WO2018057967A2 - Constructions ciblant des complexes peptide du vih/cmh et leurs utilisations - Google Patents

Constructions ciblant des complexes peptide du vih/cmh et leurs utilisations Download PDF

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WO2018057967A2
WO2018057967A2 PCT/US2017/053073 US2017053073W WO2018057967A2 WO 2018057967 A2 WO2018057967 A2 WO 2018057967A2 US 2017053073 W US2017053073 W US 2017053073W WO 2018057967 A2 WO2018057967 A2 WO 2018057967A2
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seq
nos
amino acid
rtmc
hiv
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WO2018057967A3 (fr
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Hong Liu
Vivien Wai-Fan CHAN
Lianxing Liu
Javier Morales
Zhiyuan Yang
Cheng Liu
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Eureka Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • This invention pertains to constructs comprising an antibody moiety that specifically bind to a complex comprising a human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) peptide and an MHC class I protein, including methods of manufacture and uses thereof such as for treating and/or diagnosing diseases.
  • HIV-1 human immunodeficiency virus 1
  • RT reverse transcriptase
  • HIV Human Immunodeficiency Virus
  • AIDS acquired immunodeficiency syndrome
  • Retroviridae family Lentiviruses are transmitted as single- stranded, positive- sense, enveloped RNA virus. HIV has been divided into two types: HIV-1 and HIV-2. HIV-1 is more virulent and more infective than HIV-2. HIV-1 is the cause of majority of HIV infections globally. HIV-2 has relatively poor capacity for transmission, it is found mainly in West Africa, with some cases in India and Europe.
  • HIV has several major genes coding for structural proteins as well as several accessory genes.
  • the HIV genome contains three major genes, gag, pol, and env, encoding major structural proteins as well as essential viral enzymes.
  • Pol codes reverse transcriptase (RT), RNase
  • Reverse transcriptase is required to transcribe DNA from RNA template. Integrase is necessary to integrate the double- stranded viral DNA into the host genome. HIV protease is required to cleave the precursor Gag polyprotein to produce structural proteins.
  • Reverse transcriptase is a critical enzyme in the HIV replication cycle. RT is used by retroviruses to transcribe their single- stranded RNA genome into single- stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA double helix capable of integration into host cell chromosomes.
  • Functional HIV1-RT is a heterodimer containing subunits of 66 kDa (p66) and 51 kDa (p51). p66 contains two domains, the N-terminal polymerase domain (440 residues) and the C-terminal RNase H domain (120 residues).
  • p51 is processed by proteolytic cleavage of p66 and corresponds to the polymerase domain of the p66 subunit.
  • the present application in one aspect provides constructs (such as isolated constructs) that bind to a complex comprising an HIV-1 RT peptide and an MHC class I protein (referred to herein as an "HIV-1 RT/MHC class I complex," or "RTMC").
  • the constructs (“anti-RTMC constructs") comprise an antibody moiety (referred to herein as an "anti-RTMC antibody moiety”) that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein.
  • an anti-RTMC construct (such as an isolated anti-RTMC construct) comprising an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein.
  • the HIV-1 RT/MHC class I complex is present on a cell surface.
  • the HIV-1 RT/MHC class I complex is present on the surface of an immune cell, such as a T cell.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the MHC class I protein is HLA-A.
  • the MHC class I protein is HLA-A02.
  • the MHC class I protein is the HLA-A*02:01 subtype of the HLA-A02 allele.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety cross-reacts with a complex comprising the HIV-1 RT peptide and a second MHC class I protein having a different HLA allele than the MHC class I protein.
  • the antibody moiety cross-reacts with a complex comprising a variant of the HIV-1 RT peptide comprising one amino acid substitution (such as a conservative amino acid substitution) and the MHC class I protein.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the HIV-1 RT peptide is about 8 to about 12 (such as about any of 8, 9, 10, 11, or 12) amino acids in length.
  • the HIV-1 RT peptide is derived from the region corresponding to amino acids 181-189 of SEQ ID NO: 1.
  • the HIV-RT peptide is derived from the region corresponding to amino acids 181-189 of SEQ ID NO: 1.
  • 1 RT peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1
  • the HIV-1 RT peptide has the amino acid sequence
  • the isolated anti-RTMC construct cross-reacts with a complex comprising a variant of the HIV-1 RT peptide having the amino acid sequence of any one of YQYMDDLYV (SEQ ID NO: 5), YQYIDDLYV (SEQ ID NO: 7),
  • the HIV-1 RT peptide has the amino acid sequence YQYMDDLYV (SEQ ID NO: 5).
  • the isolated anti-RTMC construct cross-reacts with a complex comprising a variant of the HIV-1 RT peptide having the amino acid sequence of any one of YQYVDDLYV (SEQ ID NO: 6), YQYIDDLYV (SEQ ID NO: 7), CQYMDDLYV (SEQ ID NO: 8), or CQYVDDLYV (SEQ ID NO: 9) and the MHC class I protein.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety is a full-length antibody, a Fab, a Fab', a (Fab')2, an Fv, or a single chain Fv (scFv).
  • the antibody moiety is fully human, semisynthetic with human antibody framework regions, or humanized.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety binds to the HIV-1 RT/MHC class I complex with an equilibrium dissociation constant (K d ) between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the isolated anti-RTMC construct binds to the HIV-1 RT/MHC class I complex with a IQ between about 0.1 pM to about
  • 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM,
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety comprises: i) a heavy chain variable domain comprising a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of
  • SEQ ID NO: 240 or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ
  • ID NOs: 241-244 or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of
  • LC-CDR light chain complementarity determining region
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety comprises: i) a heavy chain variable domain comprising an HC- CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1,
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety comprises: i) a heavy chain variable domain comprising an HC-
  • CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96
  • an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97-124
  • an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR regions; and ii) a light chain variable domain comprising an LC-
  • CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 164-189
  • an LC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 190-207
  • an LC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 208-239; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the LC-CDR regions.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the antibody moiety comprises a) a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46 or a variant thereof having at least about 95% (such as at least about any of 95%, 96%, 97%, 98%, or 99%) sequence identify to any one of SEQ ID NOs: 19-46; and b) a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 47-74 or a variant thereof having at least about 95% (such as at least about any of 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of SEQ ID NOs: 47-74.
