PSMA-BINDING HEAVY-CHAIN ​​ANTIBODIES

Abstract

The present invention relates to a bispecific, three-chain, antibody-like molecule that binds to CD3 and PSMA, characterized in that it comprises: (a) a heavy chain variable region (HV) having CD3-binding affinity that is paired with a light chain variable region, wherein: the heavy chain variable region comprises a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60, and a CDR3 sequence from SEQ ID NO: 61, in a human HV frame; the light chain variable region (LV) comprises a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63, and a CDR3 sequence from SEQ ID NO: 64, in a human LV frame; the heavy chain variable region comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 65;and the light chain variable region comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 66; and (b) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11, and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame, in a monovalent configuration, wherein the antigen-binding domain comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 25.

Description

PSMA-BINDING HEAVY-CHAIN ​​ANTIBODIES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from the filing date of U.S. provisional patent application no. 62 / 830,130, filed on April 5, 2019, the description of which is incorporated herein in its entirety by reference. LIST OF SEQUENCES This application contains a list of sequences that has been submitted electronically in ASCII format and is incorporated herein in its entirety by reference. This ASCII copy, created on July 9, 2020, is named TNO-0016WO_SL.txt and has a size of 121,310 bytes. FIELD OF INVENTION The present invention relates to human heavy chain antibodies (e.g., UniAbs™) that bind to PSMA. The invention further relates to methods for preparing such antibodies, compositions, including pharmaceutical compositions, comprising such antibodies, and their use for treating disorders characterized by PSMA expression. BACKGROUND OF THE PSMA INVENTION PSMA, also known as Prostate-Specific Membrane Antigen and glutamate carboxypeptidase II (UniProt Q04609), is a type II transmembrane protein with alpha-linked N-acetylated acid dipeptidase, folate hydrolase, and dipeptidyl peptidase activity. It is encoded by the FOLH1 gene in humans and consists of a 19-amino-acid cytoplasmic domain, a 24-amino-acid transmembrane portion, and a 707-amino-acid extracellular portion. The protein is enzymatically active as a non-covalent homodimer. PSMA is expressed in the epithelial tissue of the prostate gland and is upregulated in prostate cancer and the neovasculature of solid tumors. It is also expressed at low levels in healthy tissues such as the brain, kidneys, and salivary glands, but its overexpression in malignant prostate tissue makes it an attractive target for prostate cancer therapy.It may also be relevant for the therapy or imaging of solid tumors, given its high expression in malignant neovasculature. Monoclonal antibodies, antibody-drug conjugates, and chimeric antigen receptor T lymphocytes targeting PSMA have been described for the treatment of metastatic prostate cancer (Hernandez-Hoyos et al. 2016, PMID: 27406985, DÍPippo et al. 2014, PMID: 25327986, Serganova et al. 2016, PMID: 28345023). In addition, PSMA-specific radionuclide conjugates are being investigated for imaging and treatment of prostate cancer (e.g., Hofman et al., 2018 PMID: 29752180). Heavy chain antibodies In a conventional IgG antibody, the association of the heavy and light chains is partly due to a hydrophobic interaction between the constant region of the light chain and the CH1 constant domain of the heavy chain. Additional residues in the frame 2 (FR2) and frame 4 (FR4) regions of the heavy chain also contribute to this hydrophobic interaction between the heavy and light chains. However, it is known that camelid sera (the suborder Tylopoda, which includes camels, dromedaries, and llamas) contain a major type of antibody composed solely of paired heavy chain antibodies (heavy chain-only antibodies, or UniAbs™). Camelid UniAbs™ (from Camelus dromedarius, Camelus bactrianus, Lama glama, Lama guanaco, Lama alpaca, and Lama vicugna) have a unique structure consisting of a single variable domain (VHH), a hinge region, and two constant domains (CH2 and CH3), which are highly homologous to the CH2 and CH3 domains of classical antibodies. These UniAbs™ lack the first constant region domain (CH1), which is present in the genome but is spliced ​​in during mRNA processing. The absence of the CH1 domain explains the absence of the light chain in UniAbs™, since this domain is the anchoring site for the constant domain of the light chain.Tal UniAbs™ evolved naturally to confer antigen-binding specificity and high affinity for three CDRs of conventional antibodies or fragments thereof (Muyldermans, 2001; J Biotechnol 74:277-302; Reveis et al., 2005; Expert Opin Biol Ther 5:111-124). Cartilaginous fish, such as sharks, have also developed a distinctive type of immunoglobulin, called IgNAR, which lacks light polypeptide chains and is composed entirely of heavy chains. IgNAR molecules can be manipulated by molecular engineering to produce the variable domain of a single heavy chain polypeptide (vNAR) (Nuttall et al. Eur. J. Biochem. 270, 3543-3554 (2003); Nuttall et al. Function and Bioinformatics 55, 187-197 (2004); Dooley et al., Molecular Immunology 40, 25-33 (2003)). The ability of heavy-chain-only antibodies devoid of a light chain to bind to antigen was established in the 1960s (Jaton et al. (1968) Biochemistry, 7, 4185-4195). Heavy-chain immunoglobulin physically separated from the light chain retained 80% of the antigen-binding activity relative to the tetrameric antibody. Sitia et al. (1990) Cell, 60, 781-790 demonstrated that deletion of the CH1 domain from a rearranged mouse μ gene results in the production of a heavy-chain-only antibody, devoid of a light chain, in mammalian cell culture. The antibodies produced retained VH-binding specificity and effector functions. Heavy chain antibodies with high specificity and affinity against a variety of antigens can be generated by immunization (van der Linden, RH, et al. Biochim. Biophys. Acta. 1431,37-46 (1999)), and the VHH portion can be easily cloned and expressed in yeast (Frenken, LGJ, et al. J. Biotechnol. 78, 11-21 (2000)). Their expression levels, solubility, and stability are significantly higher than those of the classical F(ab) or Fv fragments (Ghahroudi, MA et al. FEBS Lett. 414, 521-526 (1997)). Mice in which the light chain (L) λ (lambda) locus and / or the L λ and κ (kappa) chain loci have been functionally silenced and the antibodies produced by such mice are described in U.S. patents 7,541,513 and 8,367,888. Recombinant production of heavy chain-only antibodies in mice and rats has been reported, for example, in WO2006008548, U.S. application publication no. s20100122358, Nguyen et al., 2003, Immunology; 109 (1), 93-101; Brüggemann et al., Crit. Rev. Immunol.; 2006, 26(5):377-90; and Zou et al., 2007, J Exp Med; 204(13): 3271-3283. The production of inactivated rats by embryonic microinjections of zinc-finger nucleases is described in Geurts et al., 2009, Science, 325 (5939):433. Soluble heavy-chain-only antibodies and transgenic rodents comprising a heterologous heavy-chain locus producing such antibodies are described in U.S. patents no.a8,883,150 and 9,365,655. CAR-T structures comprising single-domain antibodies as the binding (targeting) domain are described, for example, in Iri-Sofla et al., 2011, Experimental Cell Research 317:2630-2641 and Jamnani et al., 2014, Biochim Biophys Acta, 1840:378-386. SUMMARY OF THE INVENTION Aspects of the invention relate to heavy chain antibodies, including, but not limited to, UniAbs™, with PSMA-binding affinity. Other aspects of the invention relate to methods for preparing such antibodies, compositions comprising such antibodies, and their use in the treatment of disorders characterized by PSMA expression. In some embodiments, a PSMA-binding antibody comprises a first heavy-chain variable region comprising: (a) a CDR1 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 1 to 10; and / or (b) a CDR2 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 11 to 17; and / or (c) a CDR3 having two or fewer substitutions in the amino acid sequences of SEQ ID NO: 18 to 23. In some embodiments, the antibody further comprises a second heavy-chain variable region comprising: (a) a CDR1 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 1 to 10; and / or (b) a CDR2 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 11 to 17; and / or (c) a CDR3 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 18 to 23.In some embodiments, the CDR1, CDR2, and CDR3 sequences are present in a human framework. In some embodiments, an antibody further comprises a heavy chain constant region sequence in the absence of a CH1 sequence. In some modalities, the first variable heavy chain region of the antibody comprises: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10; and / or (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17; and / or (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23. In some embodiments, the antibody further comprises a second heavy chain variable region comprising: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10, and / or (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17, and / or (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23. In some embodiments, the antibody comprises: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10, and (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17, and (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23. In some embodiments, the antibody comprises a second heavy chain variable region comprising: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10, and (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17, and (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23. In some embodiments, the antibody comprises: (a) a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18; or (b) a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain variable region sequence having at least 95% sequence identity with any of the sequences in SEQ ID NO: 24 to 58. In some embodiments, an antibody comprises a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 24 to 58. In some embodiments, the antibody comprises a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 25 and SEQ ID NO: 38. In some embodiments, a PSMA-binding antibody comprises a first heavy-chain variable region comprising: (a) a CDR1 sequence of the formula: GGSISS Xi X2Y X3(SEQ ID NO: 67) where Xi is S or N; X2 is S or N; and X3 is Y or F; and (b) a CDR2 sequence of the formula: X4X5X6S G X7T (SEQ ID NO: 68) where X4 is I or V; X5 is D or Y; Xθ is Y or D; and X7 is Y or S; and (c) a CDR3 sequence ΜΛ / a / ZUZ 1 / un zzuo formula: AR Η KAATA DFDY (SEQ ID NO: 69), in a monovalent or bivalent format. In some embodiments, a PSMA-binding antibody comprises a first heavy-chain variable region comprising: (a) a CDR1 sequence of the formula: GF Xi F X2X3Y G (SEQ ID NO: 70) where Xi is S, I or T; X2 is S, T, R or I; and X3 is R or S; and (b) a CDR2 sequence of the formula: I X4Y DGSN X5(SEQ ID NO: 71) where X4 is W or S; and X5 is R or K; and (c) a CDR3 sequence of the formula: AREPRX6GYYYX7X8SGYX9SLDY (SEQ ID NO: 72) where Xe is I or V; X7 is E or D; Xs is S or T; and X9 is Y or D, in a monovalent or bivalent format. In some embodiments, a PSMA-binding antibody comprises a first heavy-chain variable region comprising: (a) a CDR1 sequence of the formula: GGSISS X1 X2Y X3 (SEQ ID NO: 67) where X1 is S or N; X2 is S or N; and X3 is Y or F; and (b) a CDR2 sequence of the formula: X4X5X6S G X7T (SEQ ID NO: 68) where X4 is I or V; X5 is D or Y; Xe is Y or D; and X7 is Y or S; and (c) a CDR3 sequence of the formula: ARHKAATADFDY (SEQ ID NO: 69), and a second heavy chain variable region comprising: (a) a CDR1 sequence of the formula: GF X1 F X2X3Y G (SEQ ID NO: 70) where X1 is S, I or T; X2 is S, T, R or I; and X3 is R or S; and (b) a CDR2 sequence of the formula: I X4Y DGSN X5(SEQ ID NO: 71) where X4 is W or S; and X5 is R or K; and (c) a CDR3 sequence of the formula: AREPRX6GYYYX7X8SGYX9SLDY (SEQ ID NO: 72) where Xe is I or V; X7is E or D; X8is S or T; and X9is Y or D. In some embodiments, the antibody comprises a first and a second heavy chain variable region, where the first heavy chain variable region is located closer to the N-terminus than the second heavy chain variable region. In some embodiments, the first heavy chain variable region is located closer to the C-terminus than the second heavy chain variable region. In some embodiments, a PSMA-binding antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences in a human VH frame, wherein the CDR sequences comprise a sequence having two or fewer substitutions in a CDR sequence selected from the group consisting of SEQ ID NO: 1-23. In some embodiments, a PSMA-binding antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences in a human VH frame, wherein the CDR sequences are selected from the group consisting of SEQ ID NO: 1-23. In some embodiments, a PSMA-binding antibody comprises: a heavy chain variable region comprising a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18 in a human VH frame. In some embodiments, a PSMA-binding antibody comprises a heavy chain variable region comprising a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18, in a human VH frame, in a monovalent or bivalent configuration. In some embodiments, a PSMA-binding antibody comprises a variable heavy chain line comprising a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20 in a human VH frame. In some embodiments, a PSMA-binding antibody comprises a heavy chain variable region comprising a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame, in a monovalent or bivalent configuration. In some embodiments, a PSMA-binding antibody comprises: a first heavy-chain variable region comprising: a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18; and a second heavy-chain variable region comprising: a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame. In some embodiments, the antibody comprises a first heavy-chain variable region located closer to the N-terminus with respect to the second heavy-chain variable region. In some embodiments, the first heavy-chain variable region is located closer to the C-terminus with respect to the second heavy-chain variable region. In some modalities, an antibody is monospecific. In some modalities, an antibody is multispecific. In some modalities, an antibody is bispecific. In some modalities, an antibody has binding affinity for a CD3 protein and a PSMA protein. In some modalities, an antibody has binding affinity for two different epitopes on the same PSMA protein. In some modalities, an antibody has binding affinity for an effector cell. In some modalities, an antibody has binding affinity for a T-cell antigen. In some modalities, an antibody has binding affinity for CD3. In some modalities, an antibody is in CAR-T cell format. Aspects of the invention include a bispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60, and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63, and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18, in a human VH frame. Aspects of the invention include a bispecific antibody comprising: (i) a heavy chain variable region having CD3 binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame, (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (ii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11, and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame, in a monovalent or bivalent configuration. Aspects of the invention include a bispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60, and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63, and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (ii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame. Aspects of the invention include a bispecific antibody comprising: (i) a heavy chain variable region having CD3 binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame, (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence of SEQ ID NO: 7, a CDR2 sequence of SEQ ID NO: 15, and a CDR3 sequence of SEQ ID NO: 20, in a human VH frame, in a monovalent or bivalent configuration. Aspects of the invention include a multispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, wherein the antigen-binding domain comprises a first and second antigen-binding region, in a bivalent configuration, wherein: the first antigen-binding region comprises a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11 and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame;and the second antigen-binding region comprises a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame. In certain embodiments, the first antigen-binding region is located closer to the N-terminus relative to the second antigen-binding region. In certain other embodiments, the first antigen-binding region is located closer to the C-terminus relative to the second antigen-binding region. Aspects of the invention include multispecific or bispecific antibodies where the first and second antigen-binding regions of the antigen-binding domain of the anti-PSMA heavy chain antibody are connected by a polypeptide linker. In some embodiments, the polypeptide linker is a GS linker. In some embodiments, the GS linker consists of the sequence in SEQ ID NO: 73 or SEQ ID NO: 74. In some embodiments, the antigen-binding domain of the anti-PSMA heavy chain antibody is monoparatopic and induces less cytokine production compared to a biparatopic antigen-binding domain. In some embodiments, the antigen-binding domain of the anti-PSMA heavy chain antibody is monoparatopic and expands CD8+ T lymphocytes to a greater extent than a biparatopic antigen-binding domain. In some cases, an antibody is biparatopic and has a higher affinity for PSMA compared to a monoparatopic anti-PSMA antibody. In some cases, an antibody is biparatopic and has an increased effector function compared to a monoparatopic anti-PSMA antibody. The aspects of the invention relate to pharmaceutical compositions comprising an antibody described herein. Aspects of the invention relate to methods for treating a disorder characterized by PSMA expression, comprising administering to a subject with said disorder an antibody or a pharmaceutical composition described herein. In certain other aspects, the invention relates to uses of an antibody described herein in the preparation of a medicament for the treatment of a disorder characterized by PSMA expression. In further aspects, the invention relates to an antibody described herein for use in the treatment of a disorder characterized by PSMA expression. In certain other aspects, the invention relates to treatment methods comprising administering to an individual in need an effective dose of an antibody or a pharmaceutical composition described herein. With respect to these aspects, and in some modalities, the disorder is prostate cancer. Aspects of the invention relate to polynucleotides encoding an antibody described herein, vectors comprising said polynucleotides, and cells comprising said vectors. Aspects of the invention relate to methods for producing an antibody described herein, comprising growing a cell described herein under conditions permissive for antibody expression and isolating the antibody from the cell. Aspects of the invention relate to methods for preparing an antibody described