142), SYDGSN (SEQ ID NO: 125), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO:25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO:27), respectively; n. GFTFSSY (SEQ ID NO: 148), SFDGSN (SEQ ID NO: 149), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; o.
  • GFTFSTY SEQ ID NO: 154
  • SYDGSN SEQ ID NO: 125
  • RDNLRFLEWFMDV SEQ ID NO:36
  • RASQSVRSNLA SEQ ID NO:37
  • GASTRAT SEQ ID NO:38
  • HQYNDWPPYT SEQ ID NO: 39
  • 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
  • QKYNSAPLT SEQ ID NO:45
  • GFTFSSY (SEQ ID NO: 166), SSSSSY (SEQ ID NO: 167), DRGFLEDYYYYYGMDV (SEQ ID NO;48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO:50), and QQAYSFPLT (SEQ ID NO: 51), respectively; r. GGSIISY (SEQ ID NO: 290), YSSGS (SEQ ID NO:291), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO:275), SSNQRPS (SEQ ID NO:276), and AAWDDSLNGW (SEQ ID NO: 277), respectively; s.
  • GFTLSRYGMH (SEQ ID NO: 172), LISYDGSNRY (SEQ ID NO: 173), ERESSGWFEGYFDY (SEQ ID NO:6), GGNNIGSKSVH (SEQ ID NOY), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHW (SEQ ID NO:9), respectively; t. GGSISSYYWN (SEQ ID NO: 178), RIYSSGNTD (SEQ ID NO: 179), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; u.
  • VRTFSGYGMH (SEQ ID NO: 184), VISYDGSNRY (SEQ ID NO:185), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGW (SEQ ID NO:21), respectively; v.
  • GFTFTSYGMH (SEQ ID NO: 190), VISYDGSNKY (SEQ ID NO: 191), EHYDSSGYYHGYYGMDV (SEQ ID NO:24), SGSSSNIGSNYVY (SEQ ID NO:25), SNNQRPS (SEQ ID NO:26), and AARDDSLSGYV (SEQ ID NO:27), respectively; w.
  • GFTFSSYDMH (SEQ ID NO: 196), VISFDGSNKY (SEQ ID NO: 197), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO:31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; x.
  • GFTFSTYGMH (SEQ ID NO: 202), FISYDGSNKY (SEQ ID NO:203), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO:38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; y.
  • GFTLSIYSMN (SEQ ID NO: 208), SISSSSSYIF (SEQ ID NO:209), SSYGADY (SEQ ID NO: 42), RASQDITNFLA, (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO:45), respectively; z.
  • GFTFSSYSLN (SEQ ID NO: 214), SISSSSSYIS (SEQ ID NO:215), DRGFLEDYYYYYGMDV (SEQ ID NO:48), RASQGISNWL (SEQ ID NO:49), VASSLQS (SEQ ID NO:50), and QQAYSF (SEQ ID NO:51), respectively; aa.
  • GGSIISYYWS (SEQ ID NO: 296), RIYSSGSTN (SEQ ID NO: 297), VGVWPGAFDI (SEQ ID NO:274), SGSSSNIGSNTVN (SEQ ID NO:275), SSNQRPS (SEQ ID NO:276), and AAWDDSLNGW (SEQ ID NO:277), respectively;
  • bb. GFTLSRYG (SEQ ID NO: 220), ISYDGSNR (SEQ ID NO:221), ARERESSGWFEGYFDY (SEQ ID NO: 222), NIGSKS (SEQ ID NO:223), DNS, and QVWDSSSDHW (SEQ ID NOV), respectively; cc.
  • GGSISSYY SEQ ID NO: 226), IYSSGNT (SEQ ID NO: 227), ARGRGANVGLFDY (SEQ ID NO:228), NSNIGANYD (SEQ ID NO:229), GNI, and QSYDFSLSGSV (SEQ ID NO: 15), respectively; dd.
  • VRTFSGYG SEQ ID NO: 232), ISYDGSNR (SEQ ID NO:233), ARDGNWGSLDLYFDL (SEQ ID NO:234), SSNIGADYD (SEQ ID NO:235), VNN, and QSYDNTLSGW (SEQ ID NO:21), respectively; ee.
  • GFTFTSYG SEQ ID NO: 238), ISYDGSNK (SEQ ID NO:239, AREHYDSSGYYHGYYGMDV (SEQ ID NO: 240), SSNIGSNY (SEQ ID NO:241), SNN, and AARDDSLSGYV (SEQ ID NO:27), respectively; ff. GFTFSSYD (SEQ ID NO: 244), ISFDGSNK (SEQ ID NO:245), ARTYYDILTGYSHYSYGMDV (SEQ ID NO: 246), QGISNY (SEQ ID NO:247), ATS, and QKYNSAPFT (SEQ ID NO: 33), respectively; gg.
  • GFTFSTYG SEQ ID NO: 250
  • ISYDGSNK SEQ ID NO:251
  • AGRDNLRFLEWFMDV SEQ ID NO:252
  • QSVRSN SEQ ID NO: 253
  • GFTLSIYS SEQ ID NO: 256
  • ISSSSSYI SEQ ID NO:257
  • ARSSYGADY SEQ ID NO:258
  • QDITNF SEQ ID NO: 259
  • TAS TAS
  • QKYNSAPLT SEQ ID NO:45
  • GFTFSSYS SEQ ID NO: 262
  • ISSSSSYI SEQ ID NO:263
  • ARDRGFLEDYYYYYYGMDV SEQ ID NO:264
  • QGISNW SEQ ID NO:265
  • VAS VAS
  • QQAYSFPLT SEQ ID NO: 51
  • an isolated antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL) of: SEQ ID NOs: 52 and 53 respectively;
  • SEQ ID NOs: 278 and 279 respectively, and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof, comprising a VH which 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 which 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.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof, comprising a VH which 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 which 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 [0011]
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284, and 288.
  • the disclosure also provides an antibody or antigen binding fragment thereof comprising an amino acid sequence 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.
  • the disclosure also provides antibody or antigen binding fragment thereof comprising an amino acid sequence 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.
  • the disclosure also provides antibody or antigen binding fragment thereof comprising an amino acid sequence 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.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 84 and a LC of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 86 and a LC of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively; a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55; and/or a HC of SEQ ID NO: 88 and a LC of SEQ ID NO: 89; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively; a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55; and/or a HC of SEQ ID NO: 90 and a LC of SEQ ID NO: 89; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20 and 21, respectively; a VH of SEQ ID NO: 56 and a VL of SEQ ID NO: 57; and/or a HC of SEQ ID NO: 92 and a LC of SEQ ID NO: 93; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26 and 27, respectively; a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59; and/or a HC of SEQ ID NO: 94 and a LC of SEQ ID NO: 95; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively; a VH of SEQ ID NO: 60 and a VL of SEQ ID NO: 61 ; and/or a HC of SEQ ID NO: 96 and a LC of SEQ ID NO: 97; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38 and 39, respectively; a VH of SEQ ID NO: 62 and a VL of SEQ ID NO: 63; and/or a HC of SEQ ID NO: 98 and a LC of SEQ ID NO: 99; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44 and 45, respectively; a VH of SEQ ID NO: 64 and a VL of SEQ ID NO: 65; and/or a HC of SEQ ID NO: 100 and a LC of SEQ ID NO: 101; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50 and 51, respectively; a VH of SEQ ID NO: 66 and a VL of SEQ ID NO: 67; and/or a HC of SEQ ID NO: 102 and a LC of SEQ ID NO: 103; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the 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 the first antigen binding domain binds to a first epitope of PSMA and the second binding domain binds to a second epitope on PSMA.
  • the biparatopic antibody comprises two antigen-binding domains wherein: the first antigen binding domain is a Fab or a Fab fragment comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, a HCDR3 of SEQ ID NO: 6, a LCDR1 of SEQ ID NO: 7, a LCDR2 of SEQ ID NO: 8, a LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, a HC of SEQ ID NO: 268 and a LC of SEQ ID NO: 269; and the second antigen binding domain is in a scFv format comprising a HCDR1 of SEQ ID NO: 272, a HCDR2 of SEQ ID NO: 273, a HCDR3 of SEQ ID NO: 274 a LCDR1 of SEQ ID NO: 275, a LCDR2 of SEQ ID NO:
  • the disclosed isolated antibody or antigen binding fragment thereof is of an IgGl , an IgG2, an IgG3 or an IgG4 isotype.
  • the isolated antibody or antigen binding is an IgGl isotype.
  • the isolated antibody or antigen binding fragment thereof comprises an Ig constant region or the fragment of an Ig constant region, wherein the Ig constant region of the fragment or the constant region comprises at least one mutation that results in reduced binding of the antibody or antigen binding fragment thereof to a Fey receptor (FcyR).
  • FeyR Fey receptor
  • the at least one mutation that results in reduced binding of the protein to the FcyR 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- deleted/A327G/P331A/D365E/L358M, H268Q/V309L/A330S/P331S, S267E/L328F, L234F/L235E/D265 A, L234A/L235 A/G237 A/P238S/H268 A/A330S/P331
  • the mutations that results in reduced binding of the antibody or antigen binding fragment thereof to the FcyR are L234A_L235A_D265S.
  • the FcyR is FcyRI, FcyRIIA, FcyRIIB or FcyRIII, or any combination thereof.
  • the isolated antibody or antigen binding fragment thereof comprises an Ig constant region or the 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.
  • the at least one mutation that modulates the half-life of the antibody is selected from the group consisting of H435A, P257I/N434H, D376V/N434H, M252Y/S254T/T256E, M252Y/S254T/T256E/H433K/N434F, T308P/N434A and H435R, wherein residue numbering is according to the EU index.
  • the mutations that modulates the half-life of the antibody or antigen binding fragment thereof are M252Y/S254T/T256E mutations.
  • the disclosure also provides a polynucleotide encoding the isolated antibody or antigen binding fragment thereof of the disclosure.
  • the polynucleotide encoding the isolated antibody or antigen binding fragment thereof that binds PSMA comprises a polynucleotide sequence of SEQ ID NOs: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286 or 289.
  • 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 NOs: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286 or 289
  • the disclosure also provides a vector comprising the polynucleotide of the disclosure. [0040] The disclosure also provides a host cell comprising the polynucleotide or vector of the disclosure.
  • the disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to an antibody, or an antigen binding fragment thereof, with binding specificity for PSMA, and wherein the radiometal complex comprises a radiometal ion.
  • the disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to any of the antibody, or an antigen binding fragment thereof of the disclosure and wherein the radiometal complex comprises a radiometal ion.
  • the disclosure also provides a radioconjugate, wherein the antibody, or an antigen binding fragment comprises a heavy chain variable domain comprising the HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 4, 5, and 6, respectively, and a light chain variable region comprising the LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 7, 8 and 9, respectively.
  • the disclosure also provides a radioconjugate wherein the antibody, or an 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.
  • VH heavy chain variable region
  • VL light chain variable region
  • the disclosure also provides a radioconjugate wherein the antibody, or an 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) comprises the amino acid sequence of SEQ ID NO: 53.
  • VH heavy chain variable region
  • VL light chain variable region
  • the disclosure also provides a radioconjugate wherein the antibody, or an antigen binding fragment comprises a HC of SEQ ID NO: 86 and a LC of SEQ ID NO: 85; and wherein the antibody or an antigen binding fragment thereof is an IgGl comprising an Ig constant region or the 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 a Fey receptor (FcyR).
  • FcyR Fey receptor
  • the at least one mutation that results in reduced binding of the protein to the FcyR 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- deleted/A327G/P331A/D365E/L358M, H268Q/V309L/A330S/P331S, S267E/L328F, L234F/L235E/D265 A, L234A/L235 A/G237 A/P238S/H268 A/A330S/P331
  • the disclosure also provides a radioconjugate, wherein the antibody, or an antigen binding fragment comprises a HC of SEQ ID NO: 86 and a LC of SEQ ID NO: 85; and wherein the antibody or an antigen binding fragment thereof is an IgGl comprising an Ig constant region or the 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 a half-life of the antibody.
  • the at least one mutation that modulates the half-life of the antibody is selected from the group consisting of H435A, P257I/N434H, D376V/N434H, M252Y/S254T/T256E, M252Y/S254T/T256E/H433K/N434F, T308P/N434A and H435R, wherein residue numbering is according to the EU index.
  • the mutations that modulates the half-life of the antibody or antigen binding fragment thereof are M252Y/S254T/T256E mutations.
  • the disclosure also provides a radioconjugate comprising at least one radiometal complex conjugated to an antibody, or an antigen binding fragment thereof, wherein the radiometal complex comprises a chelator complexed with a radiometal ion selected from the group consisting of 225 Ac, n i In, 177 Lu,’ 32 P, 47 Sc, 67 Cu, 77 As, 89 Sr, 90 Y, "Tc, 105 Rh, 109 Pd, in Ag, 131 I, 134 Ce, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 BI, 213 BI, 223 Ra, 255 Fm, 227 Th, 177 Lu, 62 Cu, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, in In and 34
  • the radiometal ion is 225 Ac.
  • the radiometal ion is i n In.
  • the radiometal ion is 134 Xe.
  • the radiometal complex comprises a radiometal ion chelated to a compound of formula (I) or a pharmaceutical acceptable salt thereof.
  • the radiometal complex comprises a radiometal ion chelated to a compound of formula (II) or a pharmaceutical acceptable salt thereof.
  • the radiometal complex comprises a radiometal ion chelated to a compound of formula (III) or a pharmaceutical acceptable salt thereof.
  • the disclosure also provides a pharmaceutical composition comprising any of the disclosed antibody or antigen binding fragment thereof; or any of the disclosed radioconjugate, and a pharmaceutically acceptable carrier.
  • the disclosure also provides a method of treating a PSMA expressing cancer in a subject, comprising administering a therapeutically effective amount of any of the disclosed antibody or antigen fragment thereof, any of the disclosed radioconjugate, or any of the disclosed pharmaceutical compositions, to the subject for a time sufficient to treat the cancer.
  • the subject has prostate cancer.
  • the subject has renal cancer.
  • the disclosure also provides a method of detecting PSMA in a sample with a radioconjugate of the disclosure.
  • the disclosure also provides a kit comprising any of the antibody or antigen binding fragment thereof, any of the radioconjugate, or any of the pharmaceutical compositions of the disclosure.
  • 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 be limiting of the claimed antibody, antigen binding domains, antibody fragments, radioconjugates, antibody-drug conjugates, polynucleotides, vectors, cells, compositions, kits, and methods.
  • any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed antibodies, antigen binding fragments thereof, polynucleotides, vectors, cells, radioconjugates, antibody-drug conjugates, compositions, kits, and methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.
  • a feature or embodiment associated with a method of using an antigen binding domains, radioconjugate, and antibodydrug conjugate such a feature or embodiment is equally applicable to the antigen binding domain, radioconjugate, and antibody-drug conjugate.
  • the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges was explicitly recited.
  • any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.
  • transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” 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 a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed disclosure.
  • Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”
  • Embodiments described in terms of the phrase “consisting essentially of’ (or its equivalents) also provide as embodiments those independently described in terms of “consisting of.”
  • the phrase “and fragments thereof’ when appended to a list includes fragments of one or more members of the associated list.
  • the list may comprise a Markush group so that, as an example, the phrase “the group consisting of peptides A, B, and C, and fragments thereof’ specifies or recites a Markush group including A, B, C, fragments of A, fragments of B, and/or fragments of C.
  • the disclosure relates to isolated antibodies and antigen binding fragments thereof that specifically bind PSMA.
  • Antibody is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric, multimeric or biparatopic antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.
  • the term antibody includes full length antibodies, whole antibodies, intact antibodies, antibody fragments, antigen binding fragment and antigen binding domains.
  • antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen.
  • Antibody structures are well known.
  • Immunoglobulins can be assigned to five major classes (i.e., IgA, IgD, IgE, IgG and IgM), depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • the antibodies of the invention can be of any of the five major classes or corresponding sub-classes.
  • the antibodies of the invention are IgGl, IgG2, IgG3 or IgG4.
  • Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda, based on the amino acid sequences of their constant domains. Accordingly, the antibodies of the invention can contain a kappa or lambda light chain constant domain. According to some embodiments, the antibodies of the invention include heavy and/or light chain constant regions from rat or human antibodies. In addition to the heavy and light constant domains, antibodies contain an antigenbinding region that is made up of a light chain variable region and a heavy chain variable region, each of which contains three domains (i.e., complementarity determining regions 1-3; CDR1, CDR2, and CDR3). The light chain variable region domains are alternatively referred to as LCDR1, LCDR2, and LCDR3, and the heavy chain variable region domains are alternatively referred to as HCDR1, HCDR2, and HCDR3.
  • CDR complementarity determining regions
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • variable region refers to the heavy or light chain domain that is involved in the binding of the antibody to the antigen.
  • the variable domains of the heavy or light chain (VH and VL, respectively) comprise four framework regions (FR) and three complementarity determining regions (CDRs).
  • isolated refers to a homogenous population of molecules (such as synthetic polynucleotides or polypeptides) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step.
  • molecules such as synthetic polynucleotides or polypeptides
  • isolated refers to a molecule that is substantially free of other cellular material and/or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.
  • an “isolated antibody” refers to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to PSMA is substantially free of antibodies that do not bind to PSMA). In addition, an isolated antibody is substantially free of other cellular material and/or chemicals. “Isolated antibody” encompasses antibodies that are isolated to a higher purity, such as antibodies that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.