  • the antibody moiety comprises a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 47-74.
  • the anti-RTMC construct comprises a first antibody moiety that competes for binding to a target HIV-1 RT/MHC class I complex with a second antibody moiety according to any of the antibody moieties described above.
  • the first antibody moiety binds to the same, or substantially the same, epitope as the second antibody moiety.
  • binding of the first antibody moiety to the target HIV-1 RT/MHC class I complex inhibits binding of the second antibody moiety to the target HIV-1 RT/MHC class I complex by at least about 70% (such as by at least about any of 75%, 80%, 85%, 90%, 95%, 98% or 99%), or vice versa.
  • the first antibody moiety and the second antibody moiety cross-compete for binding to the target HIV-1 RT/MHC class I complex, i.e., each of the first and second antibody moieties competes with the other for binding to the target HIV-1 RT/MHC class I complex.
  • the isolated anti-RTMC construct is a full-length antibody.
  • the isolated anti-RTMC construct is monospecific.
  • the isolated anti-RTMC construct is multi- specific.
  • the isolated anti-RTMC construct is bispecific.
  • the isolated anti-RTMC molecule is a tandem scFv, a diabody (Db), a single chain diabody (scDb), a dual-affinity retargeting (DART) antibody, a dual variable domain (DVD) antibody, a knob-into-hole (KiH) antibody, a dock and lock (DNL) antibody, a chemically cross-linked antibody, a
  • the isolated anti-RTMC construct is a tandem scFv comprising two scFvs linked by a peptide linker.
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence of SEQ ID NO: 276.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the isolated anti-RTMC construct further comprises a second antigen-binding moiety that specifically binds to a second antigen.
  • the second antigen- binding moiety is an antibody moiety.
  • the second antigen is an antigen on the surface of a T cell.
  • the T cell is selected from the group consisting of a cytotoxic T cell, a helper T cell, and a natural killer T cell.
  • the second antigen is selected from the group consisting of CD3y, CD35, CD3s, CD3C, CD28, OX40, GITR, CD137, CD27, CD40L, and HVEM.
  • the second antigen is CD3s
  • the isolated anti-RTMC construct is a tandem scFv comprising an N-terminal scFv specific for the HIV-1 RT/MHC class I complex and a C-terminal scFv specific for CD3s.
  • the second antigen is an antigen on the surface of a natural killer cell, a neutrophil, a monocyte, a macrophage, or a dendritic cell.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the isolated anti-RTMC construct is a chimeric antigen receptor (CAR).
  • the chimeric antigen receptor comprises an extracellular domain comprising the antibody moiety, a transmembrane domain, and an intracellular signaling domain.
  • the intracellular signaling domain comprises a CD3 ⁇ intracellular signaling sequence and a co-stimulatory signaling sequence.
  • the co-stimulatory signaling sequence is a CD28 or 4- IBB intracellular signaling sequence.
  • the intracellular signaling domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, wherein the isolated anti-RTMC construct is a a chimeric antibody/T cell receptor (abTCR).
  • the anti-RTMC abTCR comprises an extracellular domain comprising the antibody moiety and a T cell receptor (TCR) module (TCRM) comprising TCR transmembrane domains.
  • TCR T cell receptor
  • the TCRM is capable of recruiting at least one TCR-associated signaling module.
  • the TCR-associated signaling module is selected from the group consisting of CD35s, CD3y8, and ⁇ .
  • the antibody moiety comprises: a) a first polypeptide chain comprising a first antigen-binding domain comprising V H and C H I antibody domains; and b) a second polypeptide chain comprising a second antigen-binding domain comprising V L and C L antibody domains, wherein the V H and C H I domains of the first antigen-binding domain and the V L and C L domains of the second antigen-binding domain form a Fab-like antigen-binding module that specifically binds to the RTMC.
  • the anti-RTMC construct comprises an antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, wherein the isolated anti-RTMC construct is an immunoconjugate comprising the antibody moiety and an effector molecule.
  • the effector molecule is a therapeutic agent selected from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.
  • the therapeutic agent is a drug or a toxin.
  • the effector molecule is a label.
  • a host cell expressing or associated with an anti-RTMC construct, or polypeptide component thereof.
  • a nucleic acid encoding an anti-RTMC construct, or polypeptide component thereof.
  • a vector comprising the nucleic acid.
  • an effector cell expressing or associated with an anti-RTMC construct.
  • the effector cell is a T cell.
  • a pharmaceutical composition comprising an anti-RTMC construct (such as an isolated anti-RTMC construct), a host cell, a nucleic acid, a vector, or an effector cell according to any of the embodiments described above.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • a method of detecting a cell presenting a complex comprising an HIV-1 RT peptide and an MHC class I protein on its surface comprising contacting the cell with an anti-RTMC construct (such as an isolated anti-RTMC construct) according to any of the embodiments described above comprising a) an antibody moiety that specifically binds to a complex comprising the HIV-1 RT peptide and the MHC class I protein and b) a label, and detecting the presence of the label on the cell.
  • an anti-RTMC construct such as an isolated anti-RTMC construct
  • a method of treating an individual having an HIV- 1 infection comprising administering to the individual an effective amount of a
  • the pharmaceutical composition comprising an anti-RTMC construct (such as an isolated anti- RTMC construct) according to any of the embodiments described above.
  • the pharmaceutical composition further comprises a cell (such as an effector cell) associated with the isolated anti-RTMC construct.
  • a method of treating an individual having an HIV- 1 infection comprising administering to the individual an effective amount of an effector cell expressing any of the anti-RTMC CARs or anti-RTMC abTCRs described above.
  • the effector cell is a T cell.
  • the individual is human.
  • a method of diagnosing an individual having an HIV-1 infection comprising: a) administering an effective amount of an isolated anti-RTMC construct comprising a label according to any of the embodiments described above to the individual; and b) determining the level of the label in the individual, wherein a level of the label above a threshold level indicates that the individual has the HIV-1 infection.
  • a method of diagnosing an individual having an HIV-1 infection comprising: a) contacting a sample derived from the individual with an isolated anti-RTMC construct comprising a label according to any of the embodiments described above; and b) determining the number of cells bound with the isolated anti-RTMC construct in the sample, wherein a value for the number of cells bound with the isolated anti-RTMC construct above a threshold level indicates that the individual has the HIV-1 infection.