herein, comprising immunizing a UniRat animal with a PSMA protein and identifying antibody sequences that bind to PSMA. These and other aspects will be explained in more detail in the rest of the disclosure, including the examples. BRIEF DESCRIPTION OF THE FIGURES FIG. 1, panels AB, provides a series of graphs showing serum titer as a function of dilution. FIG. 2, panel A is a graph showing cell binding to human PSMA. FIG. 2, panel B is a graph showing cell binding to PSMA in cynomolgus monkeys. FIG. 3 is a graph showing the binding competition between two antibody families according to one embodiment of the invention. FIG. 4, panel A, is a Scatchard plot showing the binding affinity to PSMA expressed on the cell surface of a bispecific antibody having binding affinity to CD3 and PSMA, wherein the PSMA arm is monoparatopic and monovalent according to an embodiment of the invention. FIG. 4, panel B, is a Scatchard plot showing the binding affinity to PSMA expressed on the cell surface of a bispecific antibody having binding affinity to CD3 and PSMA, wherein the PSMA arm is biparatopic according to an embodiment of the invention. FIG. 5, panels AC, provides schematic illustrations of: a monospecific anti-CD3 x monovalent anti-PSMA antibody (panel A); a bivalent anti-CD3 x monospecific anti-PSMA antibody (panel B); and a biparatopic anti-CD3 x bivalent anti-PSMA antibody (panel C) according to embodiments of the invention. FIG. 6 is a graph depicting T-cell-mediated lysis of PSMA-positive cells using pre-activated T cells. FIG. 7 is a graph depicting T-cell-mediated lysis of PSMA-positive cells using unstimulated T cells. FIG. 8 is a graph that represents the percentage of specific lysis of PSMA-negative DU145 cells as a function of the concentration of multispecific antibodies in the presence of pre-activated T lymphocytes. FIG. 9 is a graph showing the binding of PSMA x CD3 bispecific antibodies to PSMA-positive and PSMA-negative cells. FIG. 10 is a graph showing T-cell-mediated lysis of PSMA-positive cells. FIG. 11, panel A, is a graph that represents the proliferation of T lymphocytes as a function of antibody concentration. FIG. 11, panel B, is a graph that represents the proliferation of T lymphocytes as a function of antibody concentration. FIG. 11, panel C is a graph that represents the ratio of CD8 to CD4 of proliferating T lymphocytes. FIG. 11, panel D, is a graph representing the CD8 to CD4 ratio of proliferating T lymphocytes. FIG. 12, panel A, is a graph depicting T-cell-mediated lysis of PSMA-positive cells as a function of antibody concentration. FIG. 12, panel B, is a graph that represents the release of cytokines (IFNy) as a function of antibody concentration. FIG. 12, panel 0, is a graph that represents the release of cytokines (IL-2) as a function of antibody concentration. FIG. 13 is a graph depicting the inhibition of 22Rv1 tumor growth in a tumor xenograft model. DETAILED DESCRIPTION OF PREFERRED MODALITIES The practice of the present invention shall employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the current knowledge of the art. Such techniques are fully explained in the literature, such as, “Molecular Cloning: A Laboratory Manual”, segunda edición (Sambrook et ál., 1989); “Oligonucleotide Synthesis” (M. J. Gait, ed., 1984); “Animal Cell Culture” (R. I. Freshney, ed., 1987); “Methods in Enzymology” (Academic Press, Inc.); “Current Protocols in Molecular Biology” (F. M. Ausubel et ál., eds., 1987, y actualizaciones periódicas); “PCR: The Polymerase Chain Reaction”, (Mullís et ál., ed., 1994); “A Practical Guide to Molecular Cloning” (Perbal Bernard V., 1988); “Phage Display: A Laboratory Manual” (Barbas et ál., 2001); Harlow, Lañe y Harlow, Using Antibodies: A Laboratory Manual: Portable Protocol No. I, Coid Spring Harbor Laboratory (1998); y Harlow y Lañe, Antibodies: A Laboratory Manual, Coid Spring Harbor Laboratory; (1988). When a range of values ​​is provided, it is understood that each intermediate value, up to one-tenth of the lower limit, unless the context clearly indicates otherwise, between the upper and lower limits of that range and any other intermediate or established value within that established range, is included within the invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges included within the invention, subject to any limits specifically excluded in the established range. When the established range includes one or both of the limits, the ranges excluding any or both included limits are also included in the invention. Unless otherwise noted, antibody residues in this document are numbered according to the Kabat numbering system (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The following description presents numerous specific details to provide a more complete understanding of the present invention. However, it will be evident to a person skilled in the art that the present invention can be implemented without one or more of these specific details. In other cases, features and procedures known to those skilled in the art have not been described in order to avoid obscuring the invention. All references mentioned throughout the description, including patent applications and publications, are incorporated herein in their entirety by reference. I. Definitions “Comprises” means that the mentioned elements are necessary in the composition / method / kit, but that other elements may be included to form the composition / method / kit, etc., within the scope of the claim. “It essentially consists of” implies a limitation of the scope of the composition or method described to the materials or steps specified that do not materially affect the basic and novel features of the present invention. “Consists of” implies the exclusion from the composition, method or kit of any element, step or ingredient not specified in the claim. The antibody residues herein are numbered according to the Kabat numbering system and the EU numbering system. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1–113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)). The “EU numbering system” or “EU index” is generally used when referring to a residue in a constant region of the immunoglobulin heavy chain (e.g., the EU index stated in Kabat et al., supra). The “EU index as stated in Kabat” refers to the enumeration of residues of human EU IgG1 antibody.Unless otherwise stated herein, references to residue numbers in the variable domain of antibodies mean residue numbering according to the Kabat numbering system. Unless otherwise stated herein, references to residue numbers in the constant domain of antibodies mean residue numbering according to the EU numbering system. Antibodies, also called immunoglobulins, conventionally comprise at least one heavy chain and one light chain, where the amino-terminus domain of the heavy and light chains is of variable sequence, and is therefore commonly called the variable region domain or variable heavy (VH) or variable light (VL) domain. The two domains conventionally associate to form a specific binding region, although, as will be discussed herein, specific binding can also be achieved with variable sequences of only the heavy chain, and a variety of non-natural antibody configurations are known and used in the technique. A “functional” or “biologically active” antibody or antigen-binding molecule (including heavy-chain-only antibodies and three-chain antibody-like molecules (TCAs, described herein)) has the capacity to exert one or more of its natural activities on structural, regulatory, biochemical, or biophysical events. For example, a functional antibody or other binding molecule, such as a TCA, may have the ability to bind specifically to an antigen, and this binding may, in turn, trigger or alter a cellular or molecular event such as signal transduction or enzyme activity. A functional antibody or other binding molecule, such as a TCA, may also block ligand activation of a receptor or act as an agonist or antagonist.The ability of an antibody or other binding molecule, for example, a TCA, to exert one or more of its natural activities depends on several factors, including the proper folding and assembly of the polypeptide chains. The term “antibody” herein is used in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, monomers, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), heavy-chain-only antibodies, trichain antibodies, TCAs, single-chain Fv (scFv), nanobodies, etc., and also includes antibody fragments, provided they exhibit the desired biological activity (Miller et al. (2003) Jour. of Immunology 170:4854-4861). Antibodies may be murine, human, humanized, chimeric, or derived from other species. The term “antibody” may refer to a full-length heavy chain, a full-length light chain, an intact immunoglobulin molecule; or an immunologically active portion of any of these polypeptides, i.e., a polypeptide comprising an antigen-binding site that binds with immunospecificity to an antigen of a target of interest or a portion thereof, where such targets include, but are not limited to, one or more cancer cells that produce autoimmune antibodies associated with an autoimmune disease. The immunoglobulin described herein may be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgGA1, and IgGA2), or subclass of immunoglobulin molecule, including engineered subclasses with altered Fe portions that provide reduced or enhanced effector cell activity.The light chains of the antibodies in question can be kappa light chains (Vkappa) or lambda light chains (Vlambda). Immunoglobulins can be derived from any species. In one respect, immunoglobulin is largely of human origin. The term “monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous antibody population; that is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor quantities. Monoclonal antibodies are highly specific and are directed against a single antigenic site. Furthermore, unlike conventional (polyclonal) antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. Monoclonal antibodies according to the present invention can be prepared using the hybridoma method first described by Kohler et al., (1975) Nature 256:495, and can also be carried out through methods of recombinant protein production (see, for example, US patent no. 24,816,567). The term “variable,” as used in relation to antibodies, refers to the fact that certain parts of the antibody variable domains differ widely in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, variability is not evenly distributed across antibody variable domains. It is concentrated in three segments called hypervariable regions in the light-chain and heavy-chain variable domains. The most widely conserved parts of the variable domains are called flanking regions (FRs). Each of the natural heavy-chain and light-chain variable domains comprises four FRs, which generally adopt a β-sheet configuration, connected by three hypervariable regions that form loops connecting, and in some cases forming part of, the β-sheet structure.The hypervariable regions of each chain are held close to each other by the FRs and, with the hypervariable regions of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The constant domains are not directly involved in the binding of an antibody to an antigen, but they have various effector functions, such as the participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC). The term “hypervariable region” as used herein refers to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region generally comprises amino acid residues from a “complementarity-determining region” or “CDR” (e.g., residues 31–35 (H1), 50–65 (H2), and 95–102 (H3) in the heavy-chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and / or residues from a “hypervariable loop,” residues 26–32 (H1), 53–55 (H2), and 95–101 (H3) in the heavy-chain variable domain; Chothia and Lesk, J. Mol. Biol. 196:901–917 (1987)). In some modalities, “CDR” means a complementarity-determining region of an antibody as defined in Lefranc, MP et al., IMGT, the international database ImMunoGeneTics, Nucleic Acids Res., 27:209-212 (1999)."Frame region" or "FR" residues are those variable domain residues other than hypervariable region / CDR residues as defined herein. This document shows examples of CDR designations; however, a person skilled in the art will understand that several CDR definitions are commonly used, including Kabat's definition (see “Zhao et al. A germline knowledge-based computational approach for determining antibody complementarity determining regions.” Mol Immunol. 2010; 47:694–700), which is based on sequence variability and is the most widely used. Chothia's definition is based on the location of structural loop regions (Chothia et al. “Conformations of immunoglobulin hypervariable regions.” Nature. 1989; 342:877–883). Alternative CDR definitions of interest include, but are not limited to, those described by Honegger, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool.” J Mol Biol. 2001; 309:657–670; Ofran et al. “Automated identification of complementarity determining regions (CDRs) reveal peculiar characteristics of ΙνΙΛ / α / ΖυΖΊ / U I ZZUO CDRs and B-cell epitopes”. J Immunol. 2008;181:6230-6235; Almagro “Identification of differences in the specificity-determining residues of antibodies that recognize antigens of different size: implications for the rational design of antibody repertoires”. J Mol Recognit. 2004;17:132-143; y Padlanet ál. “Identification of specificity-determining residues in antibodies”. Faseb J. 1995;9:133-139, cada una de los cuales se incorpora específicamente mediante referencia. The terms “heavy-chain-only antibody” and “heavy-chain antibody” are used interchangeably herein and refer, in the broadest sense, to antibodies, or more or more portions of an antibody, e.g., one or more arms of an antibody, that lack the light chain of a conventional antibody. Specifically, the terms include, without limitation, homodimeric antibodies comprising the VH antigen-binding domain and the CH2 and CH3 constant domains, in the absence of the CH1 domain; functional (antigen-binding) variants of such antibodies; soluble VH variants; Ig-NAR comprising a homodimer of a variable domain (V-NAR) and five C-type constant domains (C-NAR) and functional fragments thereof; and soluble single-domain antibodies (sUniDabs™).In one embodiment, a heavy-chain-only antibody comprises a variable-region antigen-binding domain consisting of frame 1, CDR1, frame 2, CDR2, frame 3, CDR3, and frame 4. In another embodiment, a heavy-chain-only antibody comprises an antigen-binding domain, at least part of a hinge region, and CH2 and CH3 domains. In yet another embodiment, a heavy-chain-only antibody comprises an antigen-binding domain, at least part of a hinge region, and a CH2 domain. In a further embodiment, a heavy-chain-only antibody comprises an antigen-binding domain, at least part of a hinge region, and a CH3 domain. Also included herein are heavy-chain-only antibodies in which the CH2 and / or CH3 domains are truncated.In one additional embodiment, a heavy chain is composed of an antigen-binding domain and at least one CH domain (CH1, CH2, CH3, or CH4) but without a hinge region. The heavy chain-only antibody may be in the form of a dimer, in which two heavy chains are linked by disulfide bonds or otherwise covalently or non-covalently linked to each other. The heavy chain-only antibody may belong to the IgG subclass, but antibodies belonging to other subclasses, such as IgM, IgA, IgD, and IgE, are also included herein. In one particular embodiment, a heavy chain antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype, specifically the IgG1 subtype. In one embodiment, the heavy chain-only antibodies herein are used as a binding (targeting) domain of a chimeric antigen receptor (CAR).The definition specifically includes human heavy chain-only antibodies, produced by transgenic human immunoglobulin rats (UniRat™), called UniAbs™. The variable (VH) regions of UniAbs™ are called UniDabs™ and are versatile building blocks that can be linked to Fe regions or serum albumin for the development of novel therapies with multiple specificities, increased potency, and extended half-life. Because homodimeric UniAbs™ lack a light chain and therefore a VL domain, the antigen is recognized by a single domain, namely the variable domain of the heavy chain of a heavy chain antibody (VH or VHH). An “intact antibody chain,” as used herein, is one that comprises a full-length variable region and a full-length constant region (Fe). An intact “conventional” antibody comprises an intact light chain and an intact heavy chain, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, hinge, CH2, and CH3 for secreted IgG. Other isotypes, such as IgM or IgA, may have different CH domains. The constant domains may be constant domains of a natural sequence (e.g., constant domains of a native human sequence) or amino acid sequence variants thereof. The intact antibody may have one or more “effector functions,” which refer to those biological activities that can be attributed to the Fe constant region (a native sequence Fe region or an amino acid sequence variant Fe region) of an antibody.Examples of antibody effector functions include C1q binding, complement-dependent cytotoxicity, iron receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and downregulation of cell surface receptors. Constant region variants include those that alter the effector profile, iron receptor binding, and similar functions. Based on the amino acid sequence of the Fe (constant domain) in their heavy chains, antibodies and various antigen-binding proteins can be classified into different classes. There are five main classes of Fe heavy chain regions: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (sotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA, and IgG2. The Fe constant domains corresponding to the different antibody classes are designated α, δ, ε, y, and μ, respectively. The subunit structures and three-dimensional configurations of different immunoglobulin classes are well understood. Ig forms include hinge modifications or non-hinge forms (Roux et al., (1998) J. Immunol. 161:4083-4090; Lund et al., (2000) Eur. J. Biochem. 