  • the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
  • the monoclonal antibodies of the invention can be made by the hybridoma method, phage display technology, single lymphocyte gene cloning technology, or by recombinant DNA methods.
  • the monoclonal antibodies can be produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, such as a transgenic mouse or rat, having a genome comprising a human heavy chain transgene and a light chain transgene.
  • PSMA state-specific membrane antigen
  • the amino acid sequence of the human PSMA is encoded by the FOLH1 gene. Unless specified, as used herein, PSMA refers to human PSMA.
  • the amino acid sequence of human PSMA is retrievable from Uniprot (Accession# Q04609).
  • the amino acid sequence of full length human PSMA is shown in SEQ ID NO: 336.
  • the extracellular domain spans residues -4 - 750, the transmembrane domain spans residues -0 - 43 and the cytoplasmic domain spans residues-1 - 19 of SEQ ID NO:336.
  • SEQ ID NO: 336 full-length human PSMA
  • PSMA includes any PSMA variant, isoform, and species homolog, which is naturally expressed by cells (including prostate cells) or can be expressed on cells transfected with genes or cDNA encoding the polypeptide.
  • the PSMA is a human PSMA.
  • “Specifically binds,” “specific binding,” “specifically binding” or “binds” refer to a proteinaceous molecule binding to an antigen or an epitope within the antigen with greater affinity than for other antigens.
  • Epitope refers to a portion of an antigen to which an antibody specifically binds.
  • Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
  • An epitope can be composed of contiguous and/or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3 -dimensional space through the folding of the protein molecule.
  • the proteinaceous molecule binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1x1 O' 7 M or less, for example about 5xl0' 8 M or less, about IxlO' 8 M or less, about IxlO' 9 M or less, about IxlO' 10 M or less, about IxlO' 11 M or less, or about IxlO' 12 M or less, typically with the KD that is at least one hundred fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein).
  • KD equilibrium dissociation constant
  • KD refers to the dissociation constant, which is obtained from the ratio of KD to Ka (i.e., Kd/Ka) and is expressed as a molar concentration (M).
  • KD values for antibodies can be determined using methods in the art in view of the present disclosure.
  • the KD of an antibody can be determined by using surface plasmon resonance, such as by using a biosensor system, e.g., a Biacore® system, or by using bio-layer interferometry technology, such as an Octet RED96 system.
  • the smaller the value of the KD of an antibody the higher affinity that the antibody binds to a target antigen.
  • an antibody that “binds to PSMA” or that “specifically binds to PSMA” refers to an antibody that binds to PSMA, preferably human PSMA, with a KD of 1 x10 -7 M or less, preferably 1 x1 CT 8 M or less, more preferably 5x1 CT 9 M or less, 1 x1 CT 9 M or less, 5x10 -1 ° M or less, or 1 x 1 CT 10 M or less.
  • isolated antibody refers to an antibody that binds PSMA and that comprises at least one binding domain specifically binding PSMA.
  • anti- PSMA antibody refers to an antibody that specifically binds to two different epitopes on the same target protein, e.g. PSMA.
  • the anti-PSMA antibody or antigen binding fragment of the disclosure is a biparatopic antibody that binds to PSMA.
  • the biparatopic antibody of the disclosure comprises at least one receptor binding domain for a first epitope on PSMA target protein and a second receptor binding domain for a second epitope on the same PSMA target protein.
  • the KD for the first epitope and the KD for the second epitope are the same. In some embodiments the KD for the first epitope and the KD for the second epitope are the different.
  • the KD for the first epitope and the KD for the second epitope are about 1 x10 -7 M or less, preferably 1 x1 CT 8 M or less, more preferably 5x1 CT 9 M or less, 1 x1 CT 9 M or less, 5x10 -1 ° M or less, or 1 x 1 CT 10 M or less.
  • the anti-PSMA antibody of the disclosure include whole antibodies, antibody fragments that specifically bind to PSMA, and antigen binding fragments thereof that specifically binds to PSMA.
  • the anti-PSMA antibody of the disclosure include whole antibodies or full-length antibodies, Fv fragments, single chain scFv fragments (scFv), Fab, F(ab)2, or single chain antibodies.
  • the anti-PSMA antibody of the disclosure is a whole antibody or a full-length antibody.
  • the anti-PSMA antibody of the disclosure is a full-length antibodies, whole antibodies and intact antibodies.
  • Frull length antibodies are used herein interchangeably to refer to an antibody having a structure similar to a native antibody.
  • “Intact antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM).
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3).
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL).
  • VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.
  • the anti-PSMA antibody of the disclosure is an antibody fragment or an antigen binding domain that specifically binds to PSMA.
  • Antibody fragment refers to a molecule other than an intact antibody.
  • Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as a VH, a VL, a VH and aVL, a Fab, a Fab’, a F(ab')2 , a Fd and a Fv fragments, , a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv 1 ), a disulfide stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), a single domain antibody (sdab) an scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody
  • dAb or “dAb fragment” refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544 546 (1989)).
  • Fab or "Fab fragment” refers to an antibody fragment composed of VH, CHI, VL and CL domains.
  • F(ab')2 or “F(ab')2 fragment” refers to an antibody fragment containing two Fab fragments connected by a disulfide bridge in the hinge region.
  • Fd or “Fd fragment” refers to an antibody fragment composed of VH and CHI domains.
  • Fv or “Fv fragment” refers to an antibody fragment composed of the VH and the VL domains from a single arm of the antibody. Fv fragments lack the constant regions of Fab (CHI and CL) regions. The VH and VL in Fv fragments are held together by non-covalent interactions.
  • Antigen binding fragments may be linked together via a synthetic linker to form various types of single antibody designs where the VH/VL domains may be paired intramolecularly, or intermolecularly to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody.
  • the linker is a peptide linker and may include any naturally occurring amino acid. Exemplary amino acids that may be included into the linker are Gly, Ser Pro, Thr, Glu, Lys, Arg, He, Leu, His and The.
  • the linker should have a length that is adequate to link the VH and the VL in such a way that they form the correct conformation relative to one another so that they retain the desired activity, such as binding to PSMA.
  • the linker may be about 5-50 amino acids long.
  • Single chain Fv or “scFv” are fusion proteins comprising at least one antibody fragment comprising a light chain variable region (VL) and at least one antibody fragment comprising a heavy chain variable region (VH), wherein the VL and the VH are contiguously linked via a polypeptide linker, and capable of being expressed as a single chain polypeptide.
  • a scFv may have the VL and VH variable regions in either order, e.g., with respect to the N- terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.
  • the linker is a peptide linker and may include any naturally occurring amino acid.
  • Exemplary amino acids that may be included into the linker are Gly, Ser Pro, Thr, Glu, Lys, Arg, He, Leu, His and The.
  • the linker should have a length that is adequate to link the VH and the VL in such a way that they form the correct conformation relative to one another so that they retain the desired activity, such as binding to PSMA.
  • the linker may be about 5-50 amino acids long. In some embodiments, the linker is about 10-40 amino acids long. In some embodiments, the linker is about 10-35 amino acids long. In some embodiments, the linker is about 10-30 amino acids long. In some embodiments, the linker is about 10-25 amino acids long. In some embodiments, the linker is about 10-20 amino acids long. In some embodiments, the linker is about 15-20 amino acids long. In some embodiments, the linker is 6 amino acids long. In some embodiments, the linker is 7 amino acids long. In some embodiments, the linker is 8 amino acids long. In some embodiments, the linker is 9 amino acids long. In some embodiments, the linker is 10 amino acids long.
  • the linker is 11 amino acids long. In some embodiments, the linker is 12 amino acids long. In some embodiments, the linker is 13 amino acids long. In some embodiments, the linker is 14 amino acids long. In some embodiments, the linker is 15 amino acids long. In some embodiments, the linker is 16 amino acids long. In some embodiments, the linker is 17 amino acids long. In some embodiments, the linker is 18 amino acids long. In some embodiments, the linker is 19 amino acids long. In some embodiments, the linker is 20 amino acids long. In some embodiments, the linker is 21 amino acids long. In some embodiments, the linker is 22 amino acids long. In some embodiments, the linker is 23 amino acids long.
  • the linker is 24 amino acids long. In some embodiments, the linker is 25 amino acids long. In some embodiments, the linker is 26 amino acids long. In some embodiments, the linker is 27 amino acids long. In some embodiments, the linker is 28 amino acids long. In some embodiments, the linker is 29 amino acids long. In some embodiments, the linker is 30 amino acids long. In some embodiments, the linker is 31 amino acids long. In some embodiments, the linker is 32 amino acids long. In some embodiments, the linker is 33 amino acids long. In some embodiments, the linker is 34 amino acids long. In some embodiments, the linker is 35 amino acids long. In some embodiments, the linker is 36 amino acids long.
  • the linker is 37 amino acids long. In some embodiments, the linker is 38 amino acids long. In some embodiments, the linker is 39 amino acids long. In some embodiments, the linker is 40 amino acids long. Exemplary linkers that may be used are Gly rich linkers, Gly and Ser containing linkers, Gly and Ala containing linkers, Ala and Ser containing linkers, and other flexible linkers.
  • linker sequences may include portions of immunoglobulin hinge area, CL or CHI derived from any immunoglobulin heavy or light chain isotype.
  • a variety of non-proteinaceous polymers including polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers.
  • Exemplary linkers that may be used are shown in Table 2.
  • the scFv comprises, from the N- to C-terminus, a VH, a first linker (LI) and a VL (VH-L1-VL).
  • the scFv comprises, from the N-to C-terminus, the VL, the LI and the VH (VL-L1-VH).
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO:
  • the LI comprises the amino acid sequence of SEQ ID NO: 87. [00144] In some embodiments, the LI comprises the amino acid sequence of SEQ ID NO: 107.
  • the LI comprises the amino acid sequence of SEQ ID NO: 91.
  • the LI comprises the amino acid sequence of SEQ ID NO: 111.
  • the LI comprises the amino acid sequence of SEQ ID NO: 285.
  • the LI comprises the amino acid sequence of SEQ ID NO: 287.
  • Divalent or bivalent single chain variable fragments can be engineered by linking two scFvs“. (scFv)2” or “tandem scFv” or “bis-scFv” fragments refers to a fusion protein comprising two light chain variable regions (VL) and two heavy chain variable regions (VH), wherein the two VL and the two VH regions are contiguously linked via polypeptide linkers, and capable of being expressed as a single chain polypeptide.
  • the two VL and two VH regions fused by peptide linkers form a bivalent molecule VLA-linker-VHA-linker- VLB-linker-VHB to form two binding sites, capable of binding two different antigens or epitopes concurrently.
  • (ScFv)2 can be expressed as a single chain polypeptide.
  • VH and the VL domains identified herein that bind PSMA may be engineered into scFv format in either VH-linker-VL or VL-linker-VH orientation. Any of the VH and the VL domains identified herein may also be used to generate sc(Fv)2 structures, such as VH-linker-VL-linker- VL-linker-VH, VH-linker-VL-linker- VH-linker-VL, VH-linker-VH- linker- VL-linker-VL,VL-linker-VH-linker-VH-linker-VL,VL-linker-VH-linker-VL-linker-VH or VL-linker-VL-linker-VH-linker-VH.
  • ‘Diabodies” are bivalent dimers formed from two chains, each containing a VH and a VL domain. The two domains within a chain are separated by a linker that is too short to facilitate intrachain dimerization leading to two chains dimerizing in a head-to-tail arrangement.
  • the linker may be a pentameric glycine-rich linker (G4S (SEQ ID NO: 337)).
  • VHH refers to a single-domain antibody or nanobody, exclusively composed of the antigen binding domain of a heavy chain.
  • a VHH single domain antibody lacks the light chain and the CHI domain of the heavy chain of conventional Fab region.
  • the anti-PSMA antibodies of the 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.
  • the anti-PSMA antibody of the disclosure include chimeric, humanized or fully human antibodies that specifically bind to PSMA.
  • Human antibody refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci.
  • Human antibody typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both.
  • a “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes.
  • human antibody may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. W02009/085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.
  • Transgenic animals such as mice, rat or chicken carrying human immunoglobulin (Ig) loci in their genome may be used to generate antigen binding fragments that bind PSMA, and are described in for example U.S. Patent No. 6,150,584, Int. Patent Publ. No. WO1999/45962, Int. Patent Publ. Nos. W02002/066630, W02002/043478 and W01990/04036.
  • the endogenous immunoglobulin loci in such animal may be disrupted or deleted, and at least one complete or partial human immunoglobulin locus may be inserted into the genome of the animal using homologous or non-homologous recombination, using transchromosomes, or using minigenes.
  • the antibody or antigen binding fragment thereof that bind PSMA generated by immunizing non-human animals may be humanized.
  • Exemplary humanization techniques including selection of human acceptor frameworks include CDR grafting (U.S. Patent No. 5,225,539), SDR grafting (U.S. Patent No. 6,818,749), Resurfacing (Padlan, (1991) Mol Immunol 28:489-499), Specificity Determining Residues Resurfacing (U.S. Patent Publ. No. 2010/0261620), human framework adaptation (U.S. Patent No. 8,748,356) or superhumanization (U.S. Patent No. 7,709, 226).
  • CDRs or a subset of CDR residues of parental antibodies are transferred onto human frameworks that may be selected based on their overall homology to the parental frameworks, based on similarity in CDR length, or canonical structure identity, or a combination thereof.
  • Humanized antigen binding domains may be further optimized to improve their selectivity or affinity to a desired antigen by incorporating altered framework support residues to preserve binding affinity (backmutations) by techniques such as those described in Int. Patent Publ. Nos. W01090/007861 and WO1992/22653, or by introducing variation at any of the CDRs for example to improve affinity of the antigen binding domain.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds to PSMA comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences: a.
  • RYGMH (SEQ ID NO: 4), LISYDGSNRYYADSVKG (SEQ ID NO: 5) , ERESSGWFEGYFDY (SEQ ID NO: 6), GGNNIGSKSVH (SEQ ID NO: 7), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHW (SEQ ID NO: 9), respectively;
  • 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
  • QSYDFSLSGSV SEQ ID NO: 15
  • GYGMH (SEQ ID NO: 16), VISYDGSNRYYADSVKG (SEQ ID NO: 17), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO: 21), respectively; d.
  • SYGMH (SEQ ID NO: 22), VISYDGSNKYYADSVKG (SEQ ID NO: 23), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO: 25), SNNQRPS (SEQ ID NO: 26), AARDDSLSGYV (SEQ ID NO: 27), respectively; e.
  • SYDMH SEQ ID NO: 28
  • VISFDGSNKYYVDSVKG SEQ ID NO: 29
  • TYYDILTGYSHYSYGMDV SEQ ID NO: 30
  • RASQGISNYLA SEQ ID NO: 31
  • ATSTLQS SEQ ID NO: 32
  • QKYNSAPFT SEQ ID NO: 33
  • TYGMH (SEQ ID NO: 34), FISYDGSNKYYADSVKG (SEQ ID NO: 35), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO: 38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; g. IYSMN (SEQ ID NO: 40), SISSSSSYIFYADSVKG (SEQ ID NO: 41), SSYGADY (SEQ ID NO: 42), RASQDITNFLA (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO: 45), respectively; h.
  • SYSLN (SEQ ID NO: 46), SISSSSSYISYADAVKG (SEQ ID NO: 47), DRGFLEDYYYYYGMDV (SEQ ID NO: 48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO: 50), and QQAYSFPLT (SEQ ID NO: 51), respectively; i.
  • SYYWS SEQ ID NO: 272
  • RIYSSGSTNYNPSLKS SEQ ID NO: 273
  • VGVWPGAFDI SEQ ID NO: 274
  • SGSSSNIGSNTVN SEQ ID NO: 275
  • SSNQRPS SEQ ID NO: 276
  • AAWDDSLNGW SEQ ID NO: 277
  • 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
  • QVWDSSSDHW SEQ ID NO: 9
  • GGSISSY (SEQ ID NO: 130), YSSGN (SEQ ID NO: 131), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; l.
  • VRTFSGY (SEQ ID NO: 136), SYDGSN (SEQ ID NO: 125), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGW (SEQ ID NO: 21), respectively; m.
  • GFTFTSY (SEQ ID NO: 142), SYDGSN (SEQ ID NO: 125), EHYDSSGYYHGYYGMDV (SEQ ID NO: 24), SGSSSNIGSNYVY (SEQ ID NO:25), SNNQRPS (SEQ ID NO: 26), and AARDDSLSGYV (SEQ ID NO:27), respectively; n. GFTFSSY (SEQ ID NO: 148), SFDGSN (SEQ ID NO: 149), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO: 31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; o.
  • GFTFSTY SEQ ID NO: 154
  • SYDGSN SEQ ID NO: 125
  • RDNLRFLEWFMDV SEQ ID NO:36
  • RASQSVRSNLA SEQ ID NO:37
  • GASTRAT SEQ ID NO:38
  • HQYNDWPPYT SEQ ID NO: 39
  • 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
  • QKYNSAPLT SEQ ID NO:45
  • GFTFSSY (SEQ ID NO: 166), SSSSSY (SEQ ID NO: 167), DRGFLEDYYYYYGMDV (SEQ ID NO;48), RASQGISNWLA (SEQ ID NO: 49), VASSLQS (SEQ ID NO:50), and QQAYSFPLT (SEQ ID NO: 51), respectively; r. GGSIISY (SEQ ID NO: 290), YSSGS (SEQ ID NO:291), VGVWPGAFDI (SEQ ID NO: 274), SGSSSNIGSNTVN (SEQ ID NO:275), SSNQRPS (SEQ ID NO:276), and AAWDDSLNGW (SEQ ID NO: 277), respectively; s.