  • the individual is human.
  • FIG. 1 shows the results of BB7.2 FACS binding assays for T2 cells loaded with HIV-1 RT 181 peptides (WT, M184V, Ml 841, Y181C, or Y181C/M184V) or HIV-1 RT 181 peptides having single alanine substitutions at positions 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • Unloaded cells only T2 Cell
  • 2° antibody BB7.2 only (2 nd Antibody
  • unloaded cells with 2° antibody BB7.2 T Cell + 2 nd Antibody
  • FIG. 2 shows the T-cell killing of HIV-1 RT 181 M184V-loaded T2 cells mediated by anti-HIV-1 RT 181/HLA-A*02:01 bispecific antibodies prepared from various phage clones.
  • Negative controls included T2 cells loaded with P20 control peptide mix.
  • FIG. 3 shows the T-cell killing of parental SK-Hepl cells and SK-Hepl cells transduced to express HIV-1 RT 181 WT, HIV-1 RT 181 Ml 84V, or HIV-1 RT 181 Ml 841 mediated by anti-HIV-1 RT 181/MHC bispecific antibodies (BsAb).
  • FIG. 4 shows flow cytometry analysis of T cells transduced with anti-HIV CAR 10, anti- HIV CAR 14, or mock-transfected, and stained with HIV-1 RT 181-189 peptide /HLA-A*02:01 tetramers.
  • FIG. 5 shows the killing of SK-HEP-1 and SK-HEP-l-MG cell lines mediated by T cells expressing anti-HIV CAR 10 or anti-HIV CAR 14.
  • anti-RTMC constructs that comprise an antibody moiety (referred to herein as an “anti-RTMC antibody moiety”) that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein (referred to herein as an "HIV-1 RT/MHC class I complex,” or "RTMC").
  • an antibody moiety referred to herein as an “anti-RTMC antibody moiety”
  • an MHC class I protein referred to herein as an "HIV-1 RT/MHC class I complex,” or "RTMC”
  • RT is an intracellular protein that has not been successfully targeted by cytotoxic effector cell therapies against cell surface proteins.
  • YQYMDDLYV is an HLA-A2 restricted HIV-1 epitope in the HIV-1 RT.
  • the YQYMDDLYV epitope is one of the 14 most conserved regions of the HIV proteome in four major HIV-1 clades A, B, C and D (Letourneau, S., et al. (2007) PloS one, 2(10): e984; Harrer, E. et al. (1996) Journal of Infectious Diseases 173(2): 476-479).
  • This epitope is of great clinical relevance because it lies within the active site of RT and is a target of many reverse transcriptase inhibitors.
  • M184V lies in this region (Shafer, R. W., & Schapiro, J. M. (2008) AIDS reviews 10(2): 67).
  • the anti-RTMC constructs specifically recognize HIV- 1 RT/MHC class I complexes.
  • the HIV- 1 RT/MHC class I complex is on the surface of cells expressing HIV- 1 RT.
  • Anti-RTMC constructs may specifically bind to the N-terminal portion, the C- terminal portion, or the middle portion of the HIV- 1 RT peptide in the complex, and/or cross- react with at least one complex comprising the HIV- 1 RT peptide and a different subtype of the MHC class I protein (e.g.
  • the anti-RTMC construct binds to both an HIV- 1 RT peptide/HLA- A*02:01 complex and an HIV- 1 RT peptide/HLA-A*02:02 complex).
  • the anti-RTMC constructs allow for specific targeting of RTMC-presenting cells (i.e. , cells presenting on their surface an HIV- 1 RT peptide bound to an MHC molecule), such as infected cells expressing HIV- 1 RT. This strategy provides a significant technical advantage over using antibodies directed against the HIV- 1 RT protein, which may not specifically target RTMC-presenting cells.
  • the anti-RTMC antibody moiety allows for diagnosis and prognosis of HIV- 1 infections with high sensitivity to changes in the number and distribution of RTMC-presenting cells.
  • the present application thus provides constructs (such as isolated constructs) comprising an antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein.
  • the construct can be, for example, a full-length anti-RTMC antibody, a multi- specific anti-RTMC molecule (such as a bispecific anti-RTMC antibody), an anti-RTMC chimeric antigen receptor (“CAR”), or an anti-RTMC immunoconjugate.
  • nucleic acids encoding the anti-RTMC constructs or the anti-RTMC antibody moiety portion of the constructs.
  • compositions comprising an anti-RTMC construct comprising an antibody moiety that specifically binds to a complex comprising an HIV- 1 RT- peptide and an MHC class I protein.
  • the composition can be a pharmaceutical composition comprising an anti-RTMC construct or an effector cell expressing or associated with the anti- RTMC construct (for example a T cell expressing an anti-RTMC CAR or anti-RTMC abTCR).
  • kits and articles of manufacture useful for such methods.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g.
  • treatment is a reduction of pathological consequence of a disease.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • refractory or “resistant” refers to a disease that has not responded to treatment.
  • Activation refers to the state of the cell that has been sufficiently stimulated to induce a detectable increase in downstream effector functions of the CD3 signaling pathway, including, without limitation, cellular proliferation and cytokine production.
  • antibody moiety includes full-length antibodies and antigen-binding fragments thereof.
  • a full-length antibody comprises two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variables region in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC- CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3).
  • CDRs complementarity determining regions
  • CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991).
  • the three CDRs of the heavy or light chains are interposed between flanking stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops.
  • FRs framework regions
  • the constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions.
  • Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ heavy chains, respectively.
  • Several of the major antibody classes are divided into subclasses such as lgGl ( ⁇ heavy chain), lgG2 ( ⁇ 2 heavy chain), lgG3 ( ⁇ 3 heavy chain), lgG4 ( ⁇ 4 heavy chain), IgAl (al heavy chain), or lgA2 (a2 heavy chain).
  • antigen-binding fragment refers to an antibody fragment including, for example, a diabody, a Fab, a Fab', a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), an scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure.
  • an antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g. , a parent scFv) binds.
  • an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
  • epitope refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.
  • a "Fab-like antigen-binding module” refers to an antibody moiety that comprises a first polypeptide chain and a second polypeptide chain, wherein the first and second polypeptide chains comprise a VL antibody domain, a CL antibody domain, a VH antibody domain, and a CHI antibody domain.