267:7246-7256; US 2005 / 0048572; US 2004 / 0229310).The light chains of antibodies from any vertebrate species can be assigned to one of two types, designated κ (kappa) and λ (lambda), based on the amino acid sequences of their constant domains. Antibodies according to the embodiments of the invention can comprise either kappa light chain sequences or lambda light chain sequences. A “functional Fe region” possesses an “effector function” of a naturally occurring Fe region. Non-limiting examples of effector functions include C1q binding, CDC binding, Fe receptor binding, ADCC, ADCP, downregulation of cell surface receptors (e.g., B cell receptor), etc. Such effector functions generally require the Fe region to interact with a receptor, for example, the FcyRI, FcyRIIA, FcyRI1BI, FcyRIIB2, FcyRIIIA, FcyRI11B receptors and the low-affinity FcRn receptor, and this can be assessed using various known assays. A “dead” or “silenced” Fe region is one that has been mutated to retain activity with respect to, for example, extended serum half-life, but which does not activate a high-affinity Fe receptor or has a lower affinity for such a receptor. A “native sequence Fe region” comprises an amino acid sequence identical to the amino acid sequence of a naturally occurring Fe region. Human native sequence Fe regions include, for example, a native sequence human lgG1 Fe region (A and non-A allotypes); a native sequence human lgG2 Fe region; a native sequence human lgG3 Fe region; and a native sequence human lgG4 Fe region, as well as naturally occurring variants of these. A “variant Fe region” comprises an amino acid sequence that differs from that of a naturally occurring Fe region by virtue of at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fe region has at least one amino acid substitution compared to a naturally occurring Fe region or the Fe region of an original polypeptide, for example, from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a naturally occurring Fe region or in the Fe region of the original polypeptide.The variant Fe region in this specification will preferably have at least about 80% homology with respect to a naturally occurring Fe region and / or with an Fe region of an original polypeptide and, more preferably, at least about 90% homology with respect to this, more preferably at least about 95% homology with respect to this. Variant Fe sequences may include three amino acid sequences in the CH2 region to reduce FcyRI binding at positions 234, 235, and 237 according to the EU index (see Duncan et al., (1988) Nature 332:563). Two amino acid substitutions at the complement C1q binding site at positions 330 and 331 according to the EU index reduce complement fixation (see Tao et al., J. Exp. Med. 178:661 (1993) and Canfield and Morrison, J. Exp. Med. 173:1483 (1991)). Substitution in human lgG1 or lgG2 residues at positions 233-236 and lgG4 residues at positions 327, 330, and 331 greatly reduces ADCC and CDC (see, for example, Armor KL et al., 1999 Eur J Immunol. 29(8):2613-24; and Shields RL et al., 2001 J Biol Chem. 276(9):6591-604). The Fe amino acid sequence of human lgG4 (UniProtKB No. P01861) is provided herein as SEQ ID NO: 76. Silenced lgG1 is described, for example, in Boesch AW et al., “Highly parallel characterization of IgG Fe binding interactions”. MAbs, 2014. 6(4): p. 915-27, whose description is incorporated herein in its entirety by means of this reference. Other Fe variants are possible, including, but not limited to, one in which a region capable of forming a disulfide bond is deleted, or in which certain amino acid residues are removed from the N-terminus of a natural Fe molecule, or a methionine residue is added to it. Therefore, in some embodiments, one or more Fe components of the antibody may comprise one or more mutations in the hinge region to eliminate disulfide bonds. In yet another embodiment, the hinge region of an Fe molecule may be completely removed. In still another embodiment, an antibody may comprise an Fe variant. Furthermore, an Fe variant can be constructed to remove or substantially reduce effector functions by substituting (mutating), deleting, or adding amino acid residues that effect complement binding or Fe receptor binding. By way of example, a deletion can occur at a complement binding site, such as a C1q binding site. Techniques for preparing such derivatives from immunoglobulin Fe fragment sequences are described in International Patent Publications n.sWO 97 / 34631 and WO 96 / 32478. Additionally, the Fe domain can be modified by phosphorylation, sulfation, acylation, glycosylation, methylation, farnesylation, acetylation, amidation, and similar processes. In some embodiments, an antibody comprises a variant human IgG4 CH3 domain sequence comprising a T366W mutation, which may optionally be referred to herein as an IgG4 CHS button sequence. In some embodiments, an antibody comprises a variant human IgG4 CH3 domain sequence comprising a T366S mutation, an L368A mutation, and a Y407V mutation, which may optionally be referred to herein as an IgG4 CH3 button sequence. The IgG4 CH3 mutations described herein may be used in any suitable manner to place a “button” in a first heavy-chain constant region of a first monomer in an antibody dimer, and a “buttonhole” in a second heavy-chain constant region of a second monomer in an antibody dimer, thereby facilitating the appropriate pairing (heterodimerization) of the desired pair of heavy-chain polypeptide subunits in the antibody. In some embodiments, an antibody comprises a heavy-chain polypeptide subunit comprising a variant human IgG4 Fe region comprising an S228P mutation, an F234A mutation, an L235A mutation, and a T366W mutation (button). In some embodiments, an antibody comprises a heavy-chain polypeptide subunit comprising a variant human IgG4 Fe region comprising an S228P mutation, an F234A mutation, an L235A mutation, a T366S mutation, an L368A mutation, and a Y407V mutation (button). The expression “antibody comprising an Fe region” refers to an antibody comprising an Fe region. It is possible to remove the C-terminus lysine (residue 447 according to the EU numbering system) from the Fe region, for example, during antibody purification or by recombinant modification of the nucleic acid encoding the antibody. Accordingly, an antibody with an Fe region according to the present invention may comprise an antibody with or without K447. Aspects of the invention include antibodies comprising a heavy-chain-only variable region in a monovalent or bivalent configuration. As used herein, the term “monovalent configuration” as used with reference to a heavy-chain-only variable region domain means that only one heavy-chain-only variable region domain is present, having a single binding site (see FIG. 5, Panel A, right arm of antibody). In contrast, the term “bivalent configuration” as used with reference to a heavy-chain-only variable region domain means that two heavy-chain-only variable region domains are present (each having a single binding site), and are connected by a linker sequence (see FIG. 5, Panels B and C, right arms of antibodies).Non-exhaustive examples of linker sequences are further discussed herein and include, but are not limited to, GS linker sequences of various lengths. When a heavy-chain-only variable region is in a bivalent configuration, each of the two heavy-chain-only variable region domains may have binding affinity for the same antigen or for different antigens (e.g., different epitopes of the same protein; two different proteins, etc.). However, unless specifically stated otherwise, a heavy-chain-only variable region described as being in a “bivalent configuration” is understood to contain two identical heavy-chain-only variable region domains connected by a linker sequence, where each of the two heavy-chain-only variable region domains has binding affinity for the same target antigen. Aspects of the invention include antibodies having multispecific configurations, including, without limitation, bispecific, trispecific, etc. A wide variety of methods and protein configurations are known and used in bispecific monoclonal antibodies (BsMAB), trispecific antibodies, etc. Various methods have been developed for the production of multivalent artificial antibodies by recombinant fusion of variable domains from two or more antibodies. In some embodiments, a first and second antigen-binding domain in a polypeptide are linked by a polypeptide linker. A non-exhaustive example of such a polypeptide linker is a GS linker, which has an amino acid sequence of four glycine residues, followed by a serine residue, and where the sequence is repeated n times, where n is an integer ranging from 1 to approximately 10, such as 2, 3, 4, 5, 6, 7, 8, or 9. Non-exhaustive examples of such linkers include GGGGS (SEQ ID NO: 73) (n=1) and GGGGGSGGGGS (SEQ ID NO: 74) (n=2). Other suitable linkers may also be used, and are described, for example, in Chen et al., Adv Drug Deliv Rev. 2013, October 15; 65 (10): 1357-69, the description of which is incorporated here by reference in its entirety. The term “three-chain antibody-like molecule” or “TCA” is used herein to refer to antibody-like molecules comprising, essentially consisting of, or consisting of three polypeptide subunits, two of which comprise, essentially consisting of, or consisting of a heavy chain and a light chain of a monoclonal antibody, or functional antigen-binding fragments of such antibody chains, comprising an antigen-binding region and at least one OH domain. This heavy chain / light chain pair has binding specificity with respect to an antigen primer.The third polypeptide subunit comprises, essentially consists of, or consists of a single heavy-chain antibody comprising an Fe portion comprising CH2 and / or CH3 and / or CH4 domains, in the absence of a CH1 domain, and one or more antigen-binding domains (e.g., two antigen-binding domains) that bind to an epitope of a second antigen or a different epitope of the first antigen, wherein said binding domain is derived from or has sequence identity with the variable region of an antibody light or heavy chain. Portions of that variable region may be encoded by gene segments VHy / Vl, D and Jh, or Jl gene segments. The variable region may be encoded by rearranged gene segments VhDJh, VlDJh, VhJl, or VlJl. A TCA-binding compound utilizes a “heavy-chain-only antibody,” “heavy-chain antibody,” or “heavy-chain polypeptide,” which, as used herein, means a single-chain antibody comprising the CH2 and / or CH3 and / or CH4 heavy-chain constant regions, but not containing a CH1 domain. In one embodiment, the heavy-chain antibody comprises an antigen-binding domain, at least part of a hinge region, and the CH2 and CH3 domains. In another embodiment, the heavy-chain antibody comprises an antigen-binding domain, at least part of a hinge region, and a CH2 domain. In a further embodiment, the heavy-chain antibody comprises an antigen-binding domain, at least part of a hinge region, and a CH3 domain. Also included herein are heavy-chain antibodies in which the CH2 and / or CH3 domain is truncated.In one additional embodiment, the heavy chain is composed of an antigen-binding domain and at least one CH domain (CH1, CH2, CH3, or CH4) but without a hinge region. The heavy-chain-only antibody may be in the form of a dimer, in which two heavy chains are disulfide-linked or otherwise covalently or non-covalently coupled to each other and, optionally, include an asymmetric interface between one or more of the CH domains to facilitate proper pairing between polypeptide chains. The heavy-chain antibody may belong to the IgG subclass, but antibodies belonging to other subclasses, such as the IgM, IgA, IgD, and IgE subclasses, are also included herein. In one particular embodiment, the heavy-chain antibody is of the lgG1, lgG2, lgG3, or lgG4 subtype, specifically the lgG1 or lgG4 subtype.Non-exhaustive examples of a TCA-binding compound are described, for example, in documents WO2017 / 223111 and WO2018 / 052503, the descriptions of which are incorporated herein by reference in full. Heavy chain antibodies constitute about a quarter of the IgG antibodies produced by camelids, e.g., camels and llamas (Hamers-Casterman C., et al. Nature. 363, 446-448 (1993)). These antibodies are composed of two heavy chains but lack light chains. Consequently, the variable antigen-binding region is called the VHH domain and represents the smallest naturally occurring intact antigen-binding site, with a length of only 120 amino acids (Desmyter, A., et al. J. Blol. Chem. 276, 26285-26290 (2001)). Heavy chain antibodies with high specificity and affinity against a variety of antigens can be generated through immunization (van der Linden, RH, et al. Biochim. Biophys. Acta. 1431, 37-46 (1999)) and the VHH portion can be easily cloned and expressed in yeast (Frenken, LGJ, et al. J. Biotechnol. 78, 11-21 (2000)).Their expression levels, solubility, and stability are significantly higher than those of the classical F(ab) or Fv fragments (Ghahroudi, MA et al. FEBS Lett. 414, 521-526 (1997)). Sharks have also been shown to have a unique VH-like domain in their antibodies, called VNAR (Nuttall et al. Eur. J. Biochem. 270, 3543-3554 (2003); Nuttall et al. Function and Bioinformatics 55, 187-197 (2004); Dooley et al., Molecular Immunology 40, 25-33 (2003)). The term “PSMA,” as used herein, refers to a type II transmembrane protein that has alpha-bound N-acetylated acid depeptidase, folate hydrolase, and dipeptidyl peptidase activity. The term “PSMA” includes PSMA protein from any human and non-human animal species, and specifically includes human PSMA as well as PSMA from non-human mammals. The term “human PSMA,” as used herein, includes any variant, isoform, and species homolog of human PSMA (UniProt Q04609), regardless of its source or method of preparation. Therefore, “human PSMA” includes human PSMA naturally expressed by cells and PSMA expressed in cells transfected with the human PSMA gene. The terms “anti-PSMA heavy chain antibody only,” “PSMA heavy chain antibody only,” “anti-PSMA heavy chain antibody,” and “PSMA heavy chain antibody” are used interchangeably herein to refer to a single heavy chain antibody, as defined above, that binds immunospecifically to PSMA, including human PSMA, as defined above. This definition includes, without limitation, human heavy chain antibodies produced by transgenic animals, such as transgenic rats or transgenic mice expressing human immunoglobulin, including UniRats™, which produces human anti-PSMA antibodies, as defined above. “Percentage (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing spaces, if necessary, to achieve the maximum percentage of sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be achieved in several ways known to those skilled in the art, for example, by using publicly available software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR).Experts in the technique can determine appropriate parameters for aligning the sequences, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. For the purposes of this document, however, the amino acid sequence identity percentage values ​​are generated using the ALIGN-2 sequence comparison software. An “isolated” antibody is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminating components of its natural environment are materials that would interfere with the diagnostic or therapeutic uses of the antibody and may include enzymes, hormones, and other protein or non-protein solutes. In preferred modalities, the antibody shall be purified (1) to more than 95% by weight of the antibody, as determined by the Lowry method, and more preferably more than 99% by weight, (2) to a point sufficient to yield at least 15 residues of internal or N-terminal amino acid sequence, by means of a rotating cup sequencer, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions, using Coomassie blue or, preferably, silver dye.The isolated antibody includes the antibody in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. Generally, however, the isolated antibody will be prepared through at least one purification step. The antibodies of the invention include multispecific antibodies. Multispecific antibodies have more than one binding specificity. The term “multispecific” specifically includes “bispecific” and “trispecific,” as well as higher-order independent specific binding affinities, such as higher-order polyepitope specificity, as well as tetravalent antibodies and antibody fragments. The terms “multispecific antibody,” “multispecific heavy-chain-only antibody,” “multispecific heavy-chain antibody,” and “multispecific UniAb™” are used herein in the broadest sense and cover all antibodies with more than one binding specificity. The multispecific heavy-chain anti-PSMA antibodies of the present invention specifically include antibodies that bind immunospecifically to two or more non-overlapping epitopes on a PSMA protein, such as a human PSMA (i.e., bivalent and biparatopic).The multispecific heavy-chain anti-PSMA antibodies of the present invention also specifically include antibodies that bind immunospecifically to an epitope on a PSMA protein, such as human PSMA, and to an epitope on a different protein, such as, for example, a CD3 protein, such as human CD3 (i.e., bivalent and biparatopic). The multispecific heavy-chain anti-PSMA antibodies of the present invention also specifically include antibodies that bind immunospecifically to two or more non-overlapping or partially overlapping epitopes on a PSMA protein, such as human PSMA, and to an epitope on a different protein, such as, for example, a CD3 protein, such as human CD3 (i.e., trivalent and biparatopic). The antibodies of the invention include monospecific antibodies, which have a binding specificity. Monospecific antibodies specifically include antibodies comprising a single binding specificity, as well as antibodies comprising more than one binding unit with the same binding specificity. The terms “monospecific antibody,” “monospecific heavy-chain-only antibody,” “monospecific heavy-chain antibody,” and “monospecific UniAb™” are used herein in the broadest sense and encompass all antibodies with a binding specificity. The monospecific heavy-chain anti-PSMA antibodies of the present invention specifically include antibodies that bind immunospecifically to an epitope on a PSMA protein, such as a human PSMA (monovalent and monospecific).The monospecific heavy-chain anti-PSMA antibodies of the present invention also specifically include antibodies having more than one binding unit (e.g., multivalent antibodies) that bind immunospecifically to an epitope on a PSMA protein, such as human PSMA. For example, a monospecific antibody according to the embodiments of the invention may include a heavy-chain variable region comprising two antigen-binding domains, where each antigen-binding domain binds to the same epitope on a PSMA protein (i.e., bivalent and monospecific). An “epitope” is the site on the surface of an antigen molecule to which a single antibody molecule binds. Generally, an antigen has several or many different epitopes and reacts with many different antibodies. The term specifically includes linear epitopes and conformational epitopes. Epitope mapping is the process of identifying the binding sites, or epitopes, of antibodies on their target antigens. Antibody epitopes can be linear epitopes or conformational epitopes. Linear epitopes are formed by a continuous sequence of amino acids in a protein. Conformational epitopes are formed from discontinuous amino acids that join together after the protein folds into its three-dimensional structure. “Polyepitopic specificity” refers to the ability to bind specifically to two or more different epitopes on one or more identical or different targets. As stated above, the present invention specifically includes anti-PSMA heavy chain antibodies with polyepitopic specificities, namely, anti-PSMA heavy chain antibodies that bind to one or more non-overlapping epitopes on a PSMA protein, such as a human PSMA; and anti-PSMA heavy chain antibodies that bind to one or more epitopes on a PSMA protein and one epitope on a different protein, such as, for example, a CD3 protein. The term “non-overlapping epitopes” or “non-competitive epitopes” of an antigen is defined herein to mean epitope(s) that are recognized by one member of an antigen-specific antibody pair, but not by the other member.Antibody pairs or antigen-binding regions that target the same antigen on a multispecific antibody recognize that non-overlapping epitopes do not compete to bind to that antigen and can bind to that antigen simultaneously. An antibody binds “essentially to the same epitope” as a reference antibody when the two antibodies recognize identical or spherically overlapping epitopes. The most widely used and rapid methods for determining whether two epitopes bind to