  • GFTLSRYGMH (SEQ ID NO: 172), LISYDGSNRY (SEQ ID NO: 173), ERESSGWFEGYFDY (SEQ ID NO:6), GGNNIGSKSVH (SEQ ID NOY), DNSDRPS (SEQ ID NO: 8), and QVWDSSSDHW (SEQ ID NO:9), respectively; t. GGSISSYYWN (SEQ ID NO: 178), RIYSSGNTD (SEQ ID NO: 179), GRGANVGLFDY (SEQ ID NO: 12), TGSNSNIGANYDVH (SEQ ID NO: 13), GNINRPL (SEQ ID NO: 14), and QSYDFSLSGSV (SEQ ID NO: 15), respectively; u.
  • VRTFSGYGMH (SEQ ID NO: 184), VISYDGSNRY (SEQ ID NO:185), DGNWGSLDLYFDL (SEQ ID NO: 18), TGSSSNIGADYDVH (SEQ ID NO: 19), VNNNRPS (SEQ ID NO: 20), and QSYDNTLSGVV (SEQ ID NO:21), respectively; v.
  • GFTFTSYGMH (SEQ ID NO: 190), VISYDGSNKY (SEQ ID NO: 191), EHYDSSGYYHGYYGMDV (SEQ ID NO:24), SGSSSNIGSNYVY (SEQ ID NO:25), SNNQRPS (SEQ ID NO:26), and AARDDSLSGYV (SEQ ID NO:27), respectively; w.
  • GFTFSSYDMH (SEQ ID NO: 196), VISFDGSNKY (SEQ ID NO: 197), TYYDILTGYSHYSYGMDV (SEQ ID NO: 30), RASQGISNYLA (SEQ ID NO:31), ATSTLQS (SEQ ID NO: 32), and QKYNSAPFT (SEQ ID NO: 33), respectively; x.
  • GFTFSTYGMH (SEQ ID NO: 202), FISYDGSNKY (SEQ ID NO:203), RDNLRFLEWFMDV (SEQ ID NO: 36), RASQSVRSNLA (SEQ ID NO: 37), GASTRAT (SEQ ID NO:38), and HQYNDWPPYT (SEQ ID NO: 39), respectively; y.
  • GFTLSIYSMN (SEQ ID NO: 208), SISSSSSYIF (SEQ ID NO:209), SSYGADY (SEQ ID NO: 42), RASQDITNFLA, (SEQ ID NO: 43), TASTLQS (SEQ ID NO: 44), and QKYNSAPLT (SEQ ID NO:45), respectively; z.
  • GFTFSSYSLN (SEQ ID NO: 214), SISSSSSYIS (SEQ ID NO:215), DRGFLEDYYYYYGMDV (SEQ ID NO:48), RASQGISNWL (SEQ ID NO:49), VASSLQS (SEQ ID NO:50), and QQAYSF (SEQ ID NO:51), respectively; aa.
  • GGSIISYYWS (SEQ ID NO: 296), RIYSSGSTN (SEQ ID NO: 297), VGVWPGAFDI (SEQ ID NO:274), SGSSSNIGSNTVN (SEQ ID NO:275), SSNQRPS (SEQ ID NO:276), and AAWDDSLNGW (SEQ ID NO:277), respectively;
  • bb. GFTLSRYG (SEQ ID NO: 220), ISYDGSNR (SEQ ID NO:221), ARERESSGWFEGYFDY (SEQ ID NO: 222), NIGSKS (SEQ ID NO:223), DNS, and QVWDSSSDHW (SEQ ID NO:9), respectively; cc.
  • GGSISSYY SEQ ID NO: 226), IYSSGNT (SEQ ID NO: 227), ARGRGANVGLFDY (SEQ ID NO:228), NSNIGANYD (SEQ ID NO:229), GNI, and QSYDFSLSGSV (SEQ ID NO: 15), respectively; dd.
  • VRTFSGYG SEQ ID NO: 232), ISYDGSNR (SEQ ID NO:233), ARDGNWGSLDLYFDL (SEQ ID NO:234), SSNIGADYD (SEQ ID NO:235), VNN, and QSYDNTLSGW (SEQ ID NO:21), respectively; ee.
  • GFTFTSYG SEQ ID NO: 238), ISYDGSNK (SEQ ID NO:239, AREHYDSSGYYHGYYGMDV (SEQ ID NO: 240), SSNIGSNY (SEQ ID NO:241), SNN, and AARDDSLSGYV (SEQ ID NO:27), respectively; ff. GFTFSSYD (SEQ ID NO: 244), ISFDGSNK (SEQ ID NO:245), ARTYYDILTGYSHYSYGMDV (SEQ ID NO: 246), QGISNY (SEQ ID NO:247), ATS, and QKYNSAPFT (SEQ ID NO: 33), respectively; gg.
  • GFTFSTYG SEQ ID NO: 250
  • ISYDGSNK SEQ ID NO:251
  • AGRDNLRFLEWFMDV SEQ ID NO:252
  • QSVRSN SEQ ID NO: 253
  • GFTLSIYS SEQ ID NO: 256
  • ISSSSSYI SEQ ID NO:257
  • ARSSYGADY SEQ ID NO:258
  • QDITNF SEQ ID NO: 259
  • TAS TAS
  • QKYNSAPLT SEQ ID NO:45
  • GFTFSSYS SEQ ID NO: 262
  • ISSSSSYI SEQ ID NO:263
  • ARDRGFLEDYYYYYGMDV SEQ ID NO:264
  • QGISNW SEQ ID NO:265, VAS, and QQAYSFPLT
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NO: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NO: 10, 11, 12, 13, 14, and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NO: 16, 17, 18, 29, 20 and 21, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NO: 22, 23, 24, 25, 26 and 27, respectively.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds PSMA comprising the HCDR1, the HCDR1, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds PSMA comprising the HCDR1, the HCDR1, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38 and 39, respectively.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds PSMA comprising the HCDR1, the HCDR1, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds PSMA comprising the HCDR1, the HCDR1, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 46. 47, 48, 49, 50, and 51, respectively.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof that binds PSMA comprising the HCDR1, the HCDR1, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276, and 277, respectively.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising: a heavy chain complementarity determining region (HCDR) 1 , a HCDR2 and a HCDR3 of a heavy chain variable region (VH) of SEQ ID NO: 52 and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 of a light chain variable region (VL) of SEQ ID NO: 53; or the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 54 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 55; or the HCDR1 , the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 56 and the LCDR1 ,the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 57; or the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO:
  • the isolated protein comprising an antigen binding domain comprises the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 52 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 53 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the isolated protein comprising an antigen binding domain comprises the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 54 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 55 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the 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; or the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55; or the VH of SEQ ID NO: 56 and the VL of SEQ ID NO: 57; or the VH of SEQ ID NO: 58 and the VL of SEQ ID NO: 59; or the VH of SEQ ID NO: 60 and the VL of SEQ ID NO: 61 ; or the VH of SEQ ID NO: 62 and the VL of SEQ ID NO: 63; or the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; or the VH of SEQ ID NO: 66 and the VL of SEQ ID NO: 67; or 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
  • 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 56 and the VL of SEQ ID NO: 57.
  • 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 60 and the VL of SEQ ID NO: 61.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 62 and the VL of SEQ ID NO: 63.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 66 and the VL of SEQ ID NO: 67.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises the VH of SEQ ID NO: 278 and the VL of SEQ ID NO: 279.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284, and 288.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 84. [00184] In some embodiments, the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 85.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 86.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 88.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 89.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence of SEQ ID NO: 90.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [00199] 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 the light chain of SEQ ID NO: 269.
  • PSMA comprises a first heavy chain of SEQ ID NO: 284, a second heavy chain of SEQ ID NO: 288 and the light chain of SEQ ID NO: 269.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 84 and a LC of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 86 and a LC of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively; a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55; and/or a HC of SEQ ID NO: 88 and a LC of SEQ ID NO: 89; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14 and 15, respectively; a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55; and/or a HC of SEQ ID NO: 90 and a LC of SEQ ID NO: 89; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 16, 17, 18, 19, 20, and 21, respectively; a VH of SEQ ID NO: 56 and a VL of SEQ ID NO: 57; and/or a HC of SEQ ID NO: 92 and a LC of SEQ ID NO: 93; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 22, 23, 24, 25, 26, and 27, respectively; a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59; and/or a HC of SEQ ID NO: 94 and a LC of SEQ ID NO: 95; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 28, 29, 30, 31, 32, and 33, respectively; a VH of SEQ ID NO: 60 and a VL of SEQ ID NO: 61 ; and/or a HC of SEQ ID NO: 96 and a LC of SEQ ID NO: 97; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 34, 35, 36, 37, 38, and 39, respectively; a VH of SEQ ID NO: 62 and a VL of SEQ ID NO: 63; and/or a HC of SEQ ID NO: 98 and a LC of SEQ ID NO: 99; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 40, 41, 42, 43, 44, and 45, respectively; a VH of SEQ ID NO: 64 and a VL of SEQ ID NO: 65; and/or a HC of SEQ ID NO: 100 and a LC of SEQ ID NO: 101; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 46, 47, 48, 49, 50, and 51, respectively; a VH of SEQ ID NO: 66 and a VL of SEQ ID NO: 67; and/or a HC of SEQ ID NO: 102 and a LC of SEQ ID NO: 103; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA.
  • the 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, a CDR3 sequences having an amino acid sequence of SEQ ID NO: 6; a light chain 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, a CDR3 sequence having an amino acid sequence of SEQ ID NO: 9; combined with 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, a CDR3 sequence having an amino acid sequence of SEQ ID NO: 274; a light chain a light chain variable region comprising a CDR1 sequence having an amino acid sequence of SEQ ID NO: 275, a CDR2
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA and wherein: the first antigen binding domain is a Fab or a Fab fragment comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, a HCDR3 of SEQ ID NO: 6, a LCDR1 of SEQ ID NO: 7, a LCDR2 of SEQ ID NO: 8, a LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, a HC of SEQ ID NO: 268 and a LC of SEQ ID NO: 269; and the second antigen binding domain is in a scFv format comprising a HCDR1 of SEQ ID NO: 272, a HC
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA and wherein: the first antigen binding domain is a Fab or a Fab fragment comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, a HCDR3 of SEQ ID NO: 6, a LCDR1 of SEQ ID NO: 7, a LCDR2 of SEQ ID NO: 8, a LCDR3 of SEQ ID NO: 9, a VH of SEQ ID NO: 52, a VL of SEQ ID NO: 53, a HC of SEQ ID NO: 284 and a LC of SEQ ID NO: 269; and the second antigen binding domain is in a scFv format comprising a HCDR1 of SEQ ID NO: 272, a HCDR2
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and comprises a heavy chain of SEQ ID NO: 268 and a light chain of SEQ ID NO: 269 and the second binding domain binds to a different epitope on PSMA and comprises a heavy chain of SEQ ID NO 282.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and comprises a heavy chain of SEQ ID NO: 284 and a light chain of SEQ ID NO: 269 and the second binding domain binds to a different epitope on PSMA and comprises a heavy chain of SEQ ID NO 288.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a first binding domain that binds to a first epitope on PSMA and wherein the first binding domain comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 268 and a LC of SEQ ID NO: 269; a second binding domain that binds to a second epitope on PSMA and wherein the second binding domain comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276 and 277, respectively; a VH of SEQ ID NO: 278 and a
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising: a first binding domain that binds to a first epitope on PSMA and wherein the first binding domain comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively; a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53; and/or a HC of SEQ ID NO: 284 and a LC of SEQ ID NO: 269; a second binding domain that binds to a second epitope on PSMA and wherein the second binding domain comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 272, 273, 274, 275, 276 and 277, respectively; a VH of SEQ ID NO: 278 and a
  • the antibodies of the present disclosure include homologous antibodies, homologous antigen binding domains, functional equivalents or variants of the disclosed antibody or antigen binding fragment thereof that bind PSMA, that include polypeptides with amino acid sequences substantially identical to the amino acid sequence of the variable domain or hypervariable domain of the antibodies of the present disclosure or polypeptides with conservative substitutions.
  • the homologous antibodies and antigen binding domain, functional equivalents or variants of the disclosure have sufficient homology with the sequences of said antibody or antigen binding fragment thereof that binds PSMA and are functionally similar to the unmodified anti-PSMA antibody to retain binding to PSMA or retain at least one of the activities of the unmodified antibody.
  • antibody derivative refers to antibodies comprising one or more mutations, substitutions, deletions and/or additions of one or more amino acid residues. Such an addition, substitution or deletion can be located at any position in the molecule. In the case where several amino acids have been added, substituted or deleted, any combination of addition, substitution or deletion can be considered, on condition that the resulting antibody still has at least the advantageous properties of the antibody of the disclosure.
  • the disclosure provides amino acid sequence modification(s) of the antibodies or antigen binding fragment thereof described herein.
  • it may be desirable to improve the binding affinity and/or other biological properties of the antibody including but not limited to specificity, thermostability, expression level, effector functions, glycosylation (e.g., fucosylation), reduced immunogenicity, or solubility.
  • antibody variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by adding mutations, substitutions, deletions and/or additions of one or more amino acid residues to the antibodies and antigen binding fragment described herein.
  • the antibodies and antigen binding fragments thereof provided herein are chemically modified, for example, by the covalent attachment of any type of molecule to the antibody.
  • the antibody derivatives may include antibodies that have been chemically modified, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. Additionally, the antibody may contain one or more non-classical amino acids.
  • Variations may also include a substitution, deletion, or insertion of one or more codons encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native sequence antibody or polypeptide.
  • Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties.
  • Sequences of the disclosure may comprise amino acid sequences with at least 80% identity or homology to the sequences of the antibody or antigen binding fragment thereof, described above.
  • the sequence identity may be about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% to the antigen binding domains that bind PSMA of the disclosure.
  • Variants of the antigen binding domains that bind PSMA 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 antigen binding domain that bind PSMA are within the scope of the disclosure, as long as they retain or have improved functional properties when compared to the parent antigen binding domains.
  • Functional equivalents or variants of the antigen binding domains that bind PSMA include one or more deletions and/or additions of one or more amino acid residues. Such an addition, substitution or deletion can be located at any position in the molecule. In the case where several amino acids have been added, substituted or deleted, any combination of addition, substitution or deletion can be considered, on condition that the resulting antibody still has at least the advantageous properties of the antibody of the disclosure.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.
  • the percent (%) amino acid sequence identity with respect 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 amino acid sequences may be determined using various the algorithms that are 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.
  • a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions.
  • the antibodies of the present disclosure also include those for which binding characteristics, functional or physical properties have been improved by direct mutations.
  • variant antigen binding domains that bind PSMA comprise one or two conservative substitutions in any of the CDR regions, while retaining desired functional properties of the parent antigen binding fragments that bind PSMA.
  • the substitution is a conservative amino acid substitution made at one or more predicted non-essential amino acid residues.
  • “Conservative modifications” or “conservative substitution” refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid modifications.
  • Conservative modifications include amino acid substitutions, additions and deletions.
  • Conservative amino acid substitutions are those in which the amino acid is replaced with an amino acid residue having a similar side chain.
  • amino acids with acidic side chains e.g., aspartic acid, glutamic acid
  • basic side chains e.g., lysine, arginine, histidine
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan
  • aromatic side chains e.g, phenylalanine, tryptophan, histidine, tyrosine
  • aliphatic side chains e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine
  • amide e.g, asparagine, glutamine
  • beta-branched side chains e.g, asparagine, glutamine
  • any native residue in the polypeptide may also be substituted with alanine, as has been 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).
  • Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which results in amino acid substitutions.
  • mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant 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.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g, for antibody-directed enzyme prodrug therapy) or a polypeptide which increases the serum half-life of the antibody.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 at least 80% (e.g. at least 85%, at least 90%, at least 95%, or at least 99%) identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 80% (e.g.
  • VH of SEQ ID NO: 56 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 52 and a VL which is at least 80% (e.g. at least 85%, at least 90%, at least 95% or at least 99%) identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 52 and a VL which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 4, 5, 6, 7, 8, and 9, respectively.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 84 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 PSMA.
  • a HC which 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: 84
  • a LC which 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 PSMA.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 84 and a LC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 86 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 PSMA.
  • a HC which 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: 86
  • a LC which 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 PSMA.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 88 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 89 and wherein the antibody or antigen binding fragment thereof binds PSMA.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 PSMA.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 88 and a LC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 84 and a LC which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 88 and a LC which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively.
  • the disclosure also provides an isolated antibody comprising a HC which 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 which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 84 and a LC which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53..
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the disclosure also provides an isolated antibody comprising a HC which 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 which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 54 and a VL which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 54 and a VL which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs 10, 11, 12, 13, 14 and 15, respectively.
  • the disclosure also provides an isolated antibody comprising a HC which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody that binds PSMA comprises a HC which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 88 and a LC which 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 a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA and wherein: the first antigen binding domain comprises a VH which 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 at least 80% (e.g.
  • the second antigen binding domain comprises a VH which 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 of 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA and wherein: the first antigen binding domain comprises a heavy chain which 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 which is at least 80% (e.g.
  • the second antigen binding domain comprises a heavy chain which 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.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises comprising two antigen-binding domains, wherein the first antigen binding domain binds to an epitope of PSMA and the second binding domain binds to a different epitope on PSMA and wherein: the first antigen binding domain comprises a heavy chain which 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 which is at least 80% (e.g.