  • the VL and CL antibody domains may be on one chain with the VH and CHI antibody domains on the other chain, or the VL and CHI antibody domains may be on one chain with the VH and CL antibody domains on the other chain.
  • the first and second polypeptide chains are linked, such as by a peptide linkage, or by another chemical linkage, such as a disulfide linkage.
  • a first antibody moiety "competes" for binding to a target RTMC with a second antibody moiety when the first antibody moiety inhibits target RTMC binding of the second antibody moiety by at least about 50% (such as at least about any of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%) in the presence of an equimolar concentration of the first antibody moiety, or vice versa.
  • a high throughput process for "binning" antibodies based upon their cross-competition is described in PCT Publication No. WO 03/48731.
  • the term “specifically binds” or “is specific for” refers to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety, that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules.
  • an antibody or antibody moiety that specifically binds to a target is an antibody or antibody moiety that binds this target with greater affinity, avidity, more readily, and/or with greater duration than its bindings to other targets.
  • an antibody or antibody moiety that specifically binds to an antigen reacts with one or more antigenic determinants of the antigen (for example an HIV-1 RT peptide/MHC class I protein complex) with a binding affinity that is at least about 10 times its binding affinity for other targets.
  • one or more antigenic determinants of the antigen for example an HIV-1 RT peptide/MHC class I protein complex
  • T cell receptor refers to a heterodimeric receptor composed of ⁇ or ⁇ chains that pair on the surface of a T cell. Each ⁇ , ⁇ , ⁇ , and ⁇ chain is composed of two Ig- like domains: a variable domain (V) that confers antigen recognition through the T cell receptor.
  • V variable domain
  • CDR complementarity determining regions
  • C constant domain
  • TM transmembrane
  • the TM region associates with the invariant subunits of the CD3 signaling apparatus.
  • Each of the V domains has three CDRs. These CDRs interact with a complex between an antigenic peptide bound to a protein encoded by the major histocompatibility complex (pMHC) (Davis and Bjorkman (1988) Nature, 334, 395-402; Davis et al. (1998) Annu Rev Immunol, 16, 523-544; Murphy (2012), xix, 868 p.).
  • pMHC major histocompatibility complex
  • TCR-associated signaling molecule refers to a molecule having a
  • TCR-associated signaling molecules include CD3y8, CD35s, and ⁇ , and are essential for the signaling capacity of the TCR.
  • module when referring to a portion of a protein is meant to include structurally and/or functionally related portions of one or more polypeptides which make up the protein.
  • a transmembrane module of a dimeric receptor may refer to the portions of each polypeptide chain of the receptor that span the membrane.
  • a module may also refer to related portions of a single polypeptide chain.
  • a transmembrane module of a monomeric receptor may refer to portions of the single polypeptide chain of the receptor that span the membrane.
  • a module may also include only a single portion of a polypeptide.
  • An "isolated" anti-RTMC construct as used herein refers to an anti-RTMC construct that (1) is not associated with proteins found in nature, (2) is free of other proteins from the same source, (3) is expressed by a cell from a different species, or, (4) does not occur in nature.
  • isolated nucleic acid as used herein is intended to mean a genomic nucleic acid, cDNA, or nucleic acid of synthetic origin or some combination thereof, which by virtue of its origin the "isolated nucleic acid” (1) is not associated with all or a portion of a polynucleotide in which the "isolated nucleic acid” is found in nature, (2) is operably linked to a polynucleotide which it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence.
  • CDR complementarity determining region
  • CDR complementarity determining region
  • Residue numbering follows the nomenclature of Kabat et al., supra
  • chimeric antibodies refer to antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit a biological activity of this invention (see U.S. Patent No. 4,816,567; and Morrison et ah, Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • poly- synthetic in reference to an antibody or antibody moiety means that the antibody or antibody moiety has one or more naturally occurring sequences and one or more non-natural occurring (i.e., synthetic) sequences.
  • Fv is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the heavy and light chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • Single-chain Fv also abbreviated as “sFv” or “scFv,” are antibody fragments that comprise the V H and V L antibody domains connected into a single polypeptide chain.
  • the scFv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments prepared by constructing scFv fragments (see preceding paragraph) typically with short linkers (such as about 5 to about 10 residues) between the V H and V L domains such that inter-chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen- binding sites.
  • Bispecific diabodies are heterodimers of two "crossover" scFv fragments in which the V H and V L domains of the two antibodies are present on different polypeptide chains.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al, Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • Humanized forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a
  • hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability.
  • donor antibody such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Percent (%) amino acid sequence identity or “homology” with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the
  • polypeptide being compared after aligning the sequences considering any conservative substitutions as part of the sequence identity.
  • Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared.
  • an FcR of this invention is one that binds an IgG antibody (a ⁇ receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
  • FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor FcyRIIA contains an immunoreceptor tyro sine-based activation motif (IT AM) in its cytoplasmic domain.
  • Inhibiting receptor FcyRIIB contains an immunoreceptor tyro sine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)).
  • the term includes allotypes, such as FcyRIIIA allotypes: FcYRIIIA-Phel58, FcYRIIIA-Vall58, FcyRIIA-R131 and/or FcyRIIA-Hm. FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al.,
  • FcR neonatal receptor
  • FcRn refers to the neonatal Fc receptor (FcRn).
  • FcRn is structurally similar to major histocompatibility complex (MHC) and consists of an oc-chain noncovalently bound to 2-microglobulin.
  • MHC major histocompatibility complex
  • FcRn plays a role in the passive delivery of immunoglobulin IgGs from mother to young and the regulation of serum IgG levels.
  • FcRn can act as a salvage receptor, binding and transporting pinocytosed IgGs in intact form both within and across cells, and rescuing them from a default degradative pathway.
  • C H I domain of a human IgG Fc region (also referred to as "CI” of "HI” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system).
  • Hinge region is generally defined as stretching from Glu216 to Pro230 of human IgGl (Burton, Molec. Immunol.22: l6l-206 (1985)). Hinge regions of other IgG isotypes may be aligned with the IgGl sequence by placing the first and last cysteine residues forming inter- heavy chain S-S bonds in the same positions.
  • the "CH2 domain" of a human IgG Fc region usually extends from about amino acid 231 to about amino acid 340.