identical or spherically overlapping epitopes are competition assays, which can be configured in a number of different formats, for example, by using a labeled antigen or labeled antibody. Usually, the antigen is immobilized on a 96-well plate, and the ability of unlabeled antibodies to block the binding of labeled antibodies is measured using radioactive or enzymatic labels. The term “valent”, as used herein, refers to a specified number of binding sites on an antibody molecule. A "monovalent" antibody has one binding site. Therefore, a monovalent antibody is also monospecific. A “multivalent” antibody has two or more binding sites. Therefore, the terms “bivalent,” “trivalent,” and “tetravalent” refer to the presence of two, three, and four binding sites, respectively. Thus, a bispecific antibody according to the invention is at least bivalent and may be trivalent, tetravalent, or otherwise multivalent. A bivalent antibody according to the embodiments of the invention may have two binding sites to the same epitope (i.e., bivalent, monoparatopic) or to two different epitopes (i.e., bivalent, biparatopic). A wide variety of methods and protein configurations are known and used for the preparation of bispecific monoclonal antibodies (BsMAB), trispecific antibodies, and the like. The term “three-chain antibody-like molecule” or “TCA” is used herein to refer to antibody-like molecules comprising, essentially consisting of, or consisting of three polypeptide subunits, two of which comprise, essentially consisting of, or consisting of a heavy chain and a light chain of a monoclonal antibody, or functional antigen-binding fragments of such antibody chains, comprising an antigen-binding region and at least one CH domain. This heavy chain / light chain pair has binding specificity with respect to an antigen primer.The third polypeptide subunit comprises, essentially consists of, or consists of a heavy-chain single-antibody comprising an Fe portion comprising CH2 and / or CH3 and / or CH4 domains, in the absence of a CH1 domain, and an antigen-binding domain that binds an epitope of a second antigen or a different epitope of the first antigen, wherein said binding domain is derived from, or has sequence identity with, the variable region of an antibody light or heavy chain. Portions of that variable region may be encoded by gene segments VHy / Vl, D and Jh, or Jl gene segments. The variable region may be encoded by rearranged gene segments VhDJh, VlDJh, VhJl, or VlJl. A TCA protein uses a heavy-chain single-antibody as defined above. The term “chimeric antigen receptor” or “CAR” is used herein in the broadest sense to refer to a genetically modified receptor that grafts a desired binding specificity (e.g., the antigen-binding region of a monoclonal antibody or other ligand) onto intracellular, membrane-spanning signaling domains. Typically, the receptor is used to graft the specificity of a monoclonal antibody onto a T lymphocyte to create chimeric antigen receptors (CARs). (J Nati Cancar Inst, 2015; 108(7):dvj439; and Jackson et al., Nature Reviews Clinical Oncology, 2016; 13:370-383). CAR-T cells are T lymphocytes that have been genetically modified to produce an artificial T-cell receptor for use in immunotherapy.In one modality, “CAR-T cell” means a therapeutic T lymphocyte that expresses a transgene encoding one or more chimeric antigen receptors comprising at least one extracellular domain, one transmembrane domain, and at least one cytosolic domain. The term “human antibody” is used herein to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies herein may include amino acid residues not encoded by human germline immunoglobulin sequences, for example, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo. The term “human antibody” specifically includes heavy-chain-only antibodies having human heavy-chain variable region sequences produced by transgenic animals, such as transgenic rats or mice, in particular UniAbs™ produced by UniRats™, as defined above. The term “chimeric antibody” or “chimeric immunoglobulin” means an immunoglobulin molecule comprising amino acid sequences from at least two different Ig loci, for example, a transgenic antibody comprising a portion encoded by a human Ig locus and a portion encoded by a rat Ig locus. Chimeric antibodies include transgenic antibodies with non-human Fe regions or artificial Fe regions, and human idiotypes. Such immunoglobulins can be isolated from the animals of the invention that have been genetically modified to produce such chimeric antibodies. As used herein, the term “effector cell” refers to an immune cell involved in the effector phase of an immune response, as opposed to the activation and cognitive phases. Some effector cells express specific iron receptors and perform specific immune functions. In some cases, an effector cell, such as a natural killer cell, is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). For example, monocytes and macrophages, which express FcR, are involved in the specific destruction of target cells and in presenting antigens to other components of the immune system, or in binding to antigen-presenting cells. In some cases, an effector cell can phagocytize a target antigen or target cell. Human effector cells are leukocytes that express receptors such as T-cell receptors or FcR and perform effector functions. Preferably, the cells express at least FcγRIII and perform an ADCC effector function. Examples of human leukocytes that mediate ADCC include natural killer (NK) cells, monocytes, cytotoxic T lymphocytes, and neutrophils; NK cells are preferred. Effector cells can be isolated from a natural source, such as blood or PBMCs, as described herein. The term “immune cell” is used herein in the broadest sense, which includes, without limitation, cells of myeloid or lymphoid origin, e.g., lymphocytes (such as B lymphocytes and T lymphocytes, including cytolytic T lymphocytes (CTLs)), killer cells, natural killer (NK) cells, macrophages, monocytes, eosinophils, polymorphonuclear cells such as neutrophils, granulocytes, mast cells, and basophils. ML / a / ZUZ 1 / un zzuo Antibody “effector functions” refer to those biological activities that can be attributed to the Fe region (a naturally occurring Fe region or an amino acid sequence variant Fe region) of an antibody. Examples of antibody effector functions include C1q binding; complement-dependent cytotoxicity (CDC); Fe receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR), etc. “Antibody-dependent cell-mediated cytotoxicity” and “ADCC” refer to a cell-mediated reaction in which nonspecific cytotoxic cells expressing Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize binding antibodies on a target cell and subsequently cause infection of the target cell. The primary cells to mediate ADCC, NK cells, express only FcyRIII, whereas monocytes express FcyR1, FcyR1, and FcyRIII. FcR expression in hematopoietic cells is summarized in Table 3, on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To evaluate the ADCC activity of a molecule of interest, an in vitro ADCC assay can be performed, such as that described in U.S. Patent No. 5,500,362 or 5,821,337.The effector cells useful for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of the molecule of interest can be evaluated in vivo, for example, in an animal model, such as that described in Clynes et al. PNAS (USA) 95:652-656 (1998). “Complement-dependent cytotoxicity” or “CDC” refers to the ability of a molecule to lyse a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g., an antibody) in complex with a cognate antigen. To assess complement activation, a CDC assay can be performed, for example, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). “Binding affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise stated, as used herein, “binding affinity” refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured using common methods known in the art. Low-affinity antibodies generally bind to the antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind to the antigen more rapidly and tend to remain bound. As used herein, “Kd” or “Kd value” refers to a dissociation constant determined by BioLayer interferometry using a QK384 octet instrument (Fortebio Inc., Menlo Park, CA) in kinetics mode. For example, anti-mouse Fe sensors are loaded with mouse Fe-fused antigen and then immersed in wells containing antibody to measure concentration-dependent association rates (kon). Antibody dissociation rates (koff) are measured in the final step, where the sensors are immersed in wells containing only buffer solution. Kd is the ratio of koff / kon. (For more information, see Concepción, J., et al., Comb Chem High Throughput Screen, 12(8), 791–800, 2009). The terms “treatment,” “treat,” and similar terms are used herein generally to refer to achieving a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of the total or partial prevention of a disease or a symptom thereof, and / or therapeutic in terms of the partial or complete cure of a disease and / or an adverse effect attributable to the disease. “Treatment,” as used herein, encompasses any treatment of a disease in a mammal and includes: (a) preventing the onset of the disease in a subject who may be predisposed to the disease but has not yet been diagnosed, (b) inhibiting the disease, i.e., halting its progression, or (c) alleviating the disease, i.e., causing the disease to regress. The therapeutic agent may be administered before, during, or after the onset of the disease or injury.The treatment of the disease as it progresses, where the treatment stabilizes or reduces the patient's undesirable clinical symptoms, is of particular interest. Such treatment is preferably carried out before complete loss of function in the affected tissues. The therapy in question will be administered during the symptomatic stage of the disease and, in some cases, after the symptomatic stage of the disease. A “therapeutically effective amount” refers to the quantity of an active agent needed to provide a therapeutic benefit to a subject. For example, a “therapeutically effective amount” is an amount that induces, improves, or otherwise brings about an improvement in pathological symptoms, disease progression, or physiological conditions associated with a disease, or that improves resistance to a disorder. The term “prostate cancer”, as used herein, refers to a malignant tumor of glandular origin in the prostate gland. The term “characterized by PSMA expression” refers broadly to any disease or disorder in which PSMA expression is associated with or implicated in one or more pathological processes that are characteristic of the disease or disorder. Such disorders include, but are not limited to, prostate cancer. The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a mammal being evaluated for and / or undergoing treatment. In one modality, the mammal is a human being. The terms “subject,” “individual,” and “patient” include, but are not limited to, individuals with cancer, individuals with autoimmune diseases, with pathogenic infections, and the like. Subjects may be human, but may also include other mammals, particularly those mammals useful as laboratory models for human diseases, e.g., mice, rats, etc. The term “pharmaceutical formulation” refers to a preparation in a form that allows the biological activity of the active ingredient to be effective and that does not contain any additional components unacceptably toxic to a subject to whom the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those that can be reasonably administered to a mammalian subject to provide an effective dose of the active ingredient used. A “sterile” formulation is aseptic, or free or essentially free of all living microorganisms and their spores. A “frozen” formulation is at a temperature below 0°C. A “stable” formulation is one in which the protein essentially retains its physical and / or chemical stability and / or biological activity after storage. Preferably, the formulation essentially retains its physical and chemical stability, as well as its biological activity, after storage. The storage period is generally selected based on the desired half-life of the formulation. Various analytical techniques for measuring protein stability are available and are described in Peptide and Protein Drug Delivery, 247301. Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90) (1993), for example. Stability can be measured at a selected temperature for a selected period of time.Stability can be assessed qualitatively and / or quantitatively in a variety of ways, including assessing aggregate formation (e.g., by using size exclusion chromatography, by measuring turbidity, and / or by visual inspection); assessing charge heterogeneity using cation exchange chromatography, capillary isoelectric focusing (icIEF), or capillary zone electrophoresis; amino-end or carboxy-end sequence analysis; mass spectrometry analysis; SDS-PAGE analysis to compare reduced and intact antibody; peptide map analysis (e.g., tryptic or LYS-C); assessing the antibody's biological activity or antigen-binding function; and so on.Instability may involve any one or more of: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), trimming / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteines, N-end extension, C-end processing, glycosylation differences, etc. II. Detailed description Anti-PSMA antibodies The present invention provides a family of closely related antibodies that bind to human PSMA. The antibodies in this family comprise a set of CDR sequences as defined herein and shown in Table 1 and illustrated by the heavy chain variable region (HV) sequences provided from SEQ IDs 24 to 54 listed in Table 2. The antibody family provides several advantages that contribute to its usefulness as clinically therapeutic agents. The antibodies include members with a variety of binding affinities, allowing for the selection of a specific sequence with a desired affinity. Table 1: CDR amino acid sequences unique to anti-PSMA heavy chain antibody. SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 GGSISSSSYY (SEQ ID NO: 1) IDYSGYT (SEQ ID NO: 11) ARHKAATADFDY (SEQ ID NO: 18) GGSISSSNYF (SEQ ID NO: 2) VDYSGYT (SEQ ID NO: 12); AREPRIGYYYESSGYDSLDY (SEQ ID NO: 19) GGSISSNSYY (SEQ ID NO: 3) IYDSGST (SEQ ID NO: 13) AREPRIGYYYESSGYYSLDY (SEQ ID NO: 20) GFSFRSYG (SEQ ID NO: 4) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYDSSGYDSLDY (SEQ ID NO: 21) GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRVGYYYETSGYYSLDY (SEQ ID NO: 23) GFSFSYG (SEQ ID NO: 7) ISYDGSNR (SEQ ID NO: 17) GFSFTSYG (SEQ ID NO: 8) Table 2. Amino acid sequences of the variable domain of the chain antibody P 5 esada anti-PSMA. N.- de id. de clon SEQ_aa_FR1_FR4 SEQ ID NO. 10 325920 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGK GLEWIGSIDYS GYTYYNPSLQSRVTISVDTSKNQFSLKLSSVTAADTAVYNCARHKA ATADFDYR GQGTLVTVSS 24 15 346181 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSNYFWGWIRQSPGK GLEWIGSIDYS GYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYNCARHKA ATADFDYR GQGTLVTVSS 25 20 346165 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGK GLEWIGSVDYS GYTYYNPSLQSRVTISVDTSKNQFSLKLSSVTAADTAVYNCARHKA ATADFDYR GQGTLVTVSS 26 25 346172 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGK GLEWIGSIDYS GYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYNCARHKA ATADFDYR GQGTLVTVSS 27 30 326109 QLQLQESGPGLVKPSETLSLTCTVSGGSISSNSYYWGWIRQSPGK GLEWLGSIYDS GSTHYNPSLKSRVIISGDTSKNQFSLKLSSVTAADTAVYYCARHKAA TADFDYRG QGTLVTVSS 28 35 325867 QVQLVESGGGVVQPGRSLRLSCAASGFSFRSYGMHWVRQAPGK GLEWVAVIWY DGSNKYYADSVKGRFTISRDYSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYDSLDYRGQGTLVTVSS 29 325742 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGK 30 N.2 de id. de clon SEQ_aa_FR1_FR4 SEQ ID NO. GLEWVAVIWY DGSNKYYADSVKGRFTISRDYSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYDSLDYRGQGTLVTVSS 325748 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGK GLEGVAVIWY DGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 31 325940 QVQLVESGGGVVQPGRSLRLSCAASGFIFRSYGMHWVRQAPGKG PEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 32 325836 QVQLVESGGGVVQPGRSLRLSCAASGFSFRSYGMHWVRQAPGK GLEWVAVIWY DGSNKYYADSVKGRFTISRDYSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYD SSGYDSLDYRGQGTLVTVSS 33 326027 QVQLVESGGGVVQPGRSLRLSCAASGFSFRSYGMHWVRQAPGK GLEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYD SSGYDSLDYRGQGTLVTVSS 34 326087 QVQLVESGGGVVQPGRSLRLSCAASGFIFRSYGMHWVRQAPGKG PEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYD SSGYDSLDYRGQGTLVTVSS 35 326084 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGK GLEGVAVIWY DGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYD 36 MA / a / ZUZI / U I zzuo N.2 de id. de clon SEQ_aa_FR1_FR4 SEQ ID NO. SSGYYSLDYRGQGTLVTVSS 326028 QVQLVESGGGVVQPGRSLRLSCAASGFSFRSYGMHWVRQAPGK GLEWVAVISY DGSNKYYADSVKGRFTISRDYSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYD SSGYDSLDYRGQGTLVTVSS 37 345497 QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGK GLEGVAVIWY DGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 38 326029 QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGK GLEWVAVISY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRVGYYY ETSGYYSLDYRGQGTLVTVSS 39 345461 QVQLVESGGGVVQPGRSLRLSCAASGFSFTSYGMHWVRQAPGK GLEGVAVIWY DGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 40 345493 QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGK GLEWVAVIWY DGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 41 345436 QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGK GLEGVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 42 345443 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGK GLEGVAVIWY 43 N.2 of id. of clone SEQ_aa_FR1_FR4 SEQ ID NO. EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 345510 QVQLVESGGGVVQPGRSLRLSCAASGFFSYGMHWVRQAPGK GLEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYCAR EPRIGGGYLDYS 57 345438 QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGK GPEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EPRIGYYYE SSGYYSLDYRGQGTLVTVSS 58 Selective anti-accuracy those provided in the present for development and therapeutic or other use, including, but not limited to, use as a bispecific antibody, for example, as shown in FIG. 5, panels AC, or a trispecific antibody, or as part of a CAR-T cell structure. FIG. 5, panels AC, provides illustrations of multispecific anti-CD3 x anti-PSMA antibodies, where the anti-PSMA domain is monovalent and monospecific, bivalent and monospecific, or bivalent and bispecific (biparatopic). The anti-CD3 domain contains a CH1 domain and pairs with a light chain, whereas the anti-PSMA domains are derived from heavy-chain-only antibodies and do not contain a CH1 domain or interact with a light chain. In some modalities, the two heavy chains are cleaved by the use of, for example, button-in-button technology. Returning to the antibodies depicted in FIG.Panel A represents a bispecific anti-CD3 x anti-PSMA antibody where the anti-PSMA binding arm is monovalent and monospecific, and the antigen-binding domain of the anti-PSMA arm is in a monovalent configuration, meaning only one antigen-binding domain is present. Panel B shows a bispecific anti-CD3 x anti-PSMA antibody where the anti-PSMA binding arm is bivalent and monospecific, and the antigen-binding domain of the anti-PSMA arm is in a bivalent configuration, meaning there are two identical antigen-binding domains located in tandem. Panel C represents a bispecific anti-CD3 x anti-PSMA antibody where the anti-PSMA binding arm is bivalent and biparatopic, and