  • the second antigen binding domain comprises a heavy chain which 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.
  • the anti-PSMA antibody or antigen binding fragment thereof of the present disclosure and their functional equivalents may be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds that may be used to adjust, alter, improve or moderate antibody characteristics as desired.
  • antibodies with increased in vivo half-lives can be generated by attaching half-life extending moiety such as albumin, albumin variants, albumin-binding proteins and/or domains, transferrin and fragments and analogues thereof, immunoglobulins (Ig) or fragments thereof, such as Fc regions to the antibody, antigen binding fragment of the disclosure.
  • half-life extending moiety such as albumin, albumin variants, albumin-binding proteins and/or domains, transferrin and fragments and analogues thereof, immunoglobulins (Ig) or fragments thereof, such as Fc regions to the antibody, antigen binding fragment of the disclosure.
  • Additional half-life extending moieties include polyethylene glycol (PEG) molecules, such as PEG5000 or PEG20,000, fatty acids and fatty acid esters of different chain lengths, for example laurate, myristate, stearate, arachidate, behenate, oleate, arachidonate, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like, polylysine, octane, carbohydrates (dextran, cellulose, oligo- or polysaccharides) for desired properties.
  • PEG polyethylene glycol
  • fatty acids and fatty acid esters of different chain lengths for example laurate, myristate, stearate, arachidate, behenate, oleate, arachidonate, octanedioic acid, tetradecanedioic acid, oct
  • Half-life extending moieties can be attached to antibodies or antibody fragments or derivatives with or without a multifunctional linker either through conjugation to the N- or C- terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues.
  • well known chemical coupling methods may be used to attach the moieties to the recombinantly produced antibody or antigen binding fragment of the disclosure.
  • a pegyl moiety may for example be conjugated to the antibody or antigen binding fragment thereof that bind PSMA by incorporating a cysteine residue to the C-terminus of the antibody or antigen binding fragment that bind PSMA or engineering cysteines into residue positions that face away from the PSMA binding site and attaching a pegyl group to the cysteine using well known methods.
  • the half-life extending moiety is albumin.
  • the half-life extending moiety is the albumin binding domain. [00351] In some embodiments, the half-life extending moiety is transferrin.
  • the half-life extending moiety is polyethylene glycol.
  • the half-life extending moiety is an Ig constant region or a fragment of the Ig constant region.
  • the half-life extending moiety is an Ig.
  • the half-life extending moiety is a fragment of the Ig.
  • the half-life extending moiety is the Ig constant region.
  • the half-life extending moiety is the fragment of the Ig constant region.
  • the half-life extending moiety is the Fc region.
  • the Ig constant region or the fragment of the Ig constant region, such as the Fc region present in the antibody or antigen binding fragment thereof of the disclosure may be of any allotype or isotype, i.e., IgGl, IgG2, IgG3, IgG4, IgM, IgA and IgE.
  • the Ig constant region or the fragment of the Ig constant region is an IgGl isotype.
  • the Ig constant region or the fragment of the Ig constant region is an IgG2 isotype.
  • the Ig constant region or the fragment of the Ig constant region is an IgG3 isotype.
  • the Ig constant region or the fragment of the Ig constant region is an IgG4 isotype.
  • Ig constant region has no influence on properties of the Ig constant region, such as binding or Fc-mediated effector functions.
  • Immunogenicity of therapeutic proteins comprising Ig constant regions of fragments thereof is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08).
  • the extent to which therapeutic proteins comprising Ig constant regions of fragments thereof induce an immune response in the host may be determined in part by the allotype of the Ig constant region (Stickler et al., (2011) Genes and Immunity 12:213-21).
  • Ig constant region allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody.
  • the antibody or antigen binding fragment thereof of the present disclosure and their functional equivalents may be conjugated to an Ig constant region or to the fragment of an Ig constant region to modulate the antibody or antigen binding fragment effector functions such as ADCC, ADCP and/or ADCP and/or pharmacokinetic properties. This may be achieved by introducing mutation(s) into the Fc that modulate binding of the mutated Fc to activating FcyRs (FcyRI, FcyRIIa, FcyRIII), inhibitory FcyRIIb and/or to FcRn.
  • the antibody or antigen binding fragment thereof that binds PSMA is conjugated to an Ig constant region or the fragment of the Ig constant region comprising at least one mutation in the Ig constant region or in the fragment of the Ig constant region.
  • the at least one mutation is in the Fc region.
  • the antibody or antigen binding fragment thereof that binds PSMA is conjugated to an Ig constant region or to the fragment of the 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.
  • the neonatal Fc receptor plays a central role in the cellular trafficking and serum half-life of IgGs.
  • the antibody or antigen binding fragment thereof that binds PSMA is conjugated to an Ig constant region or to the fragment of the Ig constant region comprising 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.
  • the Ig constant region or the fragment of the first Ig constant region comprises at least one mutation that modulates a half-life of the isolated antibody or antigen binding fragment thereof.
  • Fc positions that may be mutated to modulate half-life include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434 and 435.
  • Exemplary mutations that may be made singularly or in combination are mutations T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R.
  • Exemplary singular or combination mutations that may be made to increase the half-life are mutations M428L/N434S, M252Y/S254T/T256E, T250Q/M428L, N434A and T307A/E380A/N434A.
  • the at least one mutation that modulates the half-life of the antibody or antigen binding fragment thereof of the 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
  • the antibody or antigen binding fragment thereof that binds PSMA is conjugated to the Ig constant region or to the fragment of the Ig constant region comprising M252Y/S254T/T256E mutation.
  • the antibody or antigen binding fragment of the disclosure and their function equivalents is conjugated to an Ig constant region or to the fragment of the Ig constant region comprising at least one mutation in the Fc region that reduces binding of the protein to an activating Fey receptor (FcyR) and/or reduces Fc effector functions such as Clq binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).
  • FcyR activating Fey receptor
  • FcyR activating Fey receptor
  • Fc effector functions such as Clq binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).
  • Fc positions that may be mutated to reduce binding of the protein to the activating FcyR and subsequently to reduce effector function include positions 214, 233, 234, 235, 236, 237, 238, 265, 267, 268, 270, 295, 297, 309, 327, 328, 329, 330, 331 and 365.
  • Exemplary mutations that may be made singularly or in combination are mutations K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A33 OS and P331S in IgGl, IgG2, IgG3 or IgG4.
  • Exemplary combination mutations that result in proteins with reduced ADCC are mutations L234A/L235A on IgGl, L234A/L235A/D265S on IgGl, V234A/G237A/ P238S/H268A/V309L/A330S/P331S on IgG2, F234A/L235A on IgG4, S228P/F234A/ L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T7E233P/ L234V/L235A/G236-deleted/A327G/P331A/D365E/L358M on IgGl, H268Q/V309L/A330S/P331S on IgG2, S267E/L328F on IgGl, L234F/L235E/D265A on IgGl, L234A
  • the antibody or antigen binding fragment thereof that binds PSMA is conjugated to an IgGl heavy chain constant region or a fragment of the IgGl heavy chain constant region.
  • the IgGl heavy chain constant region comprises at least one mutation that results in reduced binding of the antibody to a FcyR.
  • the at least one mutation that results in reduced binding of the antibody to the FcyR 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- deleted/A327G/P331A/D365E/L358M, H268Q/V309L/A330S/P331S, S267E/L328F, L234F/L235E/D265 A, L234A/L235 A/G237 A/P238S/H268 A/A330S/P331 S, S2
  • the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the following mutations: L234A_L235A_D265S.
  • the FcyR is FcyRI, FcyRIIA, FcyRIIB or FcyRIII, or any combination thereof.
  • the antibody or antigen binding fragment of the disclosure and their function equivalents is conjugated to an Ig constant region or to a fragment of an Ig constant region comprising at least one mutation in the Fc region that enhances binding of the protein to an Fey receptor (FcyR) and/or enhances Fc effector functions such as Cl q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and/or phagocytosis (ADCP).
  • FcyR Fey receptor
  • Fc effector functions such as Cl q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and/or phagocytosis (ADCP).
  • Fc positions that may be mutated to increase binding of the protein to the activating FcyR and/or enhance Fc effector functions 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 may be made singularly or in combination are G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T and P396L.
  • Exemplary combination mutations that result in proteins with increased ADCC or ADCP are a S239D/I332E, S298A/E333A/K334A, F243L/R292P/Y300L, F243L/R292P/Y300L/P396L, F243L/R292P/Y300L/V305I/P396L and G236A/S239D/I332E.
  • Fc positions that may be mutated to enhance CDC include positions 267, 268, 324, 326, 333, 345 and 430.
  • Exemplary mutations that may be made singularly or in combination are S267E, F1268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F and E430T.
  • Exemplary combination mutations that result in proteins with increased CDC are K326A/E333A, K326W/E333A, H268F/S324T, S267E/H268F, S267E/S324T and S267E/H268F/S324T.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and/or M252Y/S254T/T256E mutations.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53 and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and/or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 52 and a VL which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 99% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 52 and a VL which is at least 95% identical to the VL of SEQ ID NO: 53, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15 respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and/or M252Y/S254T/T256E mutations.
  • the disclosure provides an isolated antibody or antigen binding fragment thereof comprising a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55 and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and/or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which 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 a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH of SEQ ID NO: 54 and a VL which 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 HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, , respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 95% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 99% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a VH which is at least 99% identical to the VH of SEQ ID NO: 54 and a VL which is at least 95% identical to the VL of SEQ ID NO: 55, wherein the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 84 and wherein the antibody or antigen binding fragment thereof binds PSMA, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 84 and a LC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 84 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the following L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 86 and wherein the antibody or antigen binding fragment thereof binds PSMA, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising an amino acid sequence at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 85; and wherein the antibody or antigen binding fragment thereof binds PSMA, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 99% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations .
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the following L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which 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 is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 88 and a LC which 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 IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 95% identical to the LC of SEQ ID NO: 89, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 95% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 88 and a LC which is at least 99% identical to the LC of SEQ ID NO: 89, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC which is at least 99% identical to the HC of SEQ ID NO: 86 and a LC which is at least 95% identical to the LC of SEQ ID NO: 85, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the following L234A L235A D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 100% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which is at least 100% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 100% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, 6, 7, 8, and 9, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 100% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g.
  • the antibody or antigen binding fragment comprises a HCDR1, a HCDR2, a HCDR3, a LCDRl, a LCDR2 and a LCDR3 of SEQ ID NOs: 10, 11, 12, 13, 14, and 15, respectively, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 84 and a LC which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 86 and a LC which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • IgG l A optionally wherein the first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 85, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which is at least 80% (e.g.
  • the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the antibody or antigen binding fragment thereof that binds PSMA comprises a HC of SEQ ID NO: 88 and a LC which is at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A L235A D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 99% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • the disclosure also provides an isolated antibody or antigen binding fragment thereof comprising a HC which 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 which is at least 95% (e.g. at least 85%, at least 90%, at least 95%, at least 99% or 100%) identical to the LC of SEQ ID NO: 89, wherein the antibody or antigen binding fragment comprises a VH of SEQ ID NO: 54 and a VL of SEQ ID NO: 55, and wherein the antibody or antigen binding fragment is IgGl (e.g.
  • first Ig constant region or the fragment of the first Ig constant region and/or the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations, such as wherein the first Ig constant region or the fragment of the first Ig constant region and the second Ig constant region or the fragment of the second Ig constant region comprise the L234A_L235A_D265S and /or the M252Y/S254T/T256E mutations.
  • Polynucleotides encoding the anti-PSMA antibody or antigen binding fragment of the disclosure and their functional equivalents are also provided.
  • the disclosure provides an isolated polynucleotide encoding any of the anti-PSMA antibody or antigen binding fragment thereof of the disclosure.
  • the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO: 52.
  • the disclosure provides an isolated polynucleotide encoding the VH of SEQ ID NO: 54.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 56.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 58.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 60.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 62.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 64.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 66.
  • the disclosure provides an isolated polynucleotide encoding the VHofSEQIDNO: 278.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQIDNO: 53.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQIDNO: 55.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQIDNO: 57.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQIDNO: 59.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQ ID NO: 61.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQ ID NO: 63.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQ ID NO: 65.
  • the disclosure provides an isolated polynucleotide encoding the VLofSEQ ID NO: 67. [00491] In some embodiment, the disclosure provides an isolated polynucleotide encoding the VL of SEQ ID NO: 279.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 84.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 86.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 88.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 90.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 92.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 94.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 96.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 98.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 100.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 102.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 268.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 282.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 284.
  • the disclosure provides an isolated polynucleotide encoding the heavy chain of SEQ ID NO: 288. [00506] In some embodiment, the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 85.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 89.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 93.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 95.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 97.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 99.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 101.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 103.
  • the disclosure provides an isolated polynucleotide encoding the light chain of SEQ ID NO: 269.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 52 and 53.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 84 and 85.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 86 and 85.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 54 and 55.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 88 and 89.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 52, 53, 278 and 279. [00521] In some embodiments, the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 268, 269 and 282.
  • the disclosure provides isolated polynucleotide sequences encoding polypeptide sequences of SEQ ID NOs: 284, 269 and 288.
  • the disclosure provides an isolated polynucleotide of SEQ ID NO: 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 104, 105, 106, 108, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 134, 135, 270, 271, 280, 281, 283, 286 or 289.
  • Polynucleotides encoding the anti-PSMA antibody or antigen binding fragment of the disclosure include polynucleotides with nucleic acid sequences that are substantially the same as the nucleic acid sequences of the polynucleotide of the disclosure. “Substantially the same” nucleic acid sequence is defined herein as a sequence with at least 80% identity to another nucleic acid sequence when the two sequences are aligned. Two nucleic acid sequences are substantially identical if the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the polypeptide encoded by the second nucleic acid. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.
  • Modified nucleotides may be used to generate the polynucleotides of the disclosure.
  • Exemplary modified nucleotides are 5 -fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5 -(carboxy hydroxymethyl) uracil, carboxymethylaminomethyl-2-thiouridine, 5 -carboxymethylaminomethyluracil, dihydrouracil, N 6 -substituted adenine, 7-methylguanine, 5 -methylaminomethyluracil, 5-methoxyaminomethyl- 2-thiouracil, beta-D-mannosylqueosine, 5 "-methoxy carboxymethyluracil, 5-methoxyuracil, 2- methylthio-N 6 -isopentenyladenine, uracil-5-oxyacetic acid (v), wylcyto
  • Vectors comprising polynucleotides encoding for the anti-PSMA antibodies
  • Vectors comprising DNA encoding the anti-PSMA antibody or antigen binding fragment of the disclosure are also provided.
  • the disclosed vectors can be used, for example, to generate any of the above disclosed anti-PSMA antibody, or antigen binding fragment thereof.
  • Polynucleotides encoding any of the anti-PSMA antibody or antigen binding fragment thereof of the disclosure may be incorporated into vectors using standard molecular biology methods.
  • the disclosure provides an expression vector comprising the polynucleotide of the invention.
  • Such vectors may be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon-based vectors or any other vector suitable for introduction of the synthetic polynucleotide of the invention into a given organism or genetic background by any means.
  • the vector of the disclosure may be an expression vector for the efficient synthesis of PSMA antibody polypeptide and expression of the PSMA antibody polypeptide of the disclosure in prokaryotic and eukaryotic systems, including but not limited to yeast and mammalian cell culture.
  • Exemplary vectors that may be used are Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene, La Jolla, Calif, USA); pTrc99A, pKK223-3, pKK233-3, pDR540, and pRIT5 (Pharmacia, Uppsala, Sweden).
  • Eukaryotic pWLneo, pSV2cat, pOG44, PXR1, pSG (Stratagene) pSVK3, pBPV, pMSG and pSVL (Pharmacia), pEE6.4 (Lonza) and pEE12.4 (Lonza).
  • Additional vectors include the pUC series (Lermentas 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).
  • Bacteriophage vectors such as XGT10, XGT11, XEMBL4, and XNM1149, XZapII (Stratagene) can be used.
  • Exemplary plant expression vectors include pBIOl, pBI01.2, pBI121, pBI101.3, and pBIN19 (Clontech).
  • Exemplary animal expression vectors include pEUK-Cl, pMAM, and pMAMneo (Clontech).
  • the expression vector may be a viral vector, e.g., a retroviral vector, e.g., a gamma retroviral vector.
  • the vector of the disclosure may contain a promoter and an enhancer sequence.
  • Polynucleotides encoding the PSMA binding proteins of the disclosure may be operably linked to control sequences in the expression vector(s) that ensure the expression of the PSMA binding proteins.
  • Such regulatory elements may include a transcriptional promoter, sequences encoding suitable mRNA ribosomal binding sites, and sequences that control the termination of transcription and translation.
  • Expression vectors may also include one or more non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' flanking nontranscribed sequences, 5' or 3' nontranslated sequences (such as necessary ribosome binding sites), a polyadenylation site, splice donor and acceptor sites, or transcriptional termination sequences.
  • an origin of replication that confers the ability to replicate in a host may also be incorporated.
  • Vectors of the disclosure may also contain one or more Internal Ribosome Entry Site(s) (IRES).
  • IRES Internal Ribosome Entry Site
  • the vector system will include one or more polyadenylation sites (e.g., SV40), which may be upstream or downstream of any of the aforementioned nucleic acid sequences.