  • the CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain.
  • CH3 domain (also referred to as “C2" or “H3” domain) comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e. from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an
  • a "functional Fc fragment” possesses an "effector function” of a native sequence Fc region.
  • exemplary "effector functions” include Clq binding; complement dependent
  • CDC cytotoxicity
  • ADCC phagocytosis
  • B cell receptor BCR
  • effector functions generally require the Fc region to be combined with a binding domain (e.g. an antibody variable domain) and can be assessed using various assays known in the art.
  • An antibody with a variant IgG Fc with "altered" FcR binding affinity or ADCC activity is one which has either enhanced or diminished FcR binding activity (e.g. , FcyR or FcRn) and/or
  • the variant Fc which "exhibits increased binding" to an FcR binds at least one FcR with higher affinity (e.g. , lower apparent K d or IC 50 value) than the parent polypeptide or a native sequence IgG Fc.
  • the improvement in binding compared to a parent polypeptide is about 3 fold, such as about any of 5, 10, 25, 50, 60, 100,
  • the polypeptide variant which "exhibits decreased binding" to an FcR binds at least one FcR with lower affinity
  • the decrease in binding compared to a parent polypeptide may be about 40% or more decrease in binding.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • NK cells Natural Killer (NK) cells, neutrophils, and macrophages
  • cytotoxic effector cells bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins.
  • the antibodies "arm" the cytotoxic cells and are absolutely required for such killing.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • ADCC activity of a molecule of interest may be assessed in vitro, such as that described in US Patent No. 5,500,362 or 5,821,337.
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • PBMC peripheral blood mononuclear cells
  • NK Natural Killer
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • the polypeptide comprising a variant Fc region which "exhibits increased ADCC" or mediates antibody-dependent cell- mediated cytotoxicity (ADCC) in the presence of human effector cells more effectively than a polypeptide having wild type IgG Fc or a parent polypeptide is one which in vitro or in vivo is substantially more effective at mediating ADCC, when the amounts of polypeptide with variant Fc region and the polypeptide with wild type Fc region (or the parent polypeptide) in the assay are essentially the same.
  • such variants will be identified using any in vitro ADCC assay known in the art, such as assays or methods for determining ADCC activity, e.g. in an animal model etc.
  • the variant is from about 5 fold to about 100 fold, e.g. from about 25 to about 50 fold, more effective at mediating ADCC than the wild type Fc (or parent polypeptide) .
  • CDC complement dependent cytotoxicity
  • Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to antibodies (of the appropriate subclass) which are bound to their cognate antigen.
  • Clq first component of the complement system
  • a CDC assay e.g. as described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996), may be performed.
  • Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capability are described in US patent No. 6,194,551B 1 and
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intra n(s).
  • operably linked refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter.
  • a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
  • a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
  • operably linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame.
  • homologous refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position.
  • the percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared times 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous.
  • the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.
  • an “effective amount” of an anti-RTMC construct or composition as disclosed herein is an amount sufficient to carry out a specifically stated purpose.
  • An “effective amount” can be determined empirically and by known methods relating to the stated purpose.
  • the term "therapeutically effective amount” refers to an amount of an anti-RTMC construct or composition as disclosed herein, effective to "treat” a disease in an individual.
  • the therapeutically effective amount of the anti-RTMC construct or composition as disclosed herein can reduce the number of HIV- 1 infected cells; reduce HIV- 1 replication; inhibit (i.e., slow to some extent and preferably stop) spread of the infection to uninfected cells; and/or relieve to some extent one or more of the symptoms associated with the HIV- 1 infection.
  • the anti-RTMC construct or composition as disclosed herein can kill existing HIV- 1 -infected cells, it can be cytotoxic.
  • the therapeutically effective amount is an amount that extends the survival of a patient.
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g. , the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • label when used herein refers to a detectable compound or composition which can be conjugated directly or indirectly to the anti-RTMC antibody moiety.
  • the label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.
  • Reference to "about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X”.
  • reference to "not" a value or parameter generally means and describes "other than” a value or parameter.
  • the method is not used to treat infection of type X means the method is used to treat infections of types other than X.
  • the present invention provides HIV- 1 RT/MHC class I complex- specific constructs (anti-RTMC constructs) that comprise an antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein ("HIV- 1 RT/MHC class I complex," or "RTMC").
  • the anti-RTMC construct is an isolated anti- RTMC construct.
  • the specificity of the anti-RTMC construct derives from an anti-RTMC antibody moiety, such as a full-length antibody or antigen-binding fragment thereof, that specifically binds to the RTMC.
  • reference to a moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein means that the moiety binds to the RTMC with a) an affinity that is at least about 10 (including for example at least about any of 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1000 or more) times its binding affinity for each of full-length HIV- 1 RT, free HIV- 1 RT peptide, MHC class I protein not bound to a peptide, and/or MHC class I protein bound to a non- HIV- 1 RT peptide; or b) a IQ no more than about 1/10 (such as no more than about any of 1/10, 1/20, 1/30, 1/40, 1/50, 1/75, 1/100, 1/200, 1/300, 1/400, 1/500, 1/750, 1/1000 or less) times its K d for binding to each of full-length HIV-1
  • Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation assay (RIA).
  • IQ can be determined by methods known in the art, such as surface plasmon resonance (SPR) assay utilizing, for example, Biacore instruments, or kinetic exclusion assay (KinExA) utilizing, for example, Sapidyne instruments.
  • SPR surface plasmon resonance
  • KinExA kinetic exclusion assay
  • Contemplated anti-RTMC constructs include, for example, full-length anti-RTMC antibodies, multi- specific (such as bispecific) anti-RTMC molecules, anti-RTMC chimeric antigen receptors (CARs), and anti-RTMC immunoconjugates.
  • an anti-RTMC construct (such as an isolated anti-RTMC construct) comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein.
  • the HIV-1 RT peptide comprises (such as consists of) the amino acid sequence of any one of SEQ ID NOs: 5-18.
  • the HIV-1 RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the MHC class I protein is HLA-A02.
  • the MHC class I protein is HLA-A*02:01 (GenBank Accession No.: AAO20853).
  • the anti-RTMC construct is non-naturally occurring.
  • the anti-RTMC construct is a full-length antibody.
  • the anti-RTMC construct is a multi- specific (such as bispecific) molecule.