the antigen-binding domains of the anti-PSMA arm are in a bivalent configuration. Affinity determination for a candidate protein can be performed using established techniques, such as Biacore measurements. Members of the antibody family can have an affinity for PSMA with a Kd of approximately 10⁻⁶a to 10⁻¹¹, and even, but not limited to: approximately 10⁻⁶a to 10⁻¹⁰; approximately 10⁻⁶a to 10⁻⁹; approximately 10⁻⁶a to 10⁻⁸; approximately 10⁻⁸a to 10⁻¹¹; approximately 10⁻⁸a to 10⁻¹⁰; approximately 10⁻⁸a to 10⁻⁹; approximately 10⁻⁹a to 10⁻¹⁰; or any value within these ranges. Affinity selection can be confirmed with a biological evaluation to modulate, for example, block, a biological activity of PSMA, including in vitro assays, preclinical models and clinical trials, as well as the evaluation of potential toxicity. The members of the present antibody family do not exhibit cross-reactivity with the Cynomolgus macaque PSMA protein, but can be modified to provide cross-reactivity with the Cynomolgus macaque PSMA protein or with PSMA from any other animal species, if desired. The PSMA-specific antibody family described herein comprises a VH domain, which includes CDR1, CDR2, and CDR3 sequences within a human VH structure. The CDR sequences may be located, for example, in the region around amino acid residues 26–33, 51–58, and 97–116 for CDR1, CDR2, and CDR3, respectively, of the illustrative variable region sequences provided, as set out in SEQ ID NO: 24 to 58. A person skilled in the art will understand that the CDR sequences may be in different positions if a different frame sequence is selected, although the order of the sequences will generally remain the same. The CDR1, CDR2, and CDR3 sequences of the anti-PSMA antibodies of the present invention may be included in the following structural formulas, where an X indicates a variable amino acid, which may be a specific amino acid as will be indicated below. CDR1 GGSISS Xi X2Y X3(SEQ ID NO: 67) where Xi is S or N; X2 is S or N; and X3 is Y or F; and CDR2 X4X5Xe SG X7T (SEQ ID NO: 68) where X4is I or V; ινΐΛ / a / zuz 1 / un ¿zuo X5es D or Y; Xe is Y or D; and X7es Y or S; and CDR3 ARHKAATADFDY (SEQ ID NO: 69) The CDR1, CDR2, and CDR3 sequences of the anti-PSMA antibodies of the present invention may be included in the following structural formulas, where an X indicates a variable amino acid, which may be a specific amino acid as will be indicated below. CDR1 GF Xi F X2X3Y G (SEQ ID NO: 70) where Xi is S, I or T; X2 is S, T, R or I; and X3 is R or S; and CDR2 I X4Y DGSN X5(SEQ ID NO: 71) where X4is W or S; and Xs is R or K; and CDR3 AREP RXSG YYY X7Xs SGY X9S LD Y (SEQ ID NO: 72) where X8is I or V; X7 is E or D; X8 is S or T; and X8es Y or D. Representative sequences of CDR1, CDR2, and CDR3 are shown in Tables 1 and 3. Table 3: Amino acid sequences of CDR1, CDR2, and CDR3 of the anti-PSMA heavy chain antibody. Ns of id. of clone SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 325920 GGSISSSSYY (SEQ ID NO: 1) IDYSGYT (SEQ ID NO: 11) ARHKAATADFDY (SEQ ID NO: 18) 346181 GGSISSSSEQ (IDF ID NO: 2) IDYSGYT (SEQ ID NO: 18) NO: 11) ARHKAATADFDY (SEQ ID NO: 18) 346165 GGSISSSSYY (SEQ ID NO: 1) VDYSGYT (SEQ ID NO: 12) ARHKAATADFDY (SEQ ID NO: 18) 346172 GGSISSSSYY (SEQ ID NO: 18) (SEQ ID NO: IDY: IDY NO: 1) 11) ARHKAATADFDY (SEQ ID NO: 18) N.9 de id. de clon SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 326109 GGSISSNSYY (SEQ ID NO: 3) IYDSGST (SEQ ID NO: 13) ARHKAATADFDY (SEQ ID NO: 18) 5 325867 GFSFRSYG (SEQ ID NO: 4) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYDSL DY (SEQ ID NO: 19) 10 325742 GFSFSSYG (SEQ ID NO: 5) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYDSL DY (SEQ ID NO: 19) 325748 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 15 325940 GFIFRSYG (SEQ ID NO: 6) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 20 325836 GFSFRSYG (SEQ ID NO: 4) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYDSSGYDSL DY (SEQ ID NO: 21) 326027 GFSFRSYG (SEQ ID NO: 4) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYDSSGYDSL DY (SEQ ID NO: 21) 25 326087 GFIFRSYG (SEQ ID NO: 6) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYDSSGYDSL DY (SEQ ID NO: 21) 326084 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYDSSGYYSL DY (SEQ ID NO: 22) 30 326028 GFSFRSYG (SEQ ID NO: 4) ISYDGSNK (SEQ ID NO: 16) AREPRIGYYYDSSGYDSL DY (SEQ ID NO:21) 345497 GFSFSRYG (SEQ ID NO: 7) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) ΙνΙΛ / α / ΖυΖΊ / UI ZZU3 N.2 de id. de clon SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 326029 GFSFSRYG (SEQ ID NO: 7) ISYDGSNK (SEQ ID NO: 16) AREPRVGYYYETSGYYS LDY (SEQ ID NO: 23) 345461 GFSFTSYG (SEQ ID NO: 8) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345493 GFSFSRYG (SEQ ID NO: 7) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345436 GFSFSRYG (SEQ ID NO: 7) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345443 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345490 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345482 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345485 GFSFRSYG (SEQ ID NO: 4) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345463 GFIFRSYG (SEQ ID NO: 6) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 325932 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20)345505 GFTFISYG (SEQ ID NO: 9) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) MA / a / ZUZI / UI zzuo N.2 de id. de clon SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 345508 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345480 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 326116 GFSFSRYG (SEQ ID NO: 7) ISYDGSNK (SEQ ID NO: 16) AREPRIGYYYDSSGYDSL DY (SEQ ID NO: 21) 345509 GFSFSSYG (SEQ ID NO: 5) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345444 GFTFSSYG (SEQ ID NO: 10) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345421 GFSFSSYG (SEQ ID NO: 5) IWYDGSNR (SEQ ID NO: 15) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345447 GFSFSSYG (SEQ ID NO: 5) ISYDGSNR (SEQ ID NO: 17) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345510 GFSFSSYG (SEQ ID NO: 5) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) 345438 GFSFSSYG (SEQ ID NO: 5) IWYDGSNK (SEQ ID NO: 14) AREPRIGYYYESSGYYSL DY (SEQ ID NO: 20) In some modality, an anti-PSMA antibody comprises a CDR1 sequence from any of the SEQ ID NO: 1-10. In one particular modality, the CDR1 sequence is SEQ ID NO: 2 or 7. In some modality, an anti-PSMA antibody comprises a CDR2 sequence from any of the SEQ ID NO: 11-17. In one particular modality, the CDR2 sequence is SEQ ID NO: 11 or 15. In some modalities, an anti-PSMA antibody comprises a CDR3 sequence iviA / a / ¿u¿ i / un ¿¿uo from any of SEQ ID NO: 18-23. In one particular modality, the CDR3 sequence is SEQ ID NO: 18 or 20. In an additional embodiment, a heavy-chain-only anti-PSMA antibody comprises the CDR1 sequence of SEQ ID NO: 2; the CDR2 sequence of SEQ ID NO: 11; and the CDR3 sequence of SEQ ID NO: 18. In an additional modality, an anti-PSMA antibody comprises the CDR1 sequence of SEQ ID NO:7 and the CDR2 sequence of SEQ ID NO:15; and the CDR3 sequence of SEQ ID NO:20. In an additional modality, an anti-PSMA antibody comprises any of the amino acid sequences of the variable region of the heavy chain of SEQ ID NO: 24 to 58 (Table 2). In another modality, an anti-PSMA antibody comprises the heavy chain variable region sequence of SEQ ID NO: 25. In another modality, an anti-PSMA antibody comprises the heavy chain variable line sequence of SEQ ID NO: 38. In some embodiments, a CDR sequence in an anti-PSMA antibody of the invention comprises one or two amino acid substitutions with respect to a CDR1, CDR2 and / or CDR3 sequence or set of CDR1, CDR2 and CDR3 sequences in any of the SEQ ID NO: 1 to 23 (Table 1). In some embodiments, an anti-PSMA antibody preferably comprises a heavy chain variable (H) domain in which the CDR3 sequence has a sequence identity greater than or equal to 80%, such as at least 85%, at least 90%, at least 95%, or at least 99% at the amino acid level with a CDR3 sequence of any of the antibodies whose CDR3 sequences are provided in Table 1, and binds to PSMA. In some embodiments, an anti-PSMA antibody preferably comprises a heavy chain variable domain (HV) in which the complete set of CDRs 1, 2, and 3 (combined) has a sequence identity greater than or equal to 85% (eighty-five percent) at the amino acid level with the CDRs 1, 2, and 3 (combined) of antibodies whose CDR sequences are provided in Table 1, and binds to PSMA. In some embodiments, an anti-PSMA antibody preferably comprises a heavy chain variable domain (HV) in which the complete set of CDRs 1, 2, and 3 (combined) has a sequence identity greater than or equal to 85% (eighty-five percent) at the amino acid level with the CDRs 1, 2, and 3 (combined) of antibodies whose CDR sequences are provided in Table 3, and binds to PSMA. In some embodiments, an anti-PSMA antibody comprises a heavy chain variable region sequence with at least about 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, at least 98% identity, or at least at least 99% identity with any of the heavy chain variable region sequences of SEQ ID NO: 24 to 58 (shown in Table 2), and binds to PSMA. In some embodiments, bispecific or multispecific antibodies are provided, which may have any of the configurations discussed herein, including, but not limited to, a bispecific three-chain antibody (TCA)-like molecule. In some embodiments, a multispecific antibody may comprise at least one heavy-chain variable region that has binding specificity for PSMA, and at least one heavy-chain variable region that has binding specificity for a protein other than PSMA. In some embodiments, a multispecific antibody may comprise a heavy-chain variable region comprising at least two antigen-binding domains, where each of the antigen-binding domains has binding specificity for PSMA.In some embodiments, a multispecific antibody may comprise a heavy / light chain pair that has binding specificity for a prime antigen (e.g., CD3) and a heavy chain of a single heavy chain antibody. In certain embodiments, the heavy chain of the single heavy chain antibody comprises an Fe moiety comprising CH2, CH3, and / or CH4 domains, in the absence of a CH1 domain. In one particular embodiment, a bispecific antibody comprises a heavy / light chain pair that has binding specificity for an antigen on an effector cell (e.g., a CD3 protein on a T lymphocyte) and a heavy chain of a single heavy chain antibody comprising an antigen-binding domain that has binding specificity for PSMA. In some embodiments, a multispecific antibody comprises a CD3-binding VH domain paired with a light chain variable domain. In certain embodiments, the light chain is a fixed light chain. In some embodiments, the CD3-binding VH domain comprises a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60, and a CDR3 sequence from SEQ ID NO: 61, within a human VH frame. In some embodiments, the fixed light chain comprises a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63, and a CDR3 sequence from SEQ ID NO: 64, within a human VL frame. Together, the CD3-binding VH domain and the light chain variable domain have binding affinity for CD3. In some embodiments, the CD3-binding VH domain comprises the heavy chain variable region sequence from SEQ ID NO: 65.In some embodiments, a CD3-binding VH domain comprises a sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% identity with the heavy chain variable region sequence of SEQ ID NO: 65. In some embodiments, a fixed light chain comprises a light chain variable region sequence of SEQ ID NO: 66. In some embodiments, a fixed light chain comprises a sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% identity with the heavy chain variable region sequence of SEQ ID NO: 66. The multispecific antibodies comprising the CD3-binding VH domain and the light chain variable domain described above have advantageous properties, for example, as described in PCT application number WO2018 / 052503, the description of which is incorporated herein by reference in its entirety. Any of the multispecific antibodies and antigen-binding domains described herein that have PSMA-binding affinity can be combined with the CD3-binding domains and fixed light chain domains described herein (see, for example, Table 4 and Table 5), as well as additional sequences, such as those provided in Table 6 and Table 7, to generate multispecific antibodies that have binding affinity to one or more PSMA epitopes, as well as to CD3. Table 4. Amino acid sequences of anti-CD3 light and heavy chain CDR1, CDR2, CDR3. SEQ_aa_CDR1 SEQ_aa_CDR2 SEQ_aa_CDR3 Heavy chain GFTFDDYA (SEQ ID NO: 59) ISWNSGSI (SEQ ID NO: 60) AKDSRGYGDYRLGGAY (SEQ ID NO: 61) Light chain QSVSSN (SEQ ID NO: 62) GAS (SEQ ID NO: 63) QQYNNWPWT (SEQ ID NO: 64) Tab 5. Secuencias de aminoácidos de región variable de cadena ligera y pesada antiCD3. VH EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEW VSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYC AKDSRGYGDYRLGGAYWGQGTLVTVSS (SEQ ID NO: 65) VL EIVMTQSPATLSVSPGERATLLSCRASQSVSSNLAWYQQKPGQAPRLLIYG ASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPWTFGQ GTKVEIK (SEQ ID NO: 66) Table 6: Sections of the region Fe of IgG 1 and lgG4 humans igGi humana (UniProt n.° P01857) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO: 75) lgG4 humana (UniProt n.° P01861) ASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPPVTVS WNSGALTCGVHTFPAVLQSSGLYSLSSVVTVPSSSSLGTKT YTCNVDHKPSNTKVDKVESKYGPPCPSCPAPEFLGGPSV FLFPPKDTLMISRTPEVVVVW GVEVHNACTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQNQHVHQHVHKH LSLSLGK (SEQ ID NO: 76) human lgG1 with silencing mutations (Fe region) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSSVTVPSSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNCALPAPIEKTISKKGQPREPQVYTLM EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 77). human igG4 with silencing mutations (Fe region) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT KVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 78) Table 7: Additional sequences. Sequence of the constant region of the anti-CD3 light chain (kappa light chain) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLSKADYEKHKVYACEVTHQGL SSPVTSKSF (IDGECQ79) ID NOCU antiCD3 heavy chain (VH + Fe of lgG1 wt) EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA LYYCAKDSRGYGDYRLGGGGGSTGGGGGGGSTGGGGVPGGKGGL KSTSGGTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVVVVDVSHEDPEWK FNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNCALPAPIEKTISKKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 80) Secuencia de cadena pesada antiCD3 (con Fe de lgG1 silenciada) EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA LYYCAKDSRGYGDYRLGGAYWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 81) Secuencia de región constante de cadena pesada antiCD3 (con Fe de lgG4 wt) EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA LYYCAKDSRGYGDYRLGGAYWGQGTLVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 82) AntiCD3 heavy chain constant region sequence (with Fe of lgG4 silenced) EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA LYYCAKDSRGYGDYRLGGAYWGQGTLVSSASTKGPSVFPPLAPCS RSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVVVVDVSQEDPEVQFN WYVDGVEVHNACTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIECTISCAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 83) IVIA / a / ¿U¿ I / UI ¿ZUO lgG4 silenced (hinge - CH2 - CH3; buttonhole (S228P, F234A, L235A; T366S, L368A, Y407V)) ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 84) lgG4 silenced (hinge - CH2 CH3; buttonhole (S228P, F234A, L235A;T366W)) ESKYGPPCPPCPAPEEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLLPSQEEM TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 85) Cadena ligera de longitud completa anti-CD3 (VL + kappa CL) EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRL LIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNW PWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 86) Cadena pesada anti-CD3 de longitud completa (VH + Fe de lgG4 silenciado + botón (S228P, F234A, L235A;T366W)) EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA LYYCAKDSRGYGDYRLGGAYWGQGTLVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLWCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 87); MA / a / ZUZI / U I ZZUO Cadena pesada monovalente de PSMA (id. de clon 346181) + Fe de lgG4 silenciada, ojal (S228P, F234A, L235A, T366S, L368A, Y407V QLQLQESGPGLVKPSETLSLTCTVSGGSISSSNYFWGWIRQSPGKGL EWIGSIDYSGYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY NCARHKAATADFDYRGQGTLVTVSSESKYGPPCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCS VMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 88) PSMA bivalent weight chain (id.of clone 346181) + Fe of lgG4 silenced, ojal (S228P, F234A, L235A, T366S, L368A, Y407V QLQLQESGPGLVKPSETLSLTCTVSGGSSSNYFWGWIRQSPGKGL EWIGSIDYSGYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY NCARHKAATADFDYRGQGTLVSSGGGGSGGGSQLQLQESGPG LVKPSETLSLTCTVSGGSSSNYFWGWIRQSPGKGLEWIGSIDYSG YTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYNCARHKAATA DFDYRGQGTLVTVSSESKYGPPCPPCPAPEAAGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNACTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSIEKTISKKGQ PREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQSEKSLG: IDKSLG: NO: IDK89 heavy monovalent PSMA (id.of clone 345497) + Fe of silenced lgG4, ojal (S228P, F234A, L235A, T366S, L368A, Y407V QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGKGL EGVAVIWYDGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA VYYCAREPRIGYYESGYYSLDYRGQGTLVTVSSESKYGPPCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVVVVDVSQEDPEVQFN WYVDGVEVHNACTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 90). MA / a / ZUZI / UI ZZUO 5 10 15 20 25 30 35 PSMA bivalent heavy chain (clone id. 345497) + silenced lgG4 Fe, eyelet (S228P, F234A, L235A, T366S, L368A, Y407V QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGKGL EGVAVIWYDGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA VYYCAREPRIGYYESGYYSLDYRGQGTLVTVSSGGGGGGGGGS QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGKGL EGVAVIWYDGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA VYYCAREPRIGYYESGYYSLDYRGQGTLVTVSSESKYGPPCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSIEKTISKKGQPREPQVYTLPPSQEEMTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 91) PSMA bivalent heavy chain (clone id. 346181 x id.of clone 345497) + Fe lgG4 silenced, ojal (S228P, F234A, L235A, T366S, L368A, Y407V QLQLQESGPGLVKPSETLSLTCTVSGGSSSNYFWGWIRQSPGKGL EWIGSIDYSGYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY NCARHKAATADFDYRGQGTLVSSGGGGGGGSQVQLVESGG GVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGKGLEGVAVIWYD GSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREPR IGYYESGYYSLDYRGQGTLVSSESKYGPPCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSI EKTISKKGQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQGNVFSCN SVMSEQSQSLYKHSLYKHSLYKH NO: 92) PSMA bivalent heavy chain (clone id. 345497 x id.of clone 346181) + Fe lgG4 silenced, ojal (S228P, F234A, L235A, T366S, L368A, Y407V QVQLVESGGGVVQPGRSLRLSCAASGFSFSRYGMHWVRQAPGKGL EGVAVIWYDGSNRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA VYYCAREPRIGYYESGYSLDYRGQGTLVSSGGGGSGGGS QLQLQESGPGLVKPSETLSLTCTTVSGGSSSNYFWGWIRQSPGKGL EWIGSIDYSGYTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY NCARHKAATADFDYRGQGTLVTVSSESKYGPPCPPCPAPEAAGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVVHN ACTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQGNVFSNVFSQSQSLYKHKSLYKHKSLY NO: 93). MA / a / ZUZI / UI zzuo In some embodiments, bispecific or multispecific antibodies are provided, which may have any of the configurations discussed herein, including, but not limited to, a bispecific three-chain antibody (TCA)-like molecule. In some embodiments, a bispecific antibody may comprise at least one heavy-chain variable region having binding specificity for PSMA, and at least one heavy-chain variable region having binding specificity for a protein other than PSMA. In some embodiments, a bispecific antibody may comprise a heavy-chain / light-chain pair having binding specificity for a first antigen, and a heavy-chain single-antibody heavy chain comprising an Fe portion comprising CH2 and / or CH3 and / or CH4 domains, in the absence of a CH1 domain, and an antigen-binding domain binding an epitope of a second antigen or an epitope different from the first antigen.In one particular modality, a bispecific antibody comprises a heavy chain / light chain pair that has binding specificity for an antigen on an effector cell (e.g., a CD3 protein on a T lymphocyte) and a heavy chain of a heavy chain-only antibody comprising an antigen-binding domain that has binding specificity for PSMA. In some embodiments, when an antibody of the invention is a bispecific antibody, one arm of the antibody (a binding residue or a binding unit) is specific for human PSMA, while the other arm may be specific for target cells, tumor-associated antigens, targeted antigens (e.g., integrins), pathogenic antigens, checkpoint proteins, and the like. Target cells specifically include cancer cells, including, without limitation, solid tumor cells (e.g., prostate tumors), as described below. In some embodiments, one arm of the antibody (a binding residue or a binding unit) is specific for human PSMA, while the other arm is specific for CD3. In some embodiments, an antibody comprises an anti-CD3 light chain polypeptide comprising the sequence of SEQ ID NO: 66 linked to the sequence of SEQ ID NO: 79, an anti-CD3 heavy chain polypeptide comprising the sequence of any of SEQ ID NO: 80, 81, 82, 83, 84 or 85, and an anti-PSMA heavy chain polypeptide comprising the sequence of any of SEQ ID NO: 24-58, in a monovalent or bivalent configuration, linked to the sequence of any of SEQ ID NO: 75, 76, 77, 78, 84 or 85. These sequences can be combined in various ways to produce a bispecific antibody of a desired IgG subclass, e.g., lgG1, lgG4, silenced lgG1, silenced lgG4. In a preferred embodiment, an antibody is a TCA comprising a first polypeptide comprising SEQ ID NO: 86, a second polypeptide comprising SEQ ID NO: 87 and a third polypeptide comprising SEQ ID NO: 88, 89, 90, 91, 92 or 93.In a preferred embodiment, an antibody is a TCA consisting of a first polypeptide consisting of SEQ ID NO: 86, a second polypeptide consisting of SEQ ID NO: 87, and a third polypeptide consisting of SEQ ID NO: 88, 89, 90, 91, 92, or 93. Various multispecific antibody formats are within the scope of the invention, including, without limitation, single-chain polypeptides, two-chain polypeptides, three-chain polypeptides, four-chain polypeptides, and multiples thereof. The multispecific antibodies herein specifically include multispecific T-cell antibodies (e.g., bispecific) that bind to PSMA and CD3 (anti-PSMA x anti-CD3 antibodies). Such antibodies induce potent T-cell-mediated cell death of PSMA-expressing cells. Preparation of anti-PSMA antibodies The antibodies of the present invention can be prepared by methods known in the art. In a preferred embodiment, the antibodies of the present invention are produced by transgenic animals, including transgenic mice and rats, preferably rats, in which the endogenous immunoglobulin genes are inactivated or disabled. In a preferred embodiment, the heavy chain antibodies of the present invention are produced in UniRat™. UniRat™ has its endogenous immunoglobulin genes silenced and uses a human immunoglobulin heavy chain translocus to express an optimized repertoire of diverse, naturally occurring, fully human HCAbs.While endogenous immunoglobulin loci in rats can be deactivated or silenced using a variety of technologies, in UniRat™ zinc finger (endo)nuclease (ZNF) technology was used to inactivate the endogenous rat J heavy chain locus, Ck light chain locus, and CA light chain locus. ZNF constructs for oocyte microinjection can produce lines with IgH and IgL knockouts (KOs). For further details, see, for example, Geurts et al., 2009, Science 325:433. The characterization of rats with Ig heavy chain knockouts has been reported by Menoret et al., 2010, Eur. J. Immunol. 40:2932-2941. The advantages of ZNF technology are that joining non-homologous ends to silence a gene or locus by deletions of up to several kb can also provide a target site for homologous integration (Cui et al., 2011, Nat Biotechnol 29:64-67).Human heavy chain antibodies produced in UniRat™ are called UniAbs™ and can bind to epitopes that cannot be targeted by conventional antibodies. Their high specificity, affinity, and small size make them ideal for both single- and multi-specific applications. In addition to UniAbs™, this document specifically includes heavy-chain-only antibodies lacking the VHH structure and camelid mutations, as well as their functional VH regions. Such heavy-chain-only antibodies can be produced, for example, in transgenic rats or mice comprising fully human heavy-chain-only gene loci, as described, for example, in WO2006 / 008548, but other transgenic mammals, such as rabbit, guinea pig, and rat, can also be used, with rats and mice being preferred. Heavy-chain-only antibodies, including their functional VHH or VH fragments, can also be produced using recombinant DNA technology by expressing the coding nucleic acid in a suitable eukaryotic or prokaryotic host, including, for example, mammalian cells (e.g., CHO cells), E. coli, or yeast. Heavy-chain-only antibody domains combine the advantages of antibodies and small-molecule drugs: they can be monovalent or multivalent, have low toxicity, and are inexpensive to manufacture. Due to their small size, these domains are easy to administer, including orally or topically; they are characterized by high stability, including gastrointestinal stability; and their half-life can be tailored to the desired use or indication. Furthermore, the VH and VHH domains of heavy-chain antibodies can be manufactured cost-effectively. In one particular embodiment, the heavy chain antibodies of the present invention, including UniAbs™, have the native amino acid residue at the first position of the FR4 region (amino acid position 101 according to the Kabat numbering system) substituted with another amino acid residue capable of disrupting an exposed hydrophobic patch on the surface comprising, or associated with, the native amino acid residue at that position. Such hydrophobic patches are normally buried at the interface with the constant region of the antibody's light chain, but are exposed on the surface in the HCAbs and are, at least partially, susceptible to unwanted accumulation and association of the HCAb's light chain. The substituted amino acid residue is preferably, and more preferably, positively charged, such as lysine (Lys, K), arginine (Arg, R), or histidine (His, H), preferably arginine (R).In a preferred embodiment, the heavy chain antibodies derived from transgenic animals contain a Trp to Arg mutation at position 101. The resulting HCAbs preferably have high antigen-binding affinity and solubility under physiological conditions in the absence of accumulation. As part of the present invention, it was identified that human IgG anti-PSMA heavy chain antibodies with unique sequences from UníRat™ animals (UníAb™) bind to human PSMA in cell-binding ELISA assays. The identified heavy chain variable (HV) region sequences are positive for binding to human PSMA protein and / or for binding to PSMA+ cells, and all are negative for binding to cells that do not express PSMA. See, for example, Table 8. Heavy chain antibodies that bind to non-overlapping epitopes on a PSMA protein, such as UniAbs™, can be identified using competitive binding assays, such as enzyme-linked immunosorbent assays (ELISAs) or flow cytometry competitive binding assays. For example, one can use competition between Known antibodies that bind to the target antigen and the antigen of interest. Using this approach, one can divide a pool of antibodies into those that compete with the reference antibody and those that do not. Non-competitive antibodies are identified as binding to a distinct epitope that does not overlap with the epitope bound by the reference antibody. Often, an antibody is immobilized, the antigen is bound, and a second labeled antibody (e.g., Bioti ni) is tested in an ELISA to determine its ability to bind to the captured antigen. This can also be performed using surface plasmon resonance (SPR) platforms, including the ProteOn XPR36 (BioRad, Inc.), Biacore 2000 and Biacore T200 (GE Healthcare Life Sciences), and the MX96 SPR imager (Ibis Technologies BV).), as well as on biofilm interferometry platforms, such as Octet Red384 and Octet HTX (ForteBio, Pall Inc). For further details, see the examples herein. Typically, an antibody “competes” with a reference antibody if it causes a reduction of approximately 15–100% in the binding of the reference antibody to the target antigen, as determined by standard techniques such as the competitive binding assays described above. In various modalities, the relative inhibition is at least approximately 15%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, at least approximately 55%, at least approximately 60%, at least approximately 65%, at least approximately 70%, at least approximately 75%, at least approximately 80%, at least approximately 85%, at least approximately 90%, at least approximately 95%, or more. Pharmaceutical compositions, uses and treatment methods Another aspect of the present invention is to provide pharmaceutical compositions comprising one or more antibodies of the present invention mixed with a suitable pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers used herein include, but are not limited to, adjuvants, solid carriers, water, buffer solutions, or other carriers used in the art to contain therapeutic components, or combinations thereof. In one embodiment, a pharmaceutical composition comprises a heavy chain antibody (e.g., UnlAb™) that binds to PSMA. In another embodiment, a pharmaceutical composition comprises a multispecific (including bispecific) heavy chain antibody (e.g., UnlAb™) with binding specificity for two or more non-overlapping epitopes on a PSMA protein. In a preferred embodiment, a pharmaceutical composition comprises a multispecific (including bispecific and TCA) heavy chain antibody (e.g., UniAb™) with binding specificity for PSMA and with binding specificity for a binding target on an effector cell (e.g., a binding target on a lymphocyte). T, such as, for example, a CD3 protein on a T lymphocyte). The pharmaceutical compositions of antibodies according to the present invention are prepared for storage by mixing proteins of the desired purity with optional physiologically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), such as in the form of lyophilized formulations or aqueous solutions. The acceptable carriers, excipients, or stabilizers are non-toxic to the recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens, such as methyl or propyl-paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol);Low molecular weight polypeptides (less than approximately 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes) and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under Good Manufacturing Practice (GMP) conditions. The pharmaceutical compositions may be provided as a unit dosage (i.e., the dosage for a single administration). The formulation depends on the chosen route of administration. The antibodies herein may be administered by intravenous injection or infusion, or subcutaneously. For administration by injection, the antibodies herein may be formulated in aqueous solutions, preferably in physiologically compatible buffer solutions to reduce discomfort at the injection site. The solution may contain carriers, excipients, or stabilizers as discussed above.Alternatively, the antibodies can be in lyophilized form for constitution with a suitable vehicle, e.g., sterilized pyrogen-free water, prior to use. Antibody formulations are described, for example, in U.S. Patent No. 9,034,324. Similar formulations can be used for the heavy-chain antibodies, including the UniAbs™ of the present invention. Subcutaneous antibody formulations are described, for example, in documents US20160355591 and US20160166689. Methods of use IVIA / a / ZUZ I / un ¿zuo The anti-PSMA antibodies and pharmaceutical compositions described herein may be used for the treatment of diseases and conditions characterized by PSMA expression, including, but not limited to, the conditions and diseases described later herein. PSMA is a type II transmembrane protein expressed in prostate epithelial tissue and upregulated in prostate cancer and the neovasculature of solid tumors. It is also expressed at low levels in healthy tissues such as the brain, kidneys, and salivary glands, but its overexpression in malignant prostate tissue makes it an attractive target for prostate cancer therapy. It may also be relevant for solid tumor therapy or imaging, given its high expression in malignant neovasculature. Monoclonal antibodies, antibody-drug conjugates, and PSMA-targeted chimeric antigen receptor T lymphocytes have been described for the treatment of metastatic prostate cancer (Hernandez-Hoyos et al., 2016, PMID: 27406985, DiPippo et al., 2014, PMID: 25327986, Serganova et al., 2016, PMID: 28345023).In addition, PSMA-specific radionuclide conjugates are being investigated for prostate cancer imaging and treatment (e.g., Hofman et al., 2018 PMID: 29752180). In one respect, anti-PSMA antibodies (e.g., UniAbs™) and the pharmaceutical compositions herein may be used to treat disorders characterized by PSMA expression, including, but not limited to, prostate cancer and solid tumors. The effective doses of the compositions of the present invention for the treatment of diseases vary depending on many different factors, including the means of administration, the target site, the physiological state of the subject, whether the subject is a human or an animal, other medications administered, and whether the treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals can also be treated, for example, companion animals such as dogs, cats, horses, etc., laboratory mammals such as rabbits, mice, rats, etc., and the like. Treatment dosages can be titrated to optimize safety and efficacy. Dosage levels can be easily determined by the physician and can be modified as required, for example, to adjust a subject's response to therapy. The amount of active ingredient that can be combined with carrier materials to produce an individual dosage form varies depending on the host being treated and the specific route of administration. Unit-dose forms will generally contain between approximately 1 mg and approximately 500 mg of active ingredient. In some formulations, the therapeutic dose of the agent may vary from approximately 0.0001 to 100 mg / kg, and more commonly from 0.01 to 5 mg / kg, of the host's body weight. For example, dosages may be 1 mg / kg of body weight or 10 mg / kg of body weight, or within the range of 1–10 mg / kg. An example of a treatment regimen involves administration once every two weeks, once a month, or once every 3 to 6 months. The therapeutic entities of the present invention are usually administered on multiple occasions. The intervals between single doses may be weekly, monthly, or annually. The intervals may also be irregular, as indicated by measuring the blood levels of the therapeutic entity in the patient. Alternatively, the therapeutic entities of the present invention may be administered as a sustained-release formulation, in which case less frequent administration is required.Dosage and frequency vary depending on the half-life of the polypeptide in the patient. Typically, the compositions are prepared as injectables, either as solutions or liquid suspensions; solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be prepared. The pharmaceutical compositions herein are suitable for subcutaneous or intravenous administration, directly or after reconstitution of solid compositions (e.g., lyophilized). The preparation may also be emulsified or encapsulated in liposomes or microparticles, such as a polylactide, polyglycolide, or copolymer, for an enhanced adjuvant effect, as described above. (Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28:97-119, 1997). The agents of the present invention may be administered as a depot injection or implant preparation, which may be formulated to permit sustained or pulsatile release of the active ingredient.Pharmaceutical compositions are generally formulated as sterile, substantially isotonic, and in full compliance with all Good Manufacturing Practices (GMP) regulations of the U.S. Food and Drug Administration. The toxicity of the antibodies and antibody structures described herein can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the lethal dose for 50% of the population) or the LD100 (the lethal dose for 100% of the population). The ratio of toxic to therapeutic effect is the therapeutic index. Data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that is non-toxic for human use. The dosages of the antibodies described herein are preferably within a range of circulating concentrations that includes the effective dose with little or no toxicity. The dosage may vary within this range, depending on the dosage form and route of administration.The private physician can choose the exact formulation, route of administration, and dosage in view of the patient's disorder. The compositions for administration will commonly include an antibody or other ablation agent dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. Various aqueous carriers may be used, for example, buffered saline solution and the like. These solutions are sterile and generally free of undesirable matter. These compositions can be sterilized by well-known conventional sterilization techniques. The compositions may contain pharmaceutically acceptable excipients, as required to approximate physiological conditions, such as buffering and pH-adjusting agents, toxicity-adjusting agents, and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.The concentration of active agent in these formulations can vary widely and will be selected primarily based on fluid volumes, viscosities, body weight and the like, according to the particular mode of administration selected and the patient's needs (e.g., Remington's Pharmaceutical Science (15th ed., 1980) and Goodman & Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)). Also within the scope of the invention are kits comprising the active agents and formulations thereof, and instructions for use. A kit may further contain at least one additional reagent, for example, a chemotherapeutic drug, etc. Kits typically include a label indicating the intended use of the kit's contents. The term "label," as used herein, includes any writing or recorded material supplied in or with a kit, or otherwise accompanying a kit. Now that the invention has been fully described, it will be evident to the person skilled in the art that various changes and modifications can be made without