  • Vector components may be contiguously linked or arranged in a manner that provides optimal spacing for expressing the gene products (i.e., by the introduction of “spacer” nucleotides between the ORFs) or positioned in another way.
  • Regulatory elements such as the IRES motif, may also be arranged to provide optimal spacing for expression.
  • Vectors of the disclosure may be circular or linear. They may be prepared to contain a replication system functional in a prokaryotic or eukaryotic host cell. Replication systems can be derived, e.g., from ColEl, SV40, 2p plasmid, X, bovine papilloma virus, and the like.
  • the recombinant expression vectors can be designed for either transient expression, for stable expression, or for both. Also, the recombinant expression vectors can be made for constitutive expression or for inducible expression.
  • the vectors may also comprise selection markers, which are well known in the art.
  • Selection markers include positive and negative selection marker.
  • Marker genes include biocide resistance, e.g., resistance to antibiotics, heavy metals, etc., complementation in an auxotrophic host to provide prototrophy, and the like.
  • Exemplary marker genes include antibiotic resistance genes (e.g., neomycin resistance gene, a hygromycin resistance gene, a kanamycin resistance gene, a tetracycline resistance gene, a penicillin resistance gene, histidinol resistance gene, histidinol x resistance gene), glutamine synthase genes, HSV-TK, HSV-TK derivatives for ganciclovir selection, or bacterial purine nucleoside phosphorylase gene for 6-methylpurine selection (Gadi et al., 7 Gene Then. 1738-1743 (2000)).
  • a nucleic acid sequence encoding a selection marker or the cloning site may be upstream or downstream of a nucleic acid sequence encoding a polypeptide of interest or cloning site.
  • the disclosure also provides for a host cell comprising any of the vectors of the disclosure.
  • “Host cell” refers to a cell into which a vector has been introduced. It is understood that the term host cell is intended to refer not only to the particular subject cell but to the progeny of such a cell, and also to a stable cell line generated from the particular subject cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not be identical to the parent cell but are still included within the scope of the term “host cell” as used herein. Such host cells may be eukaryotic cells, prokaryotic cells, plant cells or archeal cells.
  • Escherichia coli, bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species are examples of prokaryotic host cells.
  • Other microbes, such as yeast, are also useful for expression. Saccharomyces (e.g., S. cerevisiae) and Pichia are examples of suitable yeast host cells.
  • Exemplary eukaryotic cells may be of mammalian, insect, avian or other animal origins.
  • Mammalian eukaryotic cells include immortalized cell lines such as hybridomas 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) murine cell lines.
  • An exemplary human myeloma cell line is U266 (ATTC CRL-TIB-196).
  • Other useful cell lines include those derived from Chinese Hamster Ovary (CHO) cells such as CHO-K1SV (Lonza Biologies, Walkersville, MD), CHO-K1 (ATCC CRL-61) or DG44.
  • the disclosure provides recombinant host cells containing any of the expression vectors of the disclosure.
  • Nucleic acids encoding any of the PSMA binding proteins or fragments thereof can be used for transformation of a suitable mammalian host cell. Host cell transformation, culture, antibody expression and purification are done using well known methods.
  • Cell lines may be selected based on high level of expression of the PSMA antibody of interest and minimal contamination from host cell proteins.
  • Mammalian cell lines available as host cells for expression are well known in the art and include, but are not limited to from Chinese Hamster Ovary (CHO) cells such as CHO-K1 SV (Lonza Biologies, 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 antibody or antibody fragment of the disclosure by culturing the cells under conditions suitable for expression of the antibody and purifying the antibody from the host cell or medium surrounding the host cell.
  • CHO Chinese Hamster Ovary
  • the disclosure also provides a method of producing the anti-PSMA binding protein of the disclosure comprising culturing the host cell of the disclosure in conditions that the anti- PSMA binding protein is expressed, and recovering the anti-PSMA antibody binding protein produced by the host cell using well known methods in the art.
  • a subject protein may be substantially pure, e.g., at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or at least about 98% to 99%, or more, pure, e.g., free from contaminants such as cell debris, macromolecules, etc. other than the subject protein.
  • the disclosure also provides antibody drug conjugates (ADCs) and radioconjugates comprising the anti-PSMA antibodies of the disclosure.
  • ADCs antibody drug conjugates
  • the antibodies or antigen binding fragment thereof of the disclosure may be conjugated with pharmaceutically active moieties or diagnostic moieties to form an “antibody drug conjugate” (ADC), or a “radioconjugate”.
  • ADCs or radioconjugates of the disclosure may be used to deliver cytotoxins or other payloads to the target location.
  • antibody drug conjugate is used broadly and refers to an antibody, or antigen binding fragments thereof, conjugated to (e.g., covalently associated) a second molecule such as any pharmaceutically active moiety, a therapeutic moiety, a toxin, or a drug.
  • targeting ligand refers to any molecule that provides an enhanced affinity for a selected target, e.g., an antigen, a cell, cell type, tissue, organ, region of the body, or a compartment (e.g., a cellular, tissue or organ compartment).
  • Targeting ligands include, but are not limited to, antibodies or antigen binding fragments thereof, aptamers, polypeptides, and scaffold proteins.
  • a targeting ligand is a polypeptide.
  • the targeting ligand is an antibody or antigen binding fragment thereof, engineered domain, or scaffold protein.
  • the targeting ligand may serve as a shuttle to deliver a payload to a specific site, which is defined by the target recognized by said targeting ligand.
  • a targeting ligand for instance, targeting a receptor, delivers its payload to a site which is characterized by abundance of said receptor.
  • the targeting ligand is an anti-PSMA antibody or fragment thereof conjugated to pharmaceutical active moiety and capable of delivering a payload to a site which is characterized by the abundance of PSMA.
  • payload represents any naturally occurring or synthetically generated molecule, including small-molecular weight molecules or chemical entities that can chemically be synthesized, and larger molecules or biological entities that need to be produced by fermentation of host cells and that confer a novel functionality to a targeting ligand specific for binding to targets or antigens.
  • payload include but are not limited to drugs, toxins, cytokines, markers, oligonucleotides, antisense, small interfering RNAs oligonucleotides (siRNAs), or the like, for the generation of site-specifically conjugated antibody drug conjugates (ADCs).
  • the payload may also be a radiometal complex or a radio metal ion as described below.
  • a “drug” or “warhead” may be used interchangeably and will mean a biologically active or detectable molecule or compound, including anti-cancer agents as described below.
  • a “payload” may comprise a drug or warhead in combination with an optional linker compound.
  • the warhead on the conjugate may comprise peptides, proteins, prodrugs which are metabolized to an active agent in vivo, polymers, nucleic acid molecules, small molecules, binding agents, mimetic agents, synthetic drugs, inorganic molecules, organic molecules and radioisotopes.
  • the disclosed ADCs or radioconjugates will direct the bound payload to the target site in a relatively unreactive, non-toxic state before releasing and activating the payload.
  • This targeted release of the payload is preferably achieved through stable conjugation of the payloads via residue-specific or site-specific conjugation as describe below, and the relatively homogeneous composition of the ADC or radioconjugate preparations which minimize over-conjugated toxic species.
  • the disclosure comprises payloads of therapeutic moieties (e.g., cytotoxins), or other payloads such as diagnostic agents.
  • the selected payload may be covalently or non-covalently linked to the antibody and exhibit various stoichiometric molar ratios depending, at least in part, on the method used to affect the conjugation.
  • the conjugates of the disclosure may be represented by the formula: Ab-[L-D]n or a pharmaceutically acceptable salt thereof wherein a) Ab comprises an anti-PSMA antibody or antigen binding fragment thereof disclosed herein; b) L comprises an optional linker; c) D comprises a drug moiety or chelator; and d) n is an integer from about 1 to about 20.
  • compatible linkers will confer stability on the ADCs or radioconjugate in the extracellular environment, prevent aggregation of the ADC molecules or radioconjugate and keep the ADC and radioconjugate freely soluble in aqueous media and in a monomeric state.
  • the ADC or radioconjugate Before transport or delivery into a cell, the ADC or radioconjugate is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety. While the linkers are stable outside the target cell they are designed to be cleaved or degraded at some efficacious rate inside the cell.
  • 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 has been delivered or transported to its targeted site; and (iv) maintain a cytotoxic, cell-killing effect or a cytostatic effect of the drug moiety.
  • the stability of the ADC or radioconjugate may be measured by standard analytical techniques such as mass spectroscopy, hydrophobic interaction chromatography (HIC), HPLC, and the separation/analysis technique LC/MS.
  • analytical techniques such as mass spectroscopy, hydrophobic interaction chromatography (HIC), HPLC, and the separation/analysis technique LC/MS.
  • the anti-PSMA antibody or antigen binding fragment thereof of the disclosure is conjugated to one or more therapeutic moiety or a drug such as an anticancer agent including, but not limited to, cytotoxic agents, cytostatic agents, anti-angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapeutic agents, targeted anti-cancer agents, biological response modifiers, cancer vaccines, cytokines, hormone therapies, oligonucleotides, antisense, siRNAs, anti-metastatic agents and immunotherapeutic agents.
  • the anti-PSMA antibody or antigen binding fragment thereof of the 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.
  • cytotoxic drugs 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).
  • the toxins may achieve their cytotoxic and cytostatic effects by 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 A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa ⁇ , ricin A chain, abrin A chain, modeccinAchain, alpha-sarcin, Aleuritesfordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • exotoxin A chain from Pseudomonas aeruginosa ⁇ , ricin A chain, abrin A chain, modeccinAchain, alpha-sarcin, Aleuritesfordii proteins, dianthin proteins, Phyto
  • the anti-PSMA antibody or antigen binding fragment thereof provided herein is conjugated to one or more drugs.
  • exemplary drugs include a maytansinoid (see, e.g., U.S. Patent No. 5,208,020, 5,416,06); an auristatin such as monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see, e.g., U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298), a dolastatin, a calicheamicin or derivative thereof (see, e.g., U.S. Patent Nos.
  • the anti-PSMA antibodies or antigen binding fragments thereof of the disclosure is conjugated to a radiometal ion to form radioconjugates.
  • 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 radiometal or conjugated to a radiometal complex.
  • a radioconjugate refers to at least one radiometal complex joined, e.g., bound via a covalent bond, to an antibody or antigen binding domain.
  • a radioconjugate may comprise at least one radiometal complex that comprises a linker, wherein the radiometal complex is joined to the antibody or antigen binding domain via the linker.
  • a “radiometal complex” as used herein refers to a complex comprising a radiometal ion associated with a chelator. Typically, a radiometal ion is bound to or coordinated to a chelator via coordinate bonding.
  • the chelator is a macrocycle compound. Heteroatoms of the macrocyclic ring can participate in coordinate bonding of a radiometal ion to a chelator.
  • a chelator can be substituted with one or more substituent groups, and the one or more substituent groups can also participate in coordinate bonding of a radiometal ion to a chelator in addition to, or alternatively to the heteroatoms of the macrocyclic ring.
  • radioactive ion refers to one or more isotopes of the elements that emit particles and/or photons. Any radiometal ion known to those skilled in the art in view of the present disclosure can be used in the invention. Exemplary radioactive isotopes may be y-emitting, Auger-emitting, P-emitting, alpha-emitting or positronemitting radioactive isotope.
  • radioactive isotopes include 3 H, n 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, " m 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.
  • Exemplary metal atoms are metals with an atomic number greater than 20, such as calcium atoms, scandium atoms, titanium atoms, vanadium atoms, chromium atoms, manganese atoms, iron atoms, cobalt atoms, nickel atoms, copper atoms, zinc atoms, gallium atoms, germanium atoms, arsenic atoms, selenium atoms, bromine atoms, krypton atoms, rubidium atoms, strontium atoms, yttrium atoms, zirconium atoms, niobium atoms, molybdenum atoms, technetium atoms, ruthenium atoms, rhodium atoms, palladium atoms, silver atoms, cadmium atoms, indium atoms, tin atoms, antimony atoms, tellurium atoms, iodine
  • the radiometal ion is a “therapeutic emitter,” meaning a radiometal ion that is useful in therapeutic applications such as to damage cells, such as cancer cells.
  • a suitable radiometal for use as a therapeutic agent is one that is capable of reducing or inhibiting the growth of, or in particular killing, a cancer cell, such as a prostate cancer cell.
  • High energy radiometal selected to target cancer cells preferably acts over a short range so that the cytotoxic effects are localized to the targeted cells.
  • the radioconjugates of the disclosure can deliver a cytotoxic payload with the ability to emit alpha and/or beta particles in the vicinity of a tumor by binding onto cancer cells’ surface antigens and initiating cell death. Radiotherapy is thus delivered in a more localized fashion to decrease damage to non-cancerous cells.
  • radiometal ions suitable for use to generate the radioconjugates of the 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, "Tc, 105 Rh, 109 Pd, in Ag, i n In, 117 Sn, , 149 Tb, 152 Tb, 155 Tb, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 177 LU, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 BI, 213 BI, 223 Ra, 225 Ac, 227 Th, and 255 Fm.
  • the radiometal ion is a “therapeutic emitter,” meaning a radiometal ion that is useful in therapeutic applications.
  • therapeutic emitters include, but are not limited to, beta 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 Er, 177 LU, 186 Re, 188 Re, 194 Ir, 198 Au, 199 Au, 211 At, 212 Pb, 212 BI, 213 BI, 223 Ra, 225 Ac, 255 Fm and 227 Th, 226 Th, 230 U.
  • the radiometal ion used as a therapeutic agent is an alphaemitting radiometal ion, such as actinium-225 ( 225 Ac).
  • 225 Ac alphaemitting radiometal ion
  • the 10-day half-life of 225 Ac is long enough to facilitate radio-conjugate production, but short enough to match the circulation pharmacokinetics of delivery vehicles such as antibodies.
  • 225 Ac radioimmunoconjugates are of particular interest.
  • 225 Ac decays in a series of steps that ultimately emits 4 alpha particles before reaching a stable isotope
  • Radiometals may be used as an imaging agents or detectable label.
  • Radionuclides used to radiolabel 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-i l l, 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, cerium-134 and actinium-225.
  • radiometal used as an imaging agents or detectable label is Cerium 134 ( 134 Ce).
  • the radiometal used as an imaging agents or detectable label is Indium 111 ( in In) or Xenon 134 ( 134 Xe).
  • the radiometal ion is conjugated to the isolated antibody or the antigen binding fragment thereof of the disclosure using known methods.
  • the radiometal ion is conjugated to the antibody or antigen binding fragment of the disclosure with a linker.
  • the radiometal ion is complexed with a chelating agent or a chelator.
  • the anti-PSMA antibodies or antigen binding fragments thereof of the disclosure is conjugated to (i.e., covalently linked to) chelators and radiometal complexes to produce radioimmunoconjugates that are suitable, for example, for medicinal applications in subjects, e.g., humans, such as targeted radiotherapy.
  • the anti-PSMA antibodies or antigen binding fragments thereof of the disclosure is conjugated to (i.e., covalently linked to) chelators and radiometal complexes to produce radioimmunoconjugates that are suitable for detection.
  • the term “chelator” or “chelanf ’ refers to a chemical compound to which a radionuclide or radiometal, can be chelated via coordinate bonding to form a radiometal complex.
  • the chelator is a macrocyclic ring containing one or more heteroatoms, e.g., oxygen and/or nitrogen as ring atoms.
  • the chelator comprises a macrocyclic chelating moiety.
  • macrocyclic chelating moieties include, without limitation, 1,4,7,10- tetraazacyclododecane- 1,4, 7, 10, tetraacetic acid (DOTA), S-2-(4-isothiocyanatobenzyl)-l,4,7- triazacyclononane-l,4,7-triacetic acid (NOTA), l,4,8,l l-tetraazacyclodocedan-l,4,8,l l- tetraacetic acid (TETA), 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),l l,13-triene-4-(S)-(4- isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA), 5-S-(4-aminobenzyl)-l-oxa-4,7,10- triaza
  • the chelator is 1,4, 7, 10-tetraazacyclododecane-l, 4, 7, 10, tetraacetic acid (DOTA).
  • the chelator is S-2-(4-isothiocyanatobenzyl)-l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA).
  • the chelator is 1,4,8, 11-tetraazacyclodocedan-l, 4,8,11- tetraacetic acid (TETA).
  • the chelator is 3,6,9,15-tetraazabicyclo[9.3.1]- pentadeca-l(15),l l,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (PCTA).
  • PCTA 4,6,9-triacetic acid
  • the chelator is 5-S-(4-aminobenzyl)-l-oxa-4,7,10- triazacyclododecane-
  • the chelator is DOTA, DFO, DTP A, NOTA, TETA, DTP A, or HOPO.
  • the chelator is DOTA (1,4,7,10-Tetraazacyclododecane-
  • the chelator is H2bpl8c6 (N,N’-bis[(6-carboxy-2- pyridil)methyl]-4,13-diaza-18-crown-6) or a H2bpl8c6 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.
  • the radioconjugate of the present disclosure comprises a radiometal ion chelated to a chelator described in WO2020/229974 which is incorporated herein by reference in its entirety.
  • the chelator has the structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein: each of ring A and ring B is independently a 6-10 membered aryl or a 5-10 membered heteroaryl each of Zi and Z2 is independently -(C(Ri2)2)m- or -(CH2)n-C(Ri2)(X)-(CH2)n-; each of R14, R15, R16, and R17 is independently hydrogen, alkyl, or X, or alternatively R14 and R15 and/or Ri6 and R17 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl ring optionally substituted with X; each X is independently -L1-R4;
  • R4 is a nucleophilic moiety or an electrophilic moiety, or R4 comprises a targeting ligand; and Li is absent or a linker.