  • the anti-RTMC construct is a chimeric antigen receptor.
  • the anti-RTMC construct is an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO
  • the anti-RTMC construct binds the RTMC with a IQ between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • at least one such as at least any of 2, 3, 4, or 5
  • an anti-RTMC construct comprising an anti- RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide comprising (such as consisting of) the amino acid sequence of any one of SEQ ID NOs: 5-18 and HLA-A*02:01.
  • the HIV1- RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the anti-RTMC construct is non-naturally occurring.
  • the anti-RTMC construct is a full-length antibody.
  • the anti-RTMC construct is a multi- specific (such as bispecific) molecule.
  • the anti-RTMC construct is a chimeric antigen receptor.
  • the anti-RTMC construct is an immunoconjugate. In some embodiments, the anti-RTMC construct binds the RTMC with a IQ between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC construct comprising an anti- RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein
  • the anti-RTMC antibody moiety comprises: i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii) a light chain variable domain comprising an LC-
  • the anti-RTMC construct is non-naturally occurring.
  • the anti-RTMC construct is a full-length antibody.
  • the anti-RTMC construct is a multi- specific (such as bispecific) molecule.
  • the anti-RTMC construct is a chimeric antigen receptor.
  • the anti-RTMC construct is an immunoconjugate.
  • the anti- RTMC construct binds the RTMC with a IQ between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC construct comprising an anti- RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the anti-RTMC antibody moiety comprises: i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising (and in some
  • an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97-124; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain sequence comprising an LC- CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 164-189; or a variant thereof comprising up to about 5 (for example about about
  • an anti- RTMC construct comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein
  • the anti-RTMC antibody moiety comprises: i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising (and in some
  • the anti-RTMC construct is non-naturally occurring. In some embodiments, the anti-RTMC construct is a full-length antibody. In some embodiments, the anti-RTMC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-RTMC construct is a chimeric antigen receptor. In some embodiments, the anti-RTMC construct is an immunoconjugate.
  • the anti-RTMC construct binds the RTMC with a IQ between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC construct comprising an anti- RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the anti-RTMC antibody moiety comprises a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC construct is non-naturally occurring. In some embodiments, the anti-RTMC construct is a full- length antibody. In some embodiments, the anti-RTMC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-RTMC construct is a chimeric antigen receptor. In some embodiments, the anti-RTMC construct is an immunoconjugate.
  • the anti-RTMC construct binds the RTMC with a K d between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-RTMC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC construct comprising a first anti- RTMC antibody moiety that competes for binding to a target HIV-1 RT/MHC class I complex with a second anti-RTMC antibody moiety according to any of the anti-RTMC antibody moieties described herein.
  • the first anti-RTMC antibody moiety binds to the same, or substantially the same, epitope as the second anti-RTMC antibody moiety.
  • binding of the first anti-RTMC antibody moiety to the target HIV-1 RT/MHC class I complex inhibits binding of the second anti-RTMC antibody moiety to the target HIV-1 RT/MHC class I complex by at least about 70% (such as by at least about any of 75%, 80%, 85%, 90%, 95%, 98% or 99%), or vice versa.
  • the first anti-RTMC antibody moiety and the second anti-RTMC antibody moiety cross-compete for binding to the target HIV-1 RT/MHC class I complex, i.e., each of the first and second antibody moieties competes with the other for binding to the target HIV-1 RT/MHC class I complex.
  • an anti-RTMC construct comprising an anti-RTMC antibody moiety that competes for binding to a target HIV-1
  • RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii) a light chain variable domain comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and
  • an anti-RTMC construct comprising an anti-
  • RTMC antibody moiety that competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an
  • HC-CDRl comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97-124; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about
  • a light chain variable domain sequence comprising an LC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 164-189; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions;
  • LC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 190-207; or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 208-239; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions.
  • an anti-RTMC construct comprising an anti-RTMC antibody moiety that competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising (and in some
  • HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 208-239; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5)
  • an anti-RTMC construct comprising an anti- RTMC antibody moiety that competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising (and in some
  • an anti-RTMC construct comprising an anti-RTMC antibody moiety that competes for binding to a target HIV-1
  • RT/MHC class I complex with an antibody moiety comprising a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46, and a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 47-74.
  • the anti-RTMC construct is stable in a solution for at least about 1 month (such as at least about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer).
  • Stability can be expressed, for example, as the retention of an effector function (e.g., target cell- killing activity) of the anti-RTMC construct in an aqueous formulation kept at a storage temperature, e.g., 4° C.
  • the anti-RTMC construct retains at least 40% (such as at least about any of 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater) of an effector function in an aqueous formulation kept at a storage temperature for at least about 1 month (such as at least about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer).
  • the storage temperature is no greater than about 25° C (such as no greater than about any of 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2, 1, or 0° C, or less).
  • the effector function is target cell-killing activity.
  • the antibody moiety of the anti-RTMC construct comprises HC- CDR and LC-CDR sequences, and a tandem di-scFv bispecific anti-RTMC antibody comprising the HC-CDR and LC-CDR sequences retains at least 40% (such as at least about any of 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater) of an effector function in an aqueous formulation kept at a storage temperature for at least about 1 month (such as at least about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer), wherein the tandem di-scFv bispecific anti-RTMC antibody comprises a) a first scFv that specifically binds to a complex comprising an HIV-1 RT 181 peptide and an MHC class I
  • the storage temperature is no greater than about 25° C (such as no greater than about any of 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2, 1, or 0° C, or less).
  • the effector function is target cell-killing activity.
  • the anti-RTMC constructs comprise an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein.
  • the anti-RTMC antibody moiety specifically binds to an RTMC present on the surface of a cell.
  • the cell is a T cell.
  • the T cell is a CD4 + T cell.
  • the HIV-1 RT peptide is an MHC class I-restricted peptide. In some embodiments, the HIV-1 RT peptide is from about 8 to about 12 (such as about any of 8, 9, 10, 11, or 12) amino acids in length. [0108] In some embodiments, the HIV-1 RT peptide comprises (and in some embodiments consists of) the amino acid sequence of any one of SEQ ID NOs: 5-18.