departing from the spirit or scope of the invention. EXAMPLES Materials and methods Example 1: Immunization of UniRat™ with recombinant human PSMA Twelve UniRat™ animals were immunized with recombinant human PSMA protein fused to a histogram tag (R&D Systems cat. no.: 4234-ZN). The animals were immunized twice weekly for eight weeks. After a 35-day immunization period, serum was collected from the rats to determine serum titers. Serum titration results Summary serum titer information is shown in Figure 1, panels AB. In the graphs shown in Figure 1, panels AB, each line represents an individual animal. The graph legends show the identification number of each individual animal. Binding activity for a 12-point serum dilution series was tested by ELISA against a human PSMA+His-tagged protein and a His-tagged off-target protein. Among this group of animals, a range of serum reactivity levels to the human PSMA protein was observed. No serum response to the His-tagged off-target protein was observed. Example 2: Flow cytometry analysis of PSMA binding to positive and negative cells using UniAbs™ anti-PSMA PSMA-positive cell binding was assessed by flow cytometry (Guava easyCyte 8HT, EMD Millipore) using the LNCaP cell line (ATOO: CRL-1740), the 22Rv1 cell line (ATCC CRL-2505), a PC3 cell line (ATCC CRL-1435) stably transfected to express human PSMA, or the DU-145 cell line (ATCC HTB-81). In summary, 50,000 target cells were stained with a series of dilutions of purified UniAbs™ for 30 minutes at 4 SC. After incubation, the cells were washed twice with flow cytometry buffer (1X PBS, 1% BSA, 0.1% NaN3) and stained with R-phycoerythrin (PE) conjugated goat F(abj2) IgG anti-human antibody (Southern Biotech, n.sde cat. 204209) to detect cell-bound antibodies. After a 20-minute incubation at 4 SC, the cells were washed twice with flow cytometry buffer and the mean fluorescence intensity (MFI) was measured by flow cytometry.The MFI of cells stained with the secondary antibody was used only for background signal determination, and the binding of each antibody was rendered as a fold against the background. Binding to PSMA-positive cynomolgus cells was determined using the same protocol with the following modifications: the target cells were Freestyle 293-F cells (ThermoFisher R79007) transiently transfected to express the extracellular domain of cynomolgus PSMA. In some experiments, EC50 values ​​were calculated using GraphPad Prism 7. Table 8 summarizes the target-binding activity of several of the anti-PSMA heavy chain antibodies (HCAbs) described herein. Column 1 indicates the HCAb clone ID. Column 2 indicates LNCaP cell binding measured as a fold over the background MFI signal. Table 8: Binding to the cell line expressing PSMA Column 1: CLONE ID Column 2: LNCaP 325920 282 346181 264 346165 243 346172 216 326109 25 325867 210 325742 200 325748 193 Column 1: ID. FROM CLONE Column 2: LNCaP 325940 169 325836 163 326027 138 326087 129 326084 125 326028 117 345497 112 326029 109 345461 102 345493 101 345436 87 345443 84 345490 80 345482 80 345485 71 345463 68 325932 64 345505 59 345508 55 345480 47 326116 38 345509 37 345444 23 345421 22 345447 14 345510 13 345438 13 ML / a / ZUZ 1 / U1 zzuo The differences in PSMA binding of cynomolgus, as shown in FIG. 2, panels A and B, support the difference in the human PSMA epitope recognized by HCAb 346181 and 345497. Example 3: Binding to recombinant proteins using biolayer interferometry (BLI) Using biolayer interferometry, the binding competition between the two antibody families to which clone ID 345497 and clone ID 346181 belong was evaluated. Antigen-antibody epitope clustering analysis was performed using Octet QK-384 (ForteBio). Briefly, anti-Penta HIS capture sensors (HIS1K) were used to immobilize the antigen, recombinant human PSMA (R&D Systems catalog number: 4234ZN), for 120 seconds. After baseline readings, the sensors were immersed in solutions containing antibody 1 (325867) for 300 seconds, and another baseline reading was taken for 60 seconds. The sensors were then immersed in wells containing either antibody 1 as a positive control for blocking or antibody 2 (325920). Association and dissociation rates were measured for 300 and 600 seconds, respectively. Data analysis was performed using Octet Data Analysis HT v11.0 (ForteBio), as shown in Figure 1.Antibody 3,325920 bound to the PSMA protein previously bound to antibody 325867, indicating that these two antibodies recognize non-overlapping epitopes on PSMA. The change in binding signal is reported in nanometers. Example 4: Composition of biparatopic and bivalent anti-PSMA antibodies As shown in Table 9, clone ID 350123 is composed of the sequence from clone ID 346181 joined to the sequence from clone ID 345497 with the bridging sequence GGGGGSGGGGS (SEQ ID NO: 74). Clone ID 350122 is composed of two repeats of clone ID 346181 joined by the same linking sequence. Clone ID 350123 is biparatopic, as it is composed of two anti-PSMA domains that recognize different epitopes on PSMA. Clone ID 350122 is bivalent but not biparatopic, as it is composed of the same anti-PSMA domain in tandem. Schematic illustrations of various anti-PSMA x anti-CD3 antibodies are shown in Figure 5, AC panels. Table 9: Description of the amino acid sequence of biparatopic and bivalent anti-PSMA antibodies Clone ID Sequence 1 Linker Sequence Sequence 2 350123 346181 GGGGSGGGGG (SEQ ID NO: 74) 345497 350122 346181 GGGGSGGGGG (SEQ ID NO: 74) 346181 Example 5: Determination of affinity for human PSMA expressed on the cell surface Cell surface PSMA affinity was determined by Scatchard assay using the 22Rv1 human prostate carcinoma cell line. First, multispecific PSMAxCD3 antibodies were labeled with Alexa Fluor 488 using the Alexa Fluor 488 5-SDP Ester kit (ThermoFisher A30052). Binding to 22Rv1s was then assessed by flow cytometry (Guava easyCyte 8HT, EMD Millipore). Briefly, 100,000 target cells were stained with a series of dilutions of Alexa Fluor 488 labeled with multispecific antibodies for 1 hour at 4 SC. After incubation, the cells were washed twice with flow cytometry buffer, and the mean fluorescence intensity was measured by flow cytometry. To establish a standard curve for calculating equivalent soluble fluorophore molecules (MESF), Bangs Lab Quantum Alex Fluor 488 MESF microsphere populations 1 to 4 were combined in a single tube and run through the Guava easyCyte 8HT. Blank microspheres were analyzed in a separate tube. The MFI of each microsphere population was measured for the FITO channel. A linear regression of Log10 (MFI) versus Log10 (MESF) was plotted using GraphPad Prism 7. The MFI of each experimental sample was interpolated on the calibration curve, and the MESF was determined for each sample. Subsequently, the average amount of antibody bound per cell (AUC) was calculated by dividing the mean MESF by the degree of labeling (DOL) of the antibody. The number of ABCs was multiplied by the cell concentration to determine the total concentration of bound antibody. The concentration of free antibody was calculated by subtracting the concentration of bound antibody from the staining concentration (initial dose). The concentration of free antibody was plotted as a function of the concentration of bound antibody in GraphPad Prism 7. The resulting graph was fitted to a site-specific nonlinear regression function to determine affinity, as shown in Figure 4, panels A and B. Example 6: Multispecific antibody-mediated destruction of PSMA-positive prostate tumor cells through T cell redirection. Assays using resting T cells. Target cells were seeded at 15,000 cells per well in a 96-well plate and incubated overnight at 37°C. After incubation, increasing amounts of multispecific antibody were added along with resting human T lymphocytes at a target-to-effector cell ratio of 10:1, and the plate was incubated for an additional 48 or 72 hours at 37°C (48 hours for assays with LNCaP, MDA-PCa-2b, and PC3-PSMA cells, and 72 hours for assays with 22Rv1 cells). Cell destruction was measured using the WST-1 cell proliferation reagent (Sigma cat. no. 11644807001) or flow cytometry. In some experiments, a small sample of each supernatant was collected after incubation, but before the analysis of the viability of the target cells, and was saved for analysis of cytokine production.When cell viability was assessed using the WST-1 reagent, the reagent stock was added to each well at a 1:10 dilution and incubated for 90 minutes at 37°C. The absorbance was then measured at 450 nm (reference 690 nm) and the percentage of specific lysis was calculated. If the viability of the target cells was assessed by flow cytometry, the target cells were labeled before starting the assay with the membrane dye DiR wiA / ai¿v¿i iv i zzvo (ThermoFisher D12731). After incubation with T lymphocytes and antibody, the supernatants were either saved for cytokine analysis or discarded. The wells were then washed once to collect dead tumor cells and T lymphocytes, which were transferred to a flow cytometry plate. Any remaining adherent tumor cells were trypsinized and then added to the corresponding wells on the flow cytometry plate. Annexin-V reagent was used to stain the dead cells, and flow cytometry (BD FACSCelesta) was performed to quantify the percentage of dead tumor cells in each sample, monitored by DiR staining. Wells containing untreated target cells were used to normalize spontaneous cell destruction.In some experiments, a negative control antibody was used, which consisted of the same CD3-targeted arm as the multispecific PSMAxCD3 molecules, but replacing the tumor-targeted arm with a VH specific for the HIV gp120 protein. Figure 7 shows the T-cell-mediated lysis of PSMA-positive cells using unstimulated T cells. Unstimulated human T cells were incubated with PSMA-expressing cells (LNCaP) and different concentrations of multispecific antibodies. The biparatopic anti-PSMAxCD3 antibody (350123xCD3) outperformed the monoparatopic anti-PSMAxCD3 antibody (346181xCD3). Assays using preactivated T lymphocytes Panhuman T lymphocytes were preactivated with plate-bound OKT3 and IL-2 for three days, followed by an additional day of incubation with fresh IL-2. Target cells were trypsinized, loaded with calcein-AM (ThermoFisher C3100MP), mixed with activated T lymphocytes at an E:T ratio of 20:1, and added to the wells of a 96-well plate. Dilution series of different multispecific antibodies were added, followed by incubation for 4 hours at 37°C. The supernatants were then transferred to 96-well black plates, and absorbance was measured at 480 nm / 520 nm ex / em to quantify calcein release. Target cells incubated without T lymphocytes were used to normalize spontaneous calcein release from intact tumor cells.The addition of 2% Triton-X to control the wells containing target cells allowed for the calculation of the calcein signal corresponding to maximum cell lysis. Using this value, each experimental well was reported as a percentage of maximum cell lysis. Data analysis was performed using GraphPad Prism 7. Figure 6 shows T-cell-mediated lysis of PSMA-positive cells using preactivated T lymphocytes. Preactivated human T lymphocytes were incubated with PSMA-expressing cells (LNCaP) and different concentrations of multispecific antibodies. Tumor cell destruction was measured by calcein release and normalized to spontaneous tumor cell release in the absence of T lymphocytes. The biparatopic anti-PSMAxCD3 antibody (350123xCD3) outperformed the monoparatopic anti-PSMAxCD3 antibody. ML / a / ZUZ 1 / un zzuo Figure 8 shows that multispecific antibodies do not lyse PSMA-negative cells. Preactivated human T lymphocytes were incubated with PSMA-negative prostate cancer cells (DU145) and different concentrations of multispecific antibodies. None of the antibodies tested produced lysis of these cells. Figure 9 shows the binding of multispecific PSMAxCD3 antibodies to PSMA-positive and PSMA-negative cells. Multispecific anti-PSMAxCD3 antibodies showed binding to PSMA-positive prostate tumor cells (22Rv1), but not to PSMA-negative prostate tumor cells (DU145). The biparatopic molecule (350123) showed the strongest cell binding at the target. Figure 10 depicts T-cell-mediated lysis of PSMA-positive cells. The data in Figure 10 demonstrate that binding to PSMA through two different epitopes results in greater cell destruction compared to a bivalent but monospecific version of the antibody. Example 7: A bispecific monoparatopic PSMAxCD3 antibody induces less cytokine production than a multispecific biparatopic PSMAxCD3 antibody Cytokine production was analyzed in tumor cytotoxicity assays using resting T lymphocytes. The design of these assays is detailed elsewhere. Supernatants were collected after the assays were completed (after 72 hours of incubation for assays using 22Rv1 cells and 48 hours for all other cell lines). ELISA kits for the detection of IL-2 (Biolegend 431804) and IFNγ (Biolegend 430104) were used according to the manufacturer's protocol. Experimental supernatants were diluted prior to analysis in the ELISAs so that cytokine levels fell within the linear portion of the standard curve supplied with each kit. In some cases, cytokines could not be detected in the experimental wells, and values ​​were reported as less than or equal to the lower limit of quantification for the assay. Figure 12, panels AC, shows T-cell-mediated lysis of PSMA-positive cells and a comparison with cytokine production. Multispecific PSMAxCD3 antibodies induce T-cell-mediated lysis of the PSMA-positive prostate cancer cell line LNCaP. The biparatopic molecule (350123) stimulated more potent tumor cell destruction compared to the monoparatopic molecule (346181), but also resulted in the production of higher levels of the cytokines interferon-gamma (IFNγ) and interleukin-2 (IL-2), as exemplified in Figure 12, panels B and C. Table 10 shows T-cell-mediated lysis and cytokine production against four PSMA-positive prostate tumor cell lines. Multispecific PSMAxCD3 antibodies were tested in in vitro tumor cell cytotoxicity assays using unstimulated T cells and a series of antibody doses against a panel of four PSMA-positive tumor cell lines. After 72 hours (22Rv1) or 48 hours (MDA-PCa-2b, LNCAP, PC3-PSMA), the percentage of tumor cell destruction was calculated and reported using EC50, as well as the highest percentage of destruction achieved. Supernatants from these experimental wells were collected and analyzed by ELISA for the cytokines interferon-gamma (IFNγ) or interleukin-2 (IL-2).The monoparatopic molecule (3461881) induced approximately equivalent levels of tumor cytotoxicity against the four cell lines tested compared to the biparatopic molecule, but had higher EC50 for cytokine production and in most cases stimulated lower levels of peak cytokine production. ΙνΙΛ / α / ZυΖΊ / UI ZZUO Table 10: T cell-mediated lysis and cytokine production against four PSMA-positive prostate tumor cell lines. Cell line Antibody Cell binding EC50 (nM) Maximum cytotoxicity (% lysis) Kills EC50 (nM) IFNy max. (pg / mL) EC50 IFNy (nM) IL-2 max. (pg / ml) EC50 IL-2 (nM) 22Rv1 346181xCD3 58 45 52.8 21 150 173.8 <LLOQ NA 350123xCD3 3 53 0.42 73 031 380.2 <LLOQ NA MDA- PCa-2b 346181xCD3 28 26 23.6 14 309 116.5 524 38.5 350123xCD3 2 29 0.41 12 026 0.90 1111 1.11 LNCAP 346181xCD3 17 79 14.6 32 237 63.0 183 575 350123xCD3 2 75 0.84 60 397 3.29 1057 3.73 PC3- PSMA 346181xCD3 30 42 3.7 7340 10.1 1569 4.1 350123xCD3 6 51 0.40 10 136 1.01 3480 1.1 Example 8: Multispecific PSMAxCD3 antibodies induce T lymphocyte proliferation PSMA-positive tumor cells were seeded at a rate of 25,000 cells per well in a 96-well plate and cultured overnight at 37°C. Human pan-T lymphocytes isolated from resting PBMCs (Miltenyi 130-096-535) were labeled with CFSE lineage-tracing dye according to the manufacturer's instructions (ThermoFisher C34554). One hundred thousand labeled pan-T lymphocytes were then added to the wells containing the tumor cells, followed by a series of antibody dilutions, and incubated at 37°C, 8% CO2. After 5 days of incubation, the cells were gently mixed and transferred to a flow cytometry plate. The cells were sedimented and the supernatant was removed, followed by staining with APC-conjugated anti-CD8 (Biolegend 301049) and PE-conjugated anti-CD4 (Biolegend 317410) for 20 minutes on ice.The cells were then washed and resuspended in flow cytometry buffer for analysis (BD FACSCelesta). The cells were activated by frontal and lateral scattering and by CD4 or CD8 expression. The percentage of proliferating T lymphocytes, as indicated by positive staining for CD4 or CD8 and low or negative CFSE signal, was calculated for the entire T lymphocyte population as well as for the CD4 and CD8 subsets. Flow cytometry data were analyzed using FlowJo and plotted on GraphPad Prism 7. Figure 11, panels AD, shows that multispecific PSMAxCD3 antibodies stimulated T cell proliferation in the presence of PSMA-positive tumor cells, and that bispecific monoparatopic PSMA antibodies preferentially activated CD3+ T cells. Multispecific antibodies were incubated with PSMA-expressing tumor cells and T cells labeled with the CFSE lineage-tracing dye. After 5 days of incubation, T cell proliferation and the composition of proliferating T cells (CD8+ versus CD4+) were analyzed by flow cytometry. Panels A and B show total T cell proliferation, while panels C and D indicate the CD8+ to CD4+ T cell ratio in proliferating wells. A dashed horizontal line indicates that the CD8:CD4 ratio of unstimulated T lymphocytes is approximately 1:2 (current value = 0.64).The bispecific monoparatopic antibody PSMAxCD3 (346181) preferentially activates CD8 T lymphocytes (CD8:CD4 ratio after expansion of about 2:1) while the multispecific biparatopic antibody PSMAxCD3 (350123) less preferentially activates CD8+ T lymphocytes (CD8:CD4 ratio of about 1:1). Example 9: A multispecific antibody causes suppression of prostate tumor growth in a xenograft model Five- to six-week-old male CIEA-NOG immunodeficient mice (Taconic) were implanted subcutaneously with 10 million 22Rv1 cells in their right lower flanks, followed by the addition of 10 million human PBMCs via tail vein injection one day post-tumor implantation. Animals received treatment with 100 pg of multispecific antibody or vehicle via tail vein injection starting one day post-tumor implantation on days 1, 5, 9, and 13. Tumor volume was quantified using calipers and recorded for 25 days. Figure 13 shows the results of the 22Rv1 tumor xenograft model. The biparatopic molecule PSMAxCD3 (350123) showed inhibition of 22Rv1 tumor growth in a tumor xenograft model. Three mice were tested for each treatment group, and the change in tumor volume for each animal was represented in cubic millimeters. The animals received PBMC on day 1 after tumor implantation and were treated with antibodies on days 1, 5, 9, and 13. Two of the three animals treated with multispecific antibodies showed a delay in tumor progression. Although preferred embodiments of the invention have been shown and described herein, it will be evident to those skilled in the art that these embodiments are provided only by way of example. It will be evident to those skilled in the art that various variations, changes, and substitutions may be made without departing from the spirit of the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be employed in implementing the invention. The claims that follow are intended to define the scope of the invention and to comprise the methods and structures within the scope of the claims and their equivalents.