  • the radioconjugate of the disclosure comprises a radiometal ion chelated to a compound of formula (II)
  • Ri is hydrogen and R2 is -L1-R4; alternatively, Ri is -L1-R4 and R2 is hydrogen;
  • R3 is hydrogen; alternatively, R2 and R3 are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered cycloalkyl, wherein the 5- or 6-membered cycloalkyl is optionally substituted with -L1-R4;
  • Li is absent or a linker
  • R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand.
  • Li is absent.
  • R4 is directly bound (e.g., via covalent linkage) to the compound.
  • the radioconjugate comprises a radiometal ion chelated to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:
  • Li is absent or a linker; and R4 is a nucleophilic moiety, an electrophilic moiety, or a targeting ligand.
  • Chelators of the disclosure can be produced by any method known in the art in view of the present disclosure.
  • the pendant aromatic/heteroaromatic groups can be attached to the macrocyclic ring portion by methods known in the art, such as those exemplified and described below.
  • the disclosure also provides a chelator, preferably a chelator to which radiometal ions can be chelated via coordinate bonding.
  • an “antibody-chelator complex” or “conjugate intermediate” refers to a precursor of a radioconjugate, which comprises an antibody, or antigen binding domain, that is conjugated (joined, e.g., bound via a covalent bond) to a chelator that does not comprise a radiometal.
  • a conjugate intermediate may comprise a linker, wherein the chelator is joined to the antibody or antigen binding domain via the linker. After a radiometal is chelated to the chelator of a conjugate intermediate, it becomes a radioconjugate.
  • “DOTA- mAb” refers to a conjugate intermediate comprising a DOTA conjugated to an antibody.
  • any of the chelators described herein can comprise a radiometal ion.
  • the radiometal ion is an alpha-emitting radiometal ion.
  • the radiometal is 225 Ac.
  • the radiometal ion is a gamma-emitting radiometal ion.
  • the radiometal is n i In.
  • the radiometal is 134 Ce. Chelators of the disclosure can robustly chelate radiometal ions, particularly 225 Ac at any specific activity irrespective of metal impurities, thus forming a radiometal complex having high chelation stability in vivo and in vitro and which is stable.
  • Radiometal complexes can be produced by any method known in the art in view of the present disclosure.
  • a chelator of the invention can be mixed with a radiometal ion and the mixture incubated to allow for formation of the radiometal complex.
  • a chelator is mixed with a solution of 225 Ac(NO3)3 to form a radiocomplex comprising 225 Ac bound to the chelator via coordinate bonding.
  • Chelators of in the invention efficiently chelate radiometals, particularly 225 Ac.
  • a chelator of the invention is mixed with a solution of 225 Ac ion at a ratio by concentration of chelator to 225 Ac ion of 1 :1000, 1:500, 1 :400, 1 :300, 1:200, 1:100, 1:50, 1 :10, or 1 :5, preferably 1:5 to 1:200, more preferably 1:5 to 1 :100.
  • the radiocomplex can be characterized by instant thin layer chromatography (e.g., iTLC-SG), HPLC, LC-MS, etc.
  • the (ADCs) of the disclosure comprise a linker that links the anti-PSMA antibodies and antigen binding fragment thereof of the disclosure to a drug moiety or a chelator.
  • linker compounds can be used to conjugate the antibodies of the disclosure to the relevant drug or chelator.
  • linkers will covalently bind with the reactive residue (preferably a cysteine or lysine) and the selected drug compound.
  • the reactive residue preferably a cysteine or lysine
  • linker refers to a chemical moiety that joins a chelator or a drug to an antibody or antigen binding domain. Any suitable linker known to those skilled in the art in view of the present disclosure can be used to conjugate the antibodies of the disclosure to the relevant drug. Preferably, linkers will covalently bind with a reactive residue of the antibody. Accordingly, any linker that reacts with a selected antibody residue and may be used to provide the relatively stable conjugates (site-specific or otherwise) of the instant disclosure is compatible with the teachings herein. Ideally, linkers are designed to largely release the drug once it has been delivered to the tumor site, substantially reducing undesirable non-specific toxicity by minimizing exposure of non-targeted cells and tissue to the cytotoxic drug, thereby providing an enhanced therapeutic index.
  • the linkers can contain, for example, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl moiety, a substituted or unsubstituted aryl or heteroaryl, a polyethylene glycol (PEG) linker, a peptide linker, a sugar-based linker, or a cleavable linker, such as a disulfide linkage or a protease cleavage site such as valine-citrullinep-aminobenzyl (PAB).
  • PEG polyethylene glycol
  • PAB valine-citrullinep-aminobenzyl
  • the linker may be composed of one or more linker components.
  • exemplary linker components include 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valinecitrulline (“val-cif ’), alanine-phenylalanine (“alaphe”), p-aminobenzyloxycarbonyl (“PAB”), N- Succinimidyl 4-(2-pyridylthio) pentanoate (“SPP”), N-Succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1 carboxylate (“SMCC”), and N-Succinimidyl (4-iodo-acetyl) aminobenzoate (“SIAB”).
  • MC 6-maleimidocaproyl
  • MP maleimidopropanoyl
  • val-cif valinecitrulline
  • alaphe alanine-phenylalanine
  • PAB p-aminobenz
  • the linker is valinecitrullin-p-aminobenzyloxycaronyl (“vc- PAB”).
  • the linker may comprise amino acid residues.
  • Exemplary amino acid linker components include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide.
  • Exemplary dipeptides include: valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala- phe).
  • Exemplary tripeptides include: glycine- valine-citrulline (gly-val-cit) and glycine-glycine- glycine (gly-gly-gly).
  • Amino acid residues which comprise an amino acid linker component include those occurring naturally, as well as minor amino acids and non-naturally occurring amino acid analogs, such as citrulline.
  • Amino acid linker components can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzymes, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • a chelator or chelator-linker comprises a nucleophilic moiety or an electrophilic moiety. Reaction of the nucleophilic group or electrophilic group of a chelator or chelator-linker with an antibody or antigen binding domain comprising the corresponding reaction partner allows for covalent linkage of the antibody or antigen binding domain to the chelator-linker.
  • Conjugation reactions involving reduced cysteines and lysines include, but are not limited to, thiol-maleimide, thiol-halogeno (acyl halide), thiol-ene, thiolyne, thiol-vinylsulfone, thiol-bisulfone, thiol-thiosulfonate, thiol-pyridyl disulfide and thiolparafluoro reactions.
  • Exemplary linker structures suitable for use in the disclosure also include, but are not limited to: and wherein m is an integer of 0 to 12.
  • compatible linkers will confer stability on the ADCs in the extracellular environment, prevent aggregation of the ADC molecules and keep the ADC freely soluble in aqueous media and in a monomeric state.
  • the ADC Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety. While the linkers are stable outside the target cell they are designed to be cleaved or degraded at some efficacious rate inside the cell. Accordingly 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.
  • the stability of the ADC may be measured by standard analytical techniques such as mass spectroscopy, hydrophobic interaction chromatography (HIC), HPLC, and the separation/analysis technique LC/MS.
  • a drug moiety, chelator or chelator-linker comprises a nucleophilic moiety or an electrophilic moiety. Reaction of the nucleophilic group or electrophilic group of a chelator or chelator-linker with an antibody or antigen binding domain comprising the corresponding reaction partner allows for covalent linkage of the antibody or antigen binding domain to the drug moiety, chelator, or chelator-linker.
  • nucleophilic groups include, but are not limited to, azides, amines, and thiols.
  • electrophilic groups include, but are not limited to amine-reactive groups, thiol-reactive groups, alkynyls and cycloalkynyls.
  • An amine-reactive group preferably reacts with primary amines, including primary amines that exist at the N-terminus of each polypeptide chain and in the sidechain of lysine residues.
  • amine-reactive groups include, but are not limited to, N- hydroxy succinimide (NHS), substituted NHS (such as sulfo-NHS), isothiocyanate (-NCS), isocyanate (-NCO), esters, carboxylic acid, acyl halides, amides, alkylamides, and tetra- and per-fluoro phenyl ester.
  • a thiol-reactive group reacts with thiols, or sulfhydryls, preferably thiols present in the side-chain of cysteine residues of polypeptides.
  • thiol-reactive groups include, but are not limited to, Michael acceptors (e.g., mal eimide), haloacetyl, acyl halides, activated disulfides, and phenyloxadiazole sulfone.
  • Residue specific conjugation may be achieved through residue-specific methods (random conjugation) such as acylation of amines on lysine residues and alkylation of thiols on cysteine residues.
  • residue specific methods for conjugation include, but are not limited to, conjugation of a drug moiety, chelator, linker and/or radiometal complex to lysine residues of the antibody using a drug moiety, chelator, linker, or radiometal complex comprising, e.g., an activated ester or isothiocyanate group; conjugation of a drug moiety, chelator, linker and/or radiometal complex to cysteine residues of the antibody using a drug moiety, chelator, linker, or radiometal complex comprising, e.g., a maleimide, haloacetyl derivative, acyl halide, activated disulfide group, or methylsulfonyl phenyloxadiazole group; conjugation of a drug moiety, chelator, linker and/or radiometal complex to tyrosine resides of the antibody using a drug moiety, chelator, linker, or radiometal complex comprising
  • Residue-specific methods for conjugation to proteins are well established and most commonly involve either lysine side chains, using an activated ester or isothiocyanate, or cysteine side chains with a maleimide, haloacetyl derivative or activated disulfide (Brinkley Bioconjugate Chem 1992:2). Since most proteins have multiple lysine and cysteine residues, heterogeneous mixtures of product with different numbers of conjugated molecules at a variety of amino acid positions are typically obtained using such methods. Additional methods have been established including tyrosine-specific conjugation (Ban et al. Bioconjugate Chemistry 2013:520), methionine-specific methods (Lin et al. Science 2017 (355) 597), additional cysteine-focused approaches (Toda et al. Angew Chemie 2013:12592), and others.
  • the PSMA antibody or antibody fragment thereof of the disclosure can be conjugated to any of the radiometal complexes described herein through one or more Lysine residues of the antibody.
  • the ADCs or radioconjugates of the disclosure may be generated through conjugation of a drug moiety, chelator, linker, or radiometal complex to solvent-exposed amino groups of lysine residues present in the selected antibody.
  • Conjugation reactions involving lysines include, but are not limited to, isothiocyanate, NHS-ester, sulfonyl fluorides, fluorosulfates, dichlorotriazines, activated esters, activated sulfonamides, vinyl sulfonamides, imidoesters, isothiocyanates, salicylaldehydes, iminoboronates and a,p- unsaturated carbonyls.
  • the ADCs or radioconjugates of the disclosure may be generated through reactions exploiting sulfhydryl groups of cysteines residues present in the selected antibody.
  • Particularly preferred embodiments will comprise conjugation of antibodies comprising one or more free cysteines.
  • Conjugation reactions involving reduced cysteines include, but are not limited to, thiol-maleimide, thiol-halogeno (acyl halide), thiol-ene, thiolyne, thiol-vinylsulfone, thiol-bisulfone, thiol-thiosulfonate, thiol-pyridyl disulfide and thiolparafluoro reactions.
  • antibodies prior to conjugation, antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or (tris(2-carboxyethyl)phosphine (TCEP).
  • a reducing agent such as dithiothreitol (DTT) or (tris(2-carboxyethyl)phosphine (TCEP).
  • reactive thiol groups may be introduced into the selected antibody (or fragment thereof) by introducing one, two, three, four, or more free cysteine residues.
  • conjugation methodology may include full or partial reduction of each of the intrachain or interchain antibody disulfide bonds to provide conjugation sites.
  • free cysteines may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or (tris (2-carboxyethyl)phosphine (TCEP).
  • DTT dithiothreitol
  • TCEP tris (2-carboxyethyl)phosphine
  • conjugation of drug moiety, chelator and/or linker to the antibody or antigen binding fragment of the disclosure may be achieved through site-specific conjugation.
  • transglutaminase may be used to attach the drug moiety, chelator and/or linker to the antibody or antigen binding fragment of the disclosure.
  • Transglutaminases are enzymes that catalyzes the formation of an isopeptide bond between a free amine group on a payload and the acyl group on the side chain of a glutamine residue in an antibody or antigen binding fragment thereof.
  • Transglutaminases are protein-glutamine y- glutamyltransferases (EC 2.3.2.13), which typically catalyze pH-dependent transamidation of glutamine residues with lysine residues.
  • transglutaminases include, but are not limited to, microbial transglutaminase (mTG), human transglutaminase, tissue transglutaminase (tTG), and Factor XIII.
  • human transglutaminases include, but are not limited to, keratinocyte transglutaminase (Uniprot P22735), tissue transglutaminase (UniProt P21980), epidermal transglutaminase and prostate transglutaminase. These enzymes can be from either natural or recombinant sources.
  • Glutamine and lysine amino acids in a peptide or polypeptide can be substrates for transglutaminase crosslinking.
  • the payload can be linked to a linker comprising a lysine.
  • the transglutaminase can be any transglutaminase deemed suitable by those of skill in the art.
  • the transglutaminase can be obtained or made from a variety of sources.
  • the transglutaminase is a calcium dependent transglutaminase which requires calcium to induce enzyme conformational changes and allow enzyme activity.
  • transglutaminase can be derived from guinea pig liver and obtained through commercial sources (e.g., Sigma-Aldrich (St Louis, MO) and MP Biomedicals (Irvine, CA)).
  • the transglutaminase is derived from a fungal protein (e.g., Oomycetes, Actinomycetes, Saccharomyces, Candida, Cryptococcus, Monascus, or Rhizopus transglutaminases).
  • the transglutaminase polypeptide is derived from Myxomycetes (e.g., Physarum polycephalum transglutaminase).
  • the mTGase polypeptide is derived from a bacterial protein, such as transglutaminase from, but not limited to, Streptoverticillium mobarensis, Streptoverticillium griseocameum, Streptoverticillium ladakanum, Streptomyces mobarensis, Streptomyces viridis, Streptomyces ladakanum, Streptomyces caniferus, Streptomyces platensis, Streptomyces hygroscopius, Streptomyces netropsis, Streptomyces fradiae, Streptomyces roseovertivillatus, Streptomyces cinnamaoneous, Streptomyces griseocameum, Streptomyces lavendulae, Streptomyces lividans, Streptomyces lydicus, Streptomyces sioyansis, Actinomadura sp., Bacillus (e.
  • transglutaminase can also be a recombinant protein produced using recombinant techniques known to persons skilled in the art.
  • the transglutaminase used in the invention described herein can be a purified protein.
  • the antibody or antigen binding fragment of the disclosure is conjugated at Gln295, in the CH2 domain, using transglutaminase to generate the ADC, immunoconjugate or radioimmunoconjugate of the disclosure.
  • the antibody or antigen binding fragment of the disclosure is modified before conjugation with transglutaminase.
  • the antibody or antigen binding fragment of the disclosure used to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure comprises a substitution at position 302 of the heavy chain.
  • Such substitution can be, for example, V302S, V302A, V302I, V302L, V302M, V302T, V302F, and V302Y, preferably the amino acid substitutions V302A and V302S, wherein the amino acid numbering is according to the EU Index of Kabat.
  • the antibody or antigen binding fragment of the disclosure used to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure comprises the amino acid substitution V302A or V302S, optionally Y300L, and further comprises a glutamine substitution at heavy chain position 286, 287, 288, 289, 290, 293 or 294, preferably the amino acid substitution N286Q, A287Q, K288Q, T289Q, K290Q, E293Q or E294Q, wherein the amino acid numbering is according to the EU Index of Kabat.
  • the antibody or antigen binding fragment of the disclosure used to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure comprises the amino acid substitution V302A or V302S and at least one of the amino acid substitutions E293Q and E294Q, wherein the amino acid numbering is according to the EU Index of Kabat.
  • the antibody or antigen binding fragment of the disclosure used to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure comprises the amino acid substitution V302A or V302S and further comprises a glutamine substitution at heavy chain position 286, 287, 288, 289, 290, 293 or 294, such as the amino acid substitution N286Q, A287Q, K288Q, T289Q, K290Q, E293Q or E294Q, and/or an alanine substitution at heavy chain position 241, 243, 294 or 301, such as F241 A, F243A, E294A or R301A.
  • the antibody or antigen binding fragment of the disclosure conjugated with transglutaminase to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure is glycosylated or is a glycan intact antibody or its glycan content is unchanged compared to the native antibody.
  • the antibody or antigen binding fragment of the disclosure conjugated with transglutaminase to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure is glycosylated at position N297 or the glycan content of the antibody or antigen binding fragment thereof at position N297 is unchanged compared to the native antibody.
  • the method of producing the ADC, or radioconjugate of the disclosure comprises reacting a glycosylated or glycan intact antibody or antigen binding fragment of the disclosure with an amine compound in the presence of transglutaminase in low- ionic strength conditions.
  • Low-ionic strength conditions include, but are not limited to, solutions comprising a salt concentration of about 25 mM or less, of about 20 mM or less, of about 15 mM or less, of about 10 mM or less.
  • the antibody or antigen binding fragment of the disclosure used to produce the ADC, immunoconjugate or radioimmunoconjugate of the disclosure is modified by trimming the antibody or antigen binding fragment thereof with a bacterial endoglycosidase specific for the 6-1 ,4 linkage between a core GlcNac residue in an Fc- glycosylation site of the antibody, such as GlycINATOR (Genovis), which leaves the inner most GlcNAc intact on the Fc, allowing for the site-specific incorporation of azido sugars at that site.