  • the HIV-1 RT peptide comprises (and in some embodiments consists of) the sequence of amino acids 181-189 of HIV-1 RT (YQYMDDLYV, SEQ ID NO: 5; also referred to herein as "HIV-1 RT 181").
  • the MHC class I protein is HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G. In some embodiments, the MHC class I protein is HLA-A. In some embodiments, the HLA-A is HLA-A02. In some embodiments, the HLA-A02 is HLA-A*02:01.
  • the anti-RTMC antibody moiety is a full-length antibody.
  • the anti-RTMC antibody moiety is an antigen-binding fragment, for example an antigen-binding fragment selected from the group consisting of a Fab, a Fab', a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), and a single-chain antibody molecule (scFv).
  • the anti-RTMC antibody moiety is an scFv.
  • the anti-RTMC antibody moiety is human, humanized, or semi- synthetic.
  • the anti-RTMC antibody moiety specifically binds to the N- terminal portion of the HIV-1 RT peptide in the complex. In some embodiments, the anti-RTMC antibody moiety specifically binds to the C-terminal portion of the HIV-1 RT peptide in the complex. In some embodiments, the anti-RTMC antibody moiety specifically binds to the middle portion of the HIV- 1 RT peptide in the complex.
  • the anti-RTMC antibody moiety (or the anti-RTMC construct comprising the anti-RTMC antibody moiety) binds to the complex comprising the HIV-1 RT peptide and the MHC class I protein with an affinity that is at least about 10 (including for example at least about any of 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1000 or more) times its binding affinity for each of full-length HIV-1 RT, free HIV-1 RT peptide, MHC class I protein not bound to a peptide, and/or MHC class I protein bound to a non- HIV-1 RT peptide.
  • the anti-RTMC antibody moiety (or the anti-RTMC construct comprising the anti-RTMC antibody moiety) binds to the complex comprising the HIV-1 RT peptide and the
  • MHC class I protein with a K d no more than about 1/10 (such as no more than about any of 1/10,
  • the anti-RTMC antibody moiety (or the anti-RTMC construct comprising the anti-RTMC antibody moiety) binds to the complex comprising the HIV-1 RT peptide and the MHC class I protein with a K d between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the anti-RTMC antibody moiety (or the anti-RTMC construct comprising the anti-RTMC antibody moiety) binds to the complex comprising the HIV-1 RT peptide and the MHC class I protein with a K d between about 1 pM to about 250 pM (such as about any of 1, 10, 25, 50, 75, 100, 150, 200, or 250 pM, including any ranges between these values).
  • the anti-RTMC antibody moiety (or the anti-RTMC construct comprising the anti-RTMC antibody moiety) binds to the complex comprising the HIV-1 RT peptide and the MHC class I protein with a K d between about 1 nM to about 500 nM (such as about any of 1, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500 nM, including any ranges between these values).
  • the anti-RTMC antibody moiety specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the anti-RTMC antibody moiety cross-reacts with at least one complex comprising the HIV-1 RT peptide and an allelic variant of the MHC class I protein.
  • the allelic variant has up to about 10 (such as about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions when compared to the MHC class I protein.
  • the allelic variant is the same serotype as the MHC class I protein.
  • the allelic variant is a different serotype than the MHC class I protein.
  • the anti-RTMC antibody moiety does not cross- react with any complex comprising the HIV-1 RT peptide and an allelic variant of the MHC class I protein. In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • the anti-RTMC antibody moiety specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, wherein the anti-RTMC antibody moiety cross-reacts with at least one complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC antibody moiety does not cross-react with any complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide.
  • the anti-RTMC antibody moiety specifically binds to a complex comprising an HIV-1 RT peptide comprising (such as consisting of) the amino acid sequence of any one of SEQ ID NOs: 5-9 (SEQ ID NO: 5) and an MHC class I protein (such as
  • HLA-A02 for example HLA-A*02:01
  • the anti-RTMC antibody moiety further binds to at least one (including at least about any of 2, 3, 4, or 5) of: a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA- A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA- A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 13 and an MHC class I protein (such as HLA-A02,
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 5-9 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 6-9 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 5-9 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 13 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 5-9 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA-A02, for example HLA- A*02:01); and a complex comprising an alanine-
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of SEQ ID NO: 6 or 7 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA-A02, for example HLA- A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 13 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HIV-1 RT peptide of S
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 5-9 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 10 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 11 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA-A02, for example HLA- A*02:01); a complex comprising an alanine- substituted HIV-1 RT peptide
  • the anti-RTMC antibody moiety specifically binds to a complex comprising an HIV-1 RT peptide comprising the amino acid sequence of any one of SEQ ID NOs: 5-9 and HLA-A*02:01, wherein the anti-RTMC antibody moiety cross-reacts with at least one (including at least about any of 2, 3, 4, 5, or 6) of: a complex comprising the HIV-1 RT peptide and HLA-A*02:02 (GenBank Accession No.: AFL91480), a complex comprising the HIV-1 RT peptide and HLA-A*02:03 (GenBank Accession No.: AAA03604), a complex comprising the HIV-1 RT peptide and HLA-A*02:05 (GenBank Accession No.: AAA03603), a complex comprising the HIV-1 RT peptide and HLA-A*02:06 (GenBank Accession No.:
  • CCB78868 a complex comprising the HIV-1 RT peptide and HLA-A*02:07 (GenBank Accession No.: ACR55712), and a complex comprising the HIV-1 RT peptide and HLA- A*02: l l (GenBank Accession No.: CAB56609).
  • the anti-RTMC antibody moiety specifically binds to one or more of: a complex comprising HIV-1 RT 181 (SEQ ID NO: 5) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYVDDLYV (SEQ ID NO: 6) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYIDDLYV (SEQ ID NO: 7) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of CQYMDDLYV (SEQ ID NO: 8) and an MHC class I protein (such as HLA-A02, for example HLA-A*02
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide of SEQ ID NO: 5 and an MHC class I protein (such as HLA- A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYVDDLYV (SEQ ID NO: 6) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYIDDLYV (SEQ ID NO: 7) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT peptide of SEQ ID NO: 5 and an MHC class I protein (such as HLA-
  • A02 for example HLA-A*02:01
  • a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYVDDLYV (SEQ ID NO: 6) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYIDDLYV (SEQ ID NO: 7) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of CQYMDDLYV (SEQ ID NO: 8) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of CQYVDDLYV (SEQ ID NO: 9) and an MHC class I protein (such as HLA-A02, for example HLA
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYVDDLYV (SEQ ID NO: 6) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of
  • YQYIDDLYV SEQ ID NO: 7 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of CQYMDDLYV (SEQ ID NO: 8) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of CQYVDDLYV (SEQ ID NO: 9) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-RTMC antibody moiety specifically binds to: a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of YQYVDDLYV (SEQ ID NO: 6) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an HIV-1 RT 181 variant having the amino acid sequence of
  • YQYIDDLYV SEQ ID NO: 7
  • MHC class I protein such as HLA-A02, for example HLA-A*02:01
  • the anti-RTMC antibody moiety is a semi- synthetic antibody moiety comprising fully human sequences and one or more synthetic regions.