Claims

1. A PSMA-binding antibody comprising a first heavy-chain variable region comprising: (a) a CDR1 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 1 to 10; and / or (b) a CDR2 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 11 to 17; and / or (c) a CDR3 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 18 to 23.

2. The antibody of claim 1, further comprising a second heavy chain variable region comprising: (a) a CDR1 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 1 to 10; and / or (b) a CDR2 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 11 to 17; and / or (c) a CDR3 having two or fewer substitutions in any of the amino acid sequences of SEQ ID NO: 18 to 23.

3. The antibody of any of claims 1 or 2, wherein said CDR1, CDR2 and CDR3 sequences are present in a human framework.

4. The antibody of any of claims 1 to 3, further comprising a heavy chain constant region sequence in the absence of a CH1 sequence.

5. The antibody of any of claims 1 to 4, wherein the first heavy chain variable region comprises: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10; and / or (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17; and / or (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23.

6. The antibody of any of claims 2 to 5, wherein the second heavy chain variable region comprises: (a) a CDR1 sequence selected from the group consisting of SEQ IDs NO: 1 to 10; and / or (b) a CDR2 sequence selected from the group consisting of SEQ IDs NO: 11 to 17; and / or (c) a CDR3 sequence selected from the group consisting of SEQ IDs NO: 18 to 23.

7. The antibody of any of claims 5 to 6, comprising: (a) a CDR1 sequence selected from the group consisting of SEQ ID NO: 1 to 10; and (b) a CDR2 sequence selected from the group consisting of SEQ ID NO: 11 to 17; and (c) a CDR3 sequence selected from the group consisting of SEQ ID NO: 18 to 23.

8. The antibody of any of claims 5 to 7, wherein the second heavy chain variable region comprises: (a) a CDR1 sequence selected from the group consisting of SEQ IDs NO: 1 to 10; and (b) a CDR2 sequence selected from the group consisting of SEQ IDs NO: 11 to 17; and (c) a CDR3 sequence selected from the group consisting of SEQ IDs NO: 18 to 23.

9. The antibody of any of claims 1-8, comprising: (a) a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18; or (b) a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO:

20.

10. The antibody of any of claims 1 to 9, comprising a heavy chain variable region sequence having at least 95% sequence identity with any of the sequences in SEQ ID NO: 24 to 58.

11. The antibody of any of claims 1 to 10, comprising a heavy chain variable region sequence selected from the group consisting of SEQ ID NO: 24 to 58.

12. The antibody of claim 11, wherein the heavy chain variable region sequence is selected from the group consisting of: SEQ ID NO: 25 and SEQ ID NO:

38.

13. A PSMA-binding antibody comprising a first heavy chain variable region comprising: (a) a CDR1 sequence of the formula: GGSISS Xi X2 Y X3 (SEQ ID NO: 67) where Xi is S or N; X2 is S or N; and X3 is Y or F; and (b) a CDR2 sequence of the formula: X4 X5 X6 SG X7 T (SEQ ID NO: 68) where X4 is I or V; X5 is D or Y; X7 is Y or D; and X7 is Y or S; and (c) a CDR3 sequence of the formula: ARHKAATADFDY (SEQ ID NO: 69), in a monovalent or bivalent form.

14. A PSMA-binding antibody comprising a first heavy chain variable region comprising: (a) a CDR1 sequence of the formula: GF Xi F X2 X3 YG (SEQ ID NO: 70) where Xi is S, I or T; X2 is S, T, R or I; and X3 is R or S; and (b) a CDR2 sequence of the formula: I X4 YDGSN X5 (SEQ ID NO: 71) where X4 is W or S; and Xs is R or K; and (c) a CDR3 sequence of the formula: AREP RXSG YYY X7 Xs SGY X9 S LD Y (SEQ ID NO: 72) where Xθ is I or V; X7 is E or D; Xs is S or T; and X9 is Y or D, in a monovalent or bivalent format.

15. A PSMA-binding antibody comprising: a first heavy-chain variable region comprising: (a) a CDR1 sequence of the formula: GGSISS X1 X2 Y X3 (SEQ ID NO: 67) where X: is S or N; X2 is S or N; and X3 is YoF; and (b) a CDR2 sequence of the formula: X4 X5 x6 s G X7 T (SEQ ID NO: 68) where X4 is I or V; Xs is D or Y; Xθ is Y or D; and X7 is Y or S; and (c) a CDR3 sequence of the formula: ARHKAATADFDY (SEQ ID NO: 69), and a second heavy chain variable region comprising: (a) a CDR1 sequence of the formula: GF Xi F X2 X3 YG (SEQ ID NO: 70) where Xi is S, I or T; X2 is S, T, R or I; and X3 is R or S; and (b) a CDR2 sequence of the formula: I X4 YDGSN X5 (SEQ ID NO: 71) where X4 is W or S; and X5 is R or K; and (c) a CDR3 sequence of the formula: AREPR X6 GYYY X7 X8 SG Y X9 S LD Y (SEQ ID NO: 72) where X8 is I or V; X7 is E or D; X8 is S or T; and X9 is Yo D.

16. The antibody of claim 15, wherein the first heavy chain variable region is located closer to the N-terminus with respect to the second heavy chain variable region.

17. The antibody of claim 15, wherein the first variable heavy chain region is located closer to the C-terminus with respect to the second variable heavy chain region.

18. A PSMA-binding antibody comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences in a human VH frame, wherein the CDR sequences comprise a sequence having two or fewer substitutions in a CDR sequence selected from the group consisting of SEQ ID NO: 1-23.

19. The antibody of claim 18, comprising a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences in a human VH frame, wherein the CDR sequences are selected from the group consisting of SEQ ID NO: 1-23.

20. A PSMA-binding antibody comprising: a heavy chain region comprising a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11 and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame.

21. A PSMA-binding antibody comprising: a heavy chain variable region comprising a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11, and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame, in a monovalent or bivalent configuration.

22. A PSMA-binding antibody comprising: a heavy chain variable region comprising a CDR1 sequence of SEQ ID NO: 7, a CDR2 sequence of SEQ ID NO: 15, and a CDR3 sequence of SEQ ID NO: 20 in a human VH frame.

23. A PSMA-binding antibody comprising: a heavy chain variable region comprising a CDR1 sequence of SEQ ID NO: 7, a CDR2 sequence of SEQ ID NO: 15, and a CDR3 sequence of SEQ ID NO: 20, in a human VH frame, in a monovalent or bivalent configuration.

24. A PSMA-binding antibody comprising: a first heavy chain variable region comprising: a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11, and a CDR3 sequence from SEQ ID NO: 18; and a second heavy chain variable region comprising: a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame.

25. The antibody of claim 24, wherein the first heavy chain variable region is located closer to the N-terminus with respect to the second heavy chain variable region.

26. The antibody of claim 24, wherein the first heavy chain variable region is located closer to the C-terminus with respect to the second heavy chain variable region.

27. The antibody of any of claims 1 to 14 and 18 to 23, which is monospecific.

28. The antibody of any of claims 1 to 26, which is multispecific.

29. The antibody of claim 28, which is bispecific.

30. The antibody of claim 28 or 29, having binding affinity to a CD3 protein and a PSMA protein.

31. The antibody of claim 28 or 29, having binding affinity to two different epitopes of the same PSMA protein.

32. The antibody of claim 28 or 29, having a binding affinity to an effector cell.

33. The antibody of claim 32, having a binding affinity to a T lymphocyte antigen.

34. The antibody of claim 33, having a binding affinity to CD3.

35. The antibody of any of claims 1 to 34, which is in a CAR-T format.

36. A bispecific antibody comprising: (i) a heavy chain region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence from SEQ ID NO: 2, a CDR2 sequence from SEQ ID NO: 11 and a CDR3 sequence from SEQ ID NO: 18, in a human VH frame.

37. A bispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (i¡¡) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11, and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame, in a monovalent or bivalent configuration.

38. A bispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame.

39. A bispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (iii) an antigen-binding domain of an anti-PSMA heavy chain antibody, comprising a CDR1 sequence of SEQ ID NO: 7, a CDR2 sequence of SEQ ID NO: 15, and a CDR3 sequence of SEQ ID NO: 20, in a human VH frame, in a monovalent or bivalent configuration.

40. A multispecific antibody comprising: (i) a heavy chain variable region having CD3-binding affinity, comprising a CDR1 sequence from SEQ ID NO: 59, a CDR2 sequence from SEQ ID NO: 60 and a CDR3 sequence from SEQ ID NO: 61, in a human VH frame; (ii) a light chain variable region comprising a CDR1 sequence from SEQ ID NO: 62, a CDR2 sequence from SEQ ID NO: 63 and CDR3 sequences from SEQ ID NO: 64, in a human VL frame; and (i) an antigen-binding domain of an anti-PSMA heavy chain antibody, wherein the antigen-binding domain comprises a first and a second antigen-binding region, in a bivalent configuration, wherein: the first antigen-binding region comprises a CDR1 sequence of SEQ ID NO: 2, a CDR2 sequence of SEQ ID NO: 11 and a CDR3 sequence of SEQ ID NO: 18, in a human VH frame;and the second antigen-binding region comprises a CDR1 sequence from SEQ ID NO: 7, a CDR2 sequence from SEQ ID NO: 15, and a CDR3 sequence from SEQ ID NO: 20, in a human VH frame.; 41. The multispecific antibody of claim 40, wherein the first antigen-binding region is located closer to the N-terminus with respect to the second antigen-binding region.

42. The multispecific antibody of claim 40, wherein the first antigen-binding region is located closer to the C-terminus with respect to the second antigen-binding region.

43. The multispecific or bispecific antibody of any of claims 36 to 42, wherein the first and second antigen-binding regions of the antigen-binding domain of the anti-PSMA heavy chain antibody are connected by a polypeptide linker.

44. The multispecific or bispecific antibody of claim 43, wherein the polypeptide linker is a GS linker.

45. The multispecific or bispecific antibody of claim 44, wherein the GS linker consists of the sequence of SEQ ID NO: 73 or SEQ ID NO:

74.

46. ​​The bispecific antibody of any of claims 36 to 39, wherein the antigen-binding domain of the anti-PSMA heavy chain antibody is monoparatopic and induces less cytokine production compared to a biparatopic antigen-binding domain.

47. The bispecific antibody of any of claims 36 to 39, wherein the antigen-binding domain of the anti-PSMA heavy chain antibody is monoparatopic and expands CD8+ T lymphocytes to a greater extent than a biparatopic antigen-binding domain.

48. The antibody of any of claims 1 to 45, wherein the antibody is biparatopic and has a higher affinity for PSMA compared to a monoparatopic anti-PSMA antibody.

49. The antibody of any of claims 1 to 45, wherein the antibody is biparatopic and has an enhanced effector function compared to a monoparatopic anti-PSMA antibody.

50. A pharmaceutical composition comprising the antibody of any of claims 1 to 49.

51. A method for treating a disorder characterized by PSMA expression, comprising administering to a subject with said disorder an antibody of any of claims 1 to 49 or the pharmaceutical composition of claim 50.

52. The use of an antibody of any of claims 1 to 49, in the preparation of a medicament for the treatment of a disorder characterized by PSMA expression.

53. The antibody of any of claims 1 to 49, for use in the treatment of a disorder characterized by PSMA expression.

54. The method, use or antibody of any of claims 51 to 53, wherein the disorder is prostate cancer.

55. A polynucleotide encoding an antibody of any of claims 1 to 49.

56. A vector comprising the polynucleotide of claim 55.

57. A cell comprising the vector of claim 56.

58. A method of producing an antibody of any of claims 1 to 49, comprising growing a cell according to claim 57 under conditions allowing expression of the antibody and isolating the antibody from the cell.

59. A method for preparing an antibody of any of claims 1 to 49, comprising immunizing a UniRat animal with a PSMA protein and identifying antibody sequences that bind to PSMA.

60. A treatment method, comprising administering to an individual in need an effective dose of the antibody of any of claims 1 to 49, or the pharmaceutical composition of claim 50.