  • GlycINATOR Geneovis
  • the trimmed antibody or antigen binding fragment thereof can then be reacted with an azide-labeled sugar, such as UDP-N-azidoacetylgalactosamine (UDP-GalNAz) or UDP-6-azido 6-deoxy GalNAc, in the presence of a sugar transferase, such as GalT galactosyltransferase or GalNAc transferase, to thereby obtain the modified antibody or antigen binding fragment thereof.
  • an azide-labeled sugar such as UDP-N-azidoacetylgalactosamine (UDP-GalNAz) or UDP-6-azido 6-deoxy GalNAc
  • the antibody or antigen binding fragment thereof of the disclosure used for producing the immunoconjugate or radioimmunoconjugate of the disclosure is modified by deglycosylating the antibody or antigen binding fragment thereof with an amidase.
  • click chemistry may be used to attach the drug moiety, chelator and/or linker to the selected antibody of the disclosure.
  • click chemistry refers to a chemical philosophy introduced by Sharpless, describing chemistry tailored to generate covalent bonds quickly and reliably by joining small units comprising reactive groups together (see Kolb, et al., Angewandte Chemielnternational Edition (2001) 40: 2004-2021). Click chemistry does not refer to a specific reaction, but to a concept including, but not limited to, reactions that mimic reactions found in nature.
  • click chemistry reactions are modular, wide in scope, give high chemical yields, generate inert byproducts, are stereospecific, exhibit a large thermodynamic driving force to favor a reaction with a single reaction product, and/or can be carried out under physiological conditions.
  • a click chemistry reaction can be carried out under simple reaction conditions, uses readily available starting materials and reagents, uses non-toxic solvents or uses a solvent that is benign or easily removed, such as water, and/or provides simple product isolation by non-chromatographic methods, such as crystallization or distillation.
  • click chemistry reactions utilize reactive groups that are rarely found in naturally- occurring biomolecules and are chemically inert towards biomolecules, but when the click chemistry partners are reacted together, the reaction can take place efficiently under biologically relevant conditions, for example in cell culture conditions, such as in the absence of excess heat and/or harsh reagents.
  • click chemistry reactions require at least two molecules comprising click reaction partners that can react with each other.
  • click reaction partners that are reactive with each other are sometimes referred to herein as click chemistry handle pairs, or click chemistry pairs.
  • the click reaction partners are an azide and a strained alkyne, e.g.
  • the click reaction partners are reactive dienes and suitable tetrazine dienophiles.
  • trans-cyclooctene, norbornene, or biscyclononene can bepaired with a suitable tetrazine dienophile as a click reaction pair.
  • tetrazoles can act as latent sources of nitrile imines, which can pair with unactivated alkenes in the presence of ultraviolet light to create a click reaction pair, termed a “photo-click” reaction pair.
  • the click reaction partners are a cysteine and a maleimide.
  • a cysteine from a peptide e.g., GGGC (SEQ ID NO: 338)
  • a maleimide that is associated with a chelating agent (e.g., NOTA).
  • chelating agent e.g., NOTA
  • Other suitable click chemistry handles are known to those of skill in the art (see, e.g., Spicer et al., Selective chemical protein modification. Nature Communications. 2014; 5: p. 4740).
  • the click reaction partners are Staudinger ligation components, such as phosphine and azide.
  • the click reaction partners are Diels-Alder reaction components, such as dienes (e.g., tetrazine) and alkenes (e.g., trans-cyclooctene (TCO) or norbornene).
  • Diels-Alder reaction components such as dienes (e.g., tetrazine) and alkenes (e.g., trans-cyclooctene (TCO) or norbornene).
  • dienes e.g., tetrazine
  • alkenes e.g., trans-cyclooctene (TCO) or norbornene
  • TCO trans-cyclooctene
  • norbornene norbornene
  • a click chemistry reaction utilizes an azide group and an alkyne group, more preferably a strained alkyne group, e.g., cycloalkyne such as a cyclooctyne or cyclooctyne derivative, as the click chemistry pair or reaction partners.
  • the click chemistry reaction is a Huisgen cycloaddition or 1,3-dipolar cycloaddition between the azide (-N3) and alkyne moiety to form a 1,2,3-triazole linker.
  • Click chemistry reactions between alkynes and azides typically require the addition of a copper catalyst to promote the 1,3 -cycloaddition reaction, and are known as copper-catalyzed azidealkyne cycloaddition (CuAAC) reactions.
  • CuAAC copper-catalyzed azidealkyne cycloaddition
  • click chemistry reactions between cyclooctyne or cyclooctyne derivatives and azides typically do not require the addition of a copper catalyst, and instead proceed via strain-promoted azide-alkyne cycloaddition (SPAAC) (Debets, M.F., et al., Bioconjugation with strained alkenes and alkynes. Acc Chem Res, 2011. 44(9): p. 805-15).
  • SPAAC strain-promoted azide-alkyne cycloaddition
  • a radioimmunoconjugate can be produced by first preparing an immunoconjugate of the invention by covalently linking a chelator of the invention to an antibody or antigen-binding fragment thereof by, for example, a click chemistry reaction; the immunoconjugate can subsequently be labeled with a radiometal ion to produce a radioimmunoconjugate.
  • Radioimmunoconjugates produced by the methods described herein can be analyzed using methods known to those skilled in the art in view of the present disclosure.
  • LC/MS analysis can be used to determine the ratio of the chelator to the labeled polypeptide, e.g., antibody or antigen binding fragment thereof;
  • analytical size-exclusion chromatography can be used to determine the oligomeric state of the polypeptides and polypeptide conjugates, e.g., antibody and antibody conjugates;
  • radiochemical yield can be determined by instant thin layer chromatography (e.g., iTLC-SG), and radiochemical purity can be determined by sizeexclusion HPLC.
  • the term “drug-to-antibody ratio (DAR)” or “chelator antibody ratio (CAR)” refers, to the number of drug-linker molecules per antibody molecule or the number of chelator molecules per antibody.
  • the DAR can be measured by intact mass analysis using RP-HPLC with online mass analysis.
  • the average DAR of a conjugate intermediate of the disclosure is from about 1 to about 10, or from 1 to about 9, or from 1 to about 8, of from about 1 to about 7, or from about 1 to about 6, or from about 1 to about 5, or from about 1 to about 4, or from about 1 to about 3, or from about 2 to about 4, or from about 2 to about 3.
  • a conjugate preparation may be substantially homogeneous with respect to its DAR distribution, meaning that within the preparation is a predominant species of site-specific ADC with a particular DAR that is also uniform with respect to the site of loading (i.e., on the free cysteines).
  • site-specific antibodies or selective combination.
  • desired homogeneity may be achieved through the use of site-specific constructs in combination with selective reduction.
  • the preparations may be further purified using analytical or preparative chromatography techniques.
  • the homogeneity of the ADC sample can be analyzed using various techniques known in the art including but not limited to SDS-PAGE, HPLC (e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.) or capillary electrophoresis.
  • HPLC e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.
  • capillary electrophoresis e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.
  • the anti-PSMA antibody or antigen binding fragment thereof is conjugated to a radiometal complex with a DAR of 4. In some embodiments, the anti-PSMA antibody or antigen binding fragment thereof if conjugated to a radiometal complex with a DAR of 8.
  • any of the anti-PSMA antibodies, antigen binding fragment thereof, chelators or radiometal complexes of the disclosure can be used to produce the radioimmunoconjugates or ADCs of the disclosure.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, which specifically binds to PSMA.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises (a) a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO:4, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 5 and a VH CDR3 having an amino acid sequence of SEQ ID NO: 6; and (b) a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence of SEQ ID NO:7, a VL CDR2 having an amino acid sequence of and SEQ ID NO: 8 and a VL CDR3 having an amino acid sequence of SEQ ID NOV.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which 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/or 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.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 52, and/or a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 53.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region 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: 84, and/or a light chain constant region 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: 85.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 84, and/or a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region 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: 86, and/or a light chain constant region 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: 85.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 86, and/or a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises (a) a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO: 10, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 11 and a VH CDR3 having an amino acid sequence of SEQ ID NO: 12; and (b) a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence of SEQ ID NO: 13, a VL CDR2 having an amino acid sequence of and SEQ ID NO: 14 and a VL CDR3 having an amino acid sequence of SEQ ID NO: 15.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which 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: 54, and/or a light chain variable region (VL) having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, and/or a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 55.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region 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: 88, and/or a light chain constant region 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: 89.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 88, and/or a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region 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: 90, and/or a light chain constant region 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: 89.
  • the radioconjugate or ADC comprises an antibody, or an antigen binding domain, that specifically binds to PSMA and which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 90, and/or a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89.
  • the radioconjugate comprises an antibody, such as the PSMA antibody or antigen binding fragment thereof of the disclosure, conjugated to a radiometal complex comprising a chelator and a radiometal.
  • the PSMA antibody or antigen binding fragment thereof is covalently bound to the chelator.
  • the radiometal complex comprises a linker.
  • the radiometal ion is actinium-225 ( 225 Ac).
  • the radiometal ion is Cerium 134 ( 134 Ce).
  • the radiometal ion is Indium 111 ( in In).
  • the radioconjugate of the disclosure comprises an anti -PSMA antibody or antigen binding fragment thereof which comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti -PSMA antibody which 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, 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; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 52, a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 53; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 84, a light chain constant region 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: 85; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 84, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody or antigen binding fragment thereof which comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which 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: 54, 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: 55; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 55; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • VH heavy chain variable region
  • VL light chain variable region
  • alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclsoure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 88, a light chain constant region 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: 89; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 88, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 86, a light chain constant region 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: 85; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 86, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 90, a light chain constant region 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: 89; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alphaemitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 90, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89; and an alpha-emitting radiometal ion coordinated to a chelator moiety, wherein the alpha-emitting radiometal ion is 225 Ac.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody or antigen binding fragment thereof which comprises
  • VH heavy chain variable region
  • VL light chain variable region
  • radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which 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, 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:
  • VH heavy chain variable region
  • VL light chain variable region
  • radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 52, a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 53 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • VH heavy chain variable region
  • VL light chain variable region
  • radiometal ion coordinated to a chelator moiety
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 84, a light chain constant region 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: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 84, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 86, a light chain constant region 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: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 86, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody or antigen binding fragment thereof which comprises (a) a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO: 10, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 11 and a VH CDR3 having an amino acid sequence of SEQ ID NO: 12;
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which 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: 54, 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: 55 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 55 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • VH heavy chain variable region
  • VL light chain variable region
  • radiometal ion coordinated to a chelator moiety
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 88, a light chain constant region 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: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 88, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 90, a light chain constant region 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: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is n i In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 90, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is in In.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody or antigen binding fragment thereof which comprises
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which 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, 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 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • VH heavy chain variable region
  • VL light chain variable region
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 52, a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 53 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • VH heavy chain variable region
  • VL light chain variable region
  • radiometal ion coordinated to a chelator moiety
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 84, a light chain constant region 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: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 84, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 86, a light chain constant region 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: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 86, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 85 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region 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: 90, a light chain constant region 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: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the radioconjugate of the disclosure comprises an anti-PSMA antibody which comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 90, a light chain constant region comprising the amino acid sequence of SEQ ID NO: 89 and a radiometal ion coordinated to a chelator moiety, wherein radiometal ion is 134 Ce.
  • the chelator is any of the chelator of the disclosure.
  • composition comprising the antibody, antigen binding fragment thereof radioconjugates or ADCs of the disclosure and a pharmaceutically acceptable carrier.
  • the anti-PSMA antibody, antigen binding fragment thereof, radioconjugates or ADCs of the disclosure may be prepared as pharmaceutical compositions containing an effective amount of the antibody as an active ingredient in a pharmaceutically acceptable carrier.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered.
  • vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • 0.4% saline and 0.3% glycine may be used.
  • These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration).
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc.
  • the concentration of the antibodies, antigen binding fragments thereof, radioconjugates or ADCs of the disclosure in such pharmaceutical formulation may vary from less than about 0.5%, usually to at least about 1% to as much as 15 or 20% by weight and may be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the mode of administration selected.
  • Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin are described, for example, in e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp. 958-989.
  • a pharmaceutically acceptable carrier can include a buffer, excipient, stabilizer, or preservative.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and/or in humans.
  • Examples of pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.
  • the amounts of pharmaceutically acceptable carrier(s) in the pharmaceutical compositions may be determined experimentally based on the activities of the carrier(s) and the desired characteristics of the formulation, such as stability and/or minimal oxidation.
  • compositions may comprise buffers such as acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO, HEPES, neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); antibacterial and antifungal agents; and preservatives.
  • buffers such as acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO, HEPES, neutral buffered saline, phosphate buffered s
  • compositions of the present disclosure can be formulated for a variety of means of parenteral or non-parenteral administration.
  • the compositions can be formulated for infusion or intravenous administration.
  • Pharmaceutical compositions disclosed herein can be provided, for example, as sterile liquid preparations, e.g., isotonic aqueous solutions, emulsions, suspensions, dispersions, or viscous compositions, which may be buffered to a desirable pH.
  • Formulations suitable for oral administration can include liquid solutions, capsules, sachets, tablets, lozenges, and troches, powders liquid suspensions in an appropriate liquid and emulsions.
  • the disclosure provides methods of treating a PSMA expressing cancer in a subject with any of the antibody, antigen binding fragment thereof or pharmaceutical composition of the disclosure.
  • the disclosure provides methods of treating a PSMA expressing cancer in a subject with any of the antibody drug conjugate of the disclosure. [00688] In some embodiments, the disclosure provides methods of treating a PSMA expressing cancer in a subject with any of the radioimmunoconjugate of the disclosure.
  • Treat,” “treating,” or “treatment” of a disease or disorder such as cancer refers to accomplishing one or more of the following: reducing the severity and/or duration of the disorder, delaying the progression of the disorder, slowing the progression of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.
  • the terms “delaying the progression of’ or “slowing the progression of’ shall include (a) delaying or slowing the development of one or more symptoms or complications of the disease, condition or disorder; (b) delaying or slowing the development of one or more new/additional symptoms or complications of the disease, condition or disorder; and/or (c) delaying or slowing the progression of the disease, condition or disorder to a later stage or more serious form of said disease, condition or disorder.
  • Subject includes any human or nonhuman animal.
  • Nonhuman animal includes all vertebrates, e.g., mammals and non-mammals.
  • the terms “subject” and “patient” can be used interchangeably herein. In some embodiments, the subject or patient is human.
  • a “therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual.
  • the medical condition is a PSMA expressing cancer.
  • the medical condition is a disease or disorder of the prostate.
  • the disease or disorder is a prostate-related disease or disorder.
  • the disease or disorder is prostate cancer.
  • the prostate cancer is a primary prostate cancer.
  • the prostate cancer is a metastatic prostate cancer.
  • the prostate cancer is a castration-resistant cancer.
  • the prostate cancer is a metastatic castration-resistant cancer (mCRPC).
  • the disease or disorder of the prostate is a prostate intraepithelial neoplasia.
  • the disease or disorder of the prostate is a prostate tumor.
  • the prostate tumor is a solid tumor.
  • the disease or disorder is a clear cell renal carcinoma.
  • the disease or disorder is a renal cell carcinoma (RCC).
  • the RCC is a kidney clear cell carcinoma.
  • the RCC is a kidney papillary cell carcinoma.
  • the disease or disorder is a metastatic lesion of a RCC.
  • the disease or disorder is a bladder cancer.
  • the disease or disorder is a breast cancer.
  • the disease or disorder is a kidney cancer.
  • the disease or disorder is a neovascular disorder.
  • the disease or disorder is a cancer characterized by solid tumor growth.
  • the neovascular disorder is a clear cell renal carcinoma.
  • the disease or disorder is a colorectal cancer.
  • the disease or disorder is a breast cancer.
  • the disease or disorder is a bladder cancer.
  • the disease or disorder is a lung cancer.
  • the disease or disorder is a pancreatic cancer.
  • the disease or disorder is a non-prostate cancers.
  • the disease or disorder is a renal cancer.
  • the disease or disorder is a urothelial cancer.
  • the disease or disorder is a lung cancer.
  • the disease or disorder is a colon cancer.
  • the disease or disorder is a breast cancer.
  • the disease or disorder is a liver adenocarcinaoma.
  • the cancer can be a hyperproliferative condition or disorder, a solid tumor, a neovasculature, a soft tissue tumor, or a metastatic lesion.
  • “Cancer” is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathology type or stage of invasiveness. Examples of cancers include solid tumors, hematological malignancies, soft tissue tumors, and metastatic lesions.
  • Exemplary solid tumors include malignancies, e.g., sarcomas, and carcinomas (including adenocarcinomas and squamous cell carcinomas) of the various organ systems, such as those affecting prostate, liver, lung, breast, lymphoid, gastrointestinal (e.g., colon), genitourinary tract (e.g., renal, urothelial cells), prostate and pharynx.
  • Adenocarcinomas include malignancies such as most colon cancers, a rectal cancer, a renal-cell carcinoma, a liver cancer, a non-small cell carcinoma of the lung, a cancer of the small intestine and a cancer of the esophagus.
  • Squamous cell carcinomas include malignancies, e.g., in the lung, esophagus, skin, head and neck region, oral cavity, anus, and cervix.
  • the disclosure provides methods of treating a PSMA expressing cancer in a subject with any of the antibody, antigen binding fragment thereof or pharmaceutical composition of the disclosure.
  • the disclosure provides methods of treating a PSMA expressing cancer in a subject with any of the antibody drug conjugate of the disclosure.
  • the disclosure provides methods of treating a PSMA expressing cancer in a subject comprising administering to the subject an antibody, or an antigen binding domain that specifically binds to PSMA wherein the antibody, or an antigen binding domain that binds PSMA comprises a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO:4, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 5 and a VH CDR3 having an amino acid sequence of SEQ ID NO:6; and a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence of SEQ ID NO:7, a VL CDR2 having an amino acid sequence of and SEQ ID NO: 8 and a VL CDR3 having an amino acid sequence of SEQ ID NOV; or 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
  • the disclosure provides methods of treating PSMA expressing cancer comprising administering to the subject an antibody, or an antigen binding domain that specifically binds to PSMA wherein the antibody, or an antigen binding domain that binds PSMA comprises a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO: 10, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 11 and a VH CDR3 having an amino acid sequence of SEQ ID NO: 12; and a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence of SEQ ID NO: 13, a VL CDR2 having an amino acid sequence of and SEQ ID NO: 14 and a VL CDR3 having an amino acid sequence of SEQ ID NO: 15; or 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:
  • the PSMA expressing cancer is prostate cancer.
  • the PSMA expressing cancer is renal cancer.
  • Also provided are methods of detecting PSMA in a sample comprising obtaining the sample, contacting the sample with the anti-PSMA antibody, the antigen binding fragment thereof or the radioconjugate of the disclosure, and detecting the antibody or radioconjugate bound to PSMA in the sample.
  • the disclosure provides a method of detecting PSMA in a sample, comprising obtaining the sample, contacting the sample with the anti-PSMA antibody, antigen binding fragment thereof or the radioconjugate comprising the anti-PSMA antibody or antigen binding fragment and detecting the antibody bound to PSMA in the sample.
  • the sample may be derived from urine, blood, serum, plasma, saliva, ascites, circulating cells, circulating tumor cells, cells that are not tissue associated (i.e., free cells), tissues (e.g., surgically resected tumor tissue, biopsies, including fine needle aspiration), histological preparations, and the like.
  • the antibodies and radioconjugates of the disclosure may be used in a variety of assays to detect PSMA in the sample.
  • exemplary assays are western blot analysis, radioimmunoassay, surface plasmon resonance, immunoprecipitation, equilibrium dialysis, immunodiffusion, electrochemiluminescence (ECL) immunoassay, immunohistochemistry, fluorescence-activated cell sorting (FACS) or ELISA assay. Kits
  • kits comprising the antibody, antigen binding fragment, radioconjugates, ADCs composition, or the pharmaceutical composition of the disclosure.
  • kit and “article of manufacture” are used as synonyms.
  • the disclosure provides a kit comprising the antibody or antigen binding fragment thereof that binds PSMA.
  • the disclosure provides a kit comprising the radioconjugates, ADCs or pharmaceutical composition.
  • the kit may be used for therapeutic uses and as diagnostic kits.
  • the kit may be used to detect the presence of PSMA in a sample.
  • the kit comprises the anti-PSMA antibody or antigen binding fragment of the disclosure and reagents for detecting the PSMA binding protein.
  • the kit comprises the radioconjugates of the disclosure and reagents for detecting the PSMA binding protein.
  • the kit can include one or more other elements including: instructions for use; other reagents, e.g., a label, a therapeutic agent, or an agent useful for chelating, or otherwise coupling, an antibody to a label or therapeutic agent, or a radioprotective composition; devices or other materials for preparing the antibody for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.
  • the kit comprises the disclosed antibody, antigen binding fragment thereof radioconjugates, ADCs or pharmaceutical composition in a container and instructions for use of the kit.
  • the antibody or antigen binding fragment thereof that binds PSMA in the kit is labeled.
  • the kit comprises the disclosed antibody, antigen binding fragment thereof, radioconjugates, ADCs or pharmaceutical composition a container and instructions for use of the kit.
  • the kit comprises an antibody, antigen binding fragment thereof that binds PSMA, wherein the antibody or antigen binding fragment comprises: the VH of SEQ ID NO: 52 and the VL of SEQ ID NO: 53; the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55; the VH of SEQ ID NO: 56 and the VL of SEQ ID NO: 57; the VH of SEQ ID NO: 58 and the VL of SEQ ID NO: 59; the VH of SEQ ID NO: 60 and the VL of SEQ ID NO: 61 ; the VH of SEQ ID NO: 62 and the VL of SEQ ID NO: 63; the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; the VH of SEQ ID NO: 66 and the VL of SEQ ID NO: 67; or the VH of SEQ ID NO: 278 and the VL of SEQ ID NO: 279.
  • the kit comprises the antibody or antigen binding fragment thereof that binds PSMA comprising a VH of SEQ ID NO: 52 and a VL of SEQ ID NO: 53.
  • the kit comprises an antibody or antigen binding fragment thereof that binds PSMA comprising the amino acid sequence of SEQ ID NOs: 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 268, 269, 282, 284, or 288.
  • the kit comprises an antibody or antigen binding fragment thereof that binds PSMA comprising the amino acid sequence selected from the group consisting of (a) SEQ ID NO: 84 and SEQ ID NO: 85; (b) SEQ ID NO: 86 and SEQ ID NO: 85; (c) SEQ ID NO: 88 and SEQ ID NO: 89; (d) SEQ ID NO: 90 and SEQ ID NO: 89; (e) SEQ ID NO: 92 and SEQ ID NO: 93; f) SEQ ID NO: 94 and SEQ ID NO: 95; g) SEQ ID NO: 96 and SEQ ID NO: 97; h) SEQ ID NO: 98 and SEQ ID NO: 99; i) SEQ ID NO: 100 and SEQ ID NO:
  • the kit comprises an antibody drug conjugate comprising an anti-PSMA antibody or antigen binding fragment thereof which comprises a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence of SEQ ID NO:4, a VH CDR2 having an amino acid sequence of and SEQ ID NO: 5 and a VH CDR3 having an amino acid sequence of SEQ ID NO:6; a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence of SEQ ID NO: 7, a VL CDR2 having an amino acid sequence of and SEQ ID NO: 8 and a VL CDR3 having an amino acid sequence of SEQ ID NOV; and/or 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, a light chain variable region (VL) having at least 80%, at least 85%, at least 90%,
  • PSMA prostate-specific membrane antigen
  • ECD extracellular domains
  • Human PSMA ECD was produced based on Uniprot Accession #Q04609 sequence.
  • the ECD construct was designed with a 6X His-tag sequence (SEQ ID NO: 339) at the N-terminus (Protein AA ID PSMW39; SEQ ID NO: 1).
  • the PSMA ECD from Macaca fascicularis was produced based on NCBI Accession# EHH56646.1, fused to an Avi tag and 6X His-tag (SEQ ID NO: 339) at the N-terminus (Protein AA ID PSMW1; SEQ ID NO: 2).
  • the extracellular domain (ECD) of PSMA from Mus musculus was produced based on Uniprot Accession# 035409, fused to an Avi tag and 6X His-tag (SEQ ID NO: 339) at the N-terminus to facilitate purification (Protein AA ID PSMW29; SEQ ID NO: 3).
  • the cynomolgus and murine ECD expression constructs were used to transiently transfect HEK293-6E cells using PEI MAX (transfection grade linear polyethylenimine hydrochloride, Polysciences). Briefly, transfected cells were incubated for six days at 37 DC with 5% CO2 in a shake flask and harvested when the viability had dropped to 80%.
  • the human ECD expression construct was used to stably transfect Expi-CHO using Expifectamine-CHO (ThermoFisher Scientific) according to the recommendations of the manufacturer. Briefly, stable transfectants were selected with G418 (Thermo Fisher Scientific; Cat# 10131027). Monoclones expressing the highest levels of human PSMA ECD protein were identified by ELISA (R&D Systems; Cat#DY4234-05).
  • High PSMW39-expressing monoclones were cultured in Dynamis media (Thermo Fisher Scientific; Cat# A2661501) supplemented with 5% Cell Boost 5 (Hyclone; Cat# SH30865.01) and incubated at 37 °C, 125 rpm and 5% CO2 until the cell viability dropped below 80%. On days 2, 4, 7, 9 and 11, 6 mL of 20% D- glucose (2 g/L final cone.) and 6 mL of 200 mM L-glutamine (2mM final cone.) was added as feed to each of the flasks.
  • Ablexis® kappa, lambda, and kappa/lambda hybrid mice were used for antibody discovery.
  • Ablexis® mice generate antibodies having human variable domains linked to human CHI and CL domains, chimeric human/mouse hinge regions, and mouse Fc regions.
  • Antibodies produced by the Kappa Mouse lack sequence derived from mouse VH, DH and JH exons and mouse VK, JK and CK exons.
  • the endogenous mouse IgA is active in the Kappa Mouse.
  • the human IgK chains comprise approximately 90-95% of the naive repertoire and mouse IgA chains comprise approximately 5-10% of the naive repertoire in this strain.
  • Antibodies produced by the Lambda Mouse lack sequence derived from mouse VH, DH and JH exons and mouse VX, JX and CX exons.
  • the endogenous mouse IgK is active in the Lambda Mouse.
  • the human IgA chains comprise approximately 40% of the naive repertoire and mouse IgK chains comprise approximately 60% of the naive repertoire.
  • the preparation and use of Ablexis®, and the genomic modifications carried by such mice, is described in WO11/123708.
  • mice Ablexis kappa/lambda hybrid mice were immunized with recombinant human PSMA antigen (PSMW39.002) and cynomolgus PSMA antigen (PSMW1.009) in combination with CL413 adjuvant (InvivoGen, VAC-C413-5). Briefly, mice were boosted on Days 0, 7, 14, 21, and 28 before being bled on Day 35 for serological analysis. Serology was performed on human PSMA (+) cells C4-2B (AG000002300) and a human PSMA knockout cell line (AG000002521).
  • mice were selected for hybridoma fusion and finally boosted on Day 56 with PSMW39.002 or an equimolar mixture of PSMW39.002 and PSMW1.009.
  • This preparation also included recombinant anti-mouse CD40 mAb (R&D Systems, MAB440) to stimulate B cell expansion.
  • spleen and draining lymph nodes were harvested from these mice, pooled and homogenized into a single-cell suspension.
  • Stable hybridomas were generated by PEG-mediated fusion of mouse myeloma cell line FO with the pooled mouse homogenate, followed by HAT selection. [00726] Supernatants from these hybridomas were screened against PSMA (+) C4-2B cells by MSD.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12103922B2 (en) 2018-11-20 2024-10-01 Cornell University Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer
US12186288B2 (en) 2016-06-23 2025-01-07 Cornell University Double targeted constructs to affect tumor kill
US12268759B2 (en) 2016-06-23 2025-04-08 Cornell University Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies
WO2025183244A1 (ko) * 2024-02-29 2025-09-04 주식회사 피비앱셀 Psma에 대한 항체 및 그의 용도

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230346862A1 (en) 2022-05-02 2023-11-02 Athanor Biosciences, Inc. Cancer eradicating - bio-nanoparticles (ce-bnp)
WO2023215560A1 (en) 2022-05-05 2023-11-09 Atoosa Corporation Tumor cell/immune cell multivalent receptor engager – bio-nanoparticle (timre-bnp)
IL322949A (en) 2023-03-03 2025-10-01 Arsenal Biosciences Inc Systems targeting PSMA and CA9

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058906A1 (en) * 2008-11-07 2012-03-08 Vaughn Smider Combinatorial antibody libraries and uses thereof
US20140161800A1 (en) * 2011-04-22 2014-06-12 John W. Blankenship Prostate-Specific Membrane Antigen Binding Proteins and Related Compositions and Methods
US20140302043A1 (en) * 2011-08-03 2014-10-09 Duke University Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza hemagglutinin

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US541606A (en) 1895-06-25 Sealed package
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5606040A (en) 1987-10-30 1997-02-25 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
IL162181A (en) 1988-12-28 2006-04-10 Pdl Biopharma Inc A method of producing humanized immunoglubulin, and polynucleotides encoding the same
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6255458B1 (en) 1990-08-29 2001-07-03 Genpharm International High affinity human antibodies and human antibodies against digoxin
EP1400536A1 (en) 1991-06-14 2004-03-24 Genentech Inc. Method for making humanized antibodies
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US6818749B1 (en) 1998-10-31 2004-11-16 The United States Of America As Represented By The Department Of Health And Human Services Variants of humanized anti carcinoma monoclonal antibody cc49
AU767394C (en) 1999-12-29 2005-04-21 Immunogen, Inc. Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
CA2430013C (en) 2000-11-30 2011-11-22 Medarex, Inc. Transgenic transchromosomal rodents for making human antibodies
MXPA05000511A (es) 2001-07-12 2005-09-30 Jefferson Foote Anticuepros super humanizados.
JP5355839B2 (ja) * 2001-10-23 2013-11-27 ピーエスエムエー デベロプメント カンパニー， エル．エル．シー． Ｐｓｍａ抗体およびタンパク質マルチマー
EP1391213A1 (en) 2002-08-21 2004-02-25 Boehringer Ingelheim International GmbH Compositions and methods for treating cancer using maytansinoid CD44 antibody immunoconjugates and chemotherapeutic agents
US8748356B2 (en) 2007-10-19 2014-06-10 Janssen Biotech, Inc. Methods for use in human-adapting monoclonal antibodies
AU2008343589A1 (en) 2007-12-19 2009-07-09 Centocor Ortho Biotech Inc. Design and generation of human de novo pIX phage display libraries via fusion to pIX or pVII, vectors, antibodies and methods
JP2012505654A (ja) 2008-10-14 2012-03-08 ヤンセン バイオテツク，インコーポレーテツド 抗体をヒト化及び親和性成熟する方法
ES2984483T3 (es) 2010-03-31 2024-10-29 Ablexis Llc Ingeniería genética de ratones para la producción de anticuerpos quiméricos
US10434197B2 (en) 2010-07-23 2019-10-08 University Of Delaware Tetrazine-trans-cyclooctene ligation for the rapid construction of radionuclide labeled probes
US10556024B2 (en) 2013-11-13 2020-02-11 Whitehead Institute For Biomedical Research 18F labeling of proteins using sortases
GB201506393D0 (en) * 2015-04-15 2015-05-27 Berkel Patricius H C Van And Howard Philip W Site-specific antibody-drug conjugates
US10844111B2 (en) 2015-05-06 2020-11-24 Janssen Biotech, Inc. Prostate specific membrane antigen binding fibronectin type III domains
CR20180243A (es) 2015-10-02 2018-07-31 Genentech Inc Conjugados de anticuerpo-fármaco de pirrolobenzodiazepina y métodos de uso
CN115636880A (zh) * 2015-10-23 2023-01-24 辉瑞有限公司 抗il-2抗体及其组合物和用途
PE20181326A1 (es) * 2015-11-03 2018-08-20 Janssen Biotech Inc Anticuerpos que se unen especificamente a pd-1 y sus usos
EP3402825A1 (en) * 2016-01-12 2018-11-21 Crescendo Biologics Limited Molecules that bind prostate specific membrane antigen (psma)
MY202858A (en) * 2016-06-10 2024-05-25 Eisai R&D Man Co Ltd Lysine conjugated immunoglobulins
IL269763B2 (en) 2017-03-30 2024-08-01 Univ Cornell Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer
CA3101271A1 (en) * 2018-05-24 2019-11-28 Janssen Biotech, Inc. Anti-cd3 antibodies and uses thereof
WO2020001344A1 (en) * 2018-06-29 2020-01-02 Beijing Biocytogen Co., Ltd ANTI-CD3e ANTIBODIES AND USES THEREOF
IL279823B2 (en) * 2018-07-31 2026-02-01 Heidelberg Pharma Res Gmbh Cultured antibodies against psma
CN109467602A (zh) * 2018-11-05 2019-03-15 暨南大学 与cxcr4结合的人源蛋白及其应用
JP7699542B2 (ja) 2018-11-20 2025-06-27 コーネル ユニバーシティー 放射線核種の大環状錯体およびがんの放射線療法におけるそれらの使用
MA55718A (fr) * 2019-04-19 2022-02-23 Janssen Biotech Inc Méthodes de traitement du cancer du rein avec un anticorps anti-psma/cd3
BR112021022237A2 (pt) 2019-05-10 2022-03-29 Janssen Biotech Inc Queladores macrocíclicos e métodos de uso dos mesmos

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058906A1 (en) * 2008-11-07 2012-03-08 Vaughn Smider Combinatorial antibody libraries and uses thereof
US20140161800A1 (en) * 2011-04-22 2014-06-12 John W. Blankenship Prostate-Specific Membrane Antigen Binding Proteins and Related Compositions and Methods
US20140302043A1 (en) * 2011-08-03 2014-10-09 Duke University Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza hemagglutinin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4392454A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12186288B2 (en) 2016-06-23 2025-01-07 Cornell University Double targeted constructs to affect tumor kill
US12268759B2 (en) 2016-06-23 2025-04-08 Cornell University Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies
US12377175B2 (en) 2016-06-23 2025-08-05 Cornell University Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies
US12103922B2 (en) 2018-11-20 2024-10-01 Cornell University Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer
US12258339B2 (en) 2018-11-20 2025-03-25 Cornell University Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer
WO2025183244A1 (ko) * 2024-02-29 2025-09-04 주식회사 피비앱셀 Psma에 대한 항체 및 그의 용도

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