  • the anti-RTMC antibody moiety is a semi- synthetic antibody moiety comprising a fully human light chain variable domain and a semi- synthetic heavy chain variable domain comprising fully human FR1, HC-CDR1, FR2, HC-CDR2, FR3, and FR4 regions and a synthetic HC-CDR3.
  • the semi- synthetic heavy chain variable domain comprises a fully synthetic HC-CDR3 having a sequence from about 5 to about 25 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) amino acids in length.
  • the semi- synthetic heavy chain variable domain or the synthetic HC-CDR3 is obtained from a semi- synthetic library (such as a semi- synthetic human library) comprising fully synthetic HC-CDR3s having a sequence from about 5 to about 25 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) amino acids in length, wherein each amino acid in the sequence is randomly selected from the standard human amino acids, minus cysteine.
  • the synthetic HC-CDR3 is from about 7 to about 15 (such as about any of 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acids in length.
  • the anti-RTMC antibody moieties in some embodiments comprise specific sequences or certain variants of such sequences.
  • the amino acid substitutions in the variant sequences do not substantially reduce the ability of the anti-RTMC antibody moiety to bind the RTMC.
  • alterations that do not substantially reduce RTMC binding affinity may be made.
  • Alterations that substantially improve RTMC binding affinity or affect some other property, such as specificity and/or cross-reactivity with related variants of the RTMC, are also contemplated.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR3 comprising the amino acid sequence of any one of
  • SEQ ID NOs: 245-246 or a variant thereof comprising up to about 3 (for example about any of
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR3 comprising the amino acid sequence of any one of
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID
  • NOs: 241-244 or a variant thereof comprising up to about 3 (for example about any of 1, 2, or
  • SEQ ID NOs: 245-246 or a variant thereof comprising up to about 3 (for example about any of
  • CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC- CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253; or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions in the LC-CDR sequences.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253.
  • the sequences of the CDRs noted herein are provided in Table 2 below.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain comprising an LC- CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain comprising an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3,
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of
  • LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189
  • LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207
  • LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the LC-CDR sequences.
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, wherein the amino acid substitutions are in HC-CDRl or HC- CDR2; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of S
  • the anti-RTMC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239.
  • the sequences of the HC-CDRs from putative anti-RTMC antibody clones are provided in Table 3 below and the LC- CDRs from the clones are
  • GYTFTSYG MNPHSGNT ARSGFDI SEQID NO: 80 SEQID NO: 112 SEQID NO: 143
  • the anti-RTMC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (including for example at least any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74.
  • the heavy and light chain variable domains can be combined in various pair-wise combinations to generate a number of anti-RTMC antibody moieties.
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC- CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and 208, respectively, SEQ ID NOs: 76, 98, 126, 165, 191, and 209, respectively, SEQ ID NOs: 77, 99, 127, 164, 192, and 210, respectively, SEQ ID NOs: 78, 100, 128, 166, 193, and 211, respectively, SEQ ID NOs: 79, 101, 129, 167, 194, and 212, respectively, SEQ ID NOs: 80, 102, 130, 168, 192, and 213, respectively, SEQ ID NOs: 81, 103, 131, 169, 191, and 214, respectively, SEQ ID NOs: 80, 102, 130,
  • SEQ ID NOs: 86, 109, 138, 173, 198, and 220 respectively, SEQ ID NOs: 80, 102, 139, 174, 199, and 221, respectively, SEQ ID NOs: 79, 110, 140, 164, 192, and 208,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114, 145, 179, 202, and 225, respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the heavy chain comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, an HC- CDR2 comprising the amino acid sequence of SEQ ID NO: 97, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO 125
  • the light chain comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 164, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 208.
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and 208, respectively, SEQ ID NOs: 76, 98, 126, 165, 191, and 209, respectively, SEQ ID NOs: 77, 99, 127, 164, 192, and 210, respectively, SEQ ID NOs: 78, 100, 128, 166, 193, and 211, respectively, SEQ ID NOs: 79, 101, 129, 167, 194, and 212, respectively, SEQ ID NOs: 80, 102, 130, 168, 192, and 213, respectively, SEQ ID NOs: 81, 103, 131, 169, 191, and 214,
  • SEQ ID NOs: 86, 109, 138, 173, 198, and 220 respectively, SEQ ID NOs: 80, 102, 139, 174, 199, and 221, respectively, SEQ ID NOs: 79, 110, 140, 164, 192, and 208,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114, 145, 179, 202, and 225, respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 26 and 54, respectively, SEQ ID NOs: 27 and 55, respectively, SEQ ID NOs: 28 and 56, respectively, SEQ ID NOs: 29 and 57, respectively, SEQ ID NOs: 30 and 58, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID NOs: 19
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively.
  • the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively.
  • the anti-RTMC antibody moiety competes for binding to a target HIV-1 RT/MHC class I complex with a second anti-RTMC antibody moiety according to any of the anti-RTMC antibody moieties described herein. In some embodiments, the anti-RTMC antibody moiety binds to the same, or substantially the same, epitope as the second anti-RTMC antibody moiety.
  • binding of the anti-RTMC antibody moiety to the target HIV-1 RT/MHC class I complex inhibits binding of the second anti-RTMC antibody moiety to the target HIV-1 RT/MHC class I complex by at least about 70% (such as by at least about any of 75%, 80%, 85%, 90%, 95%, 98% or 99%), or vice versa.
  • the anti- RTMC antibody moiety and the second anti-RTMC antibody moiety cross-compete for binding to the target HIV-1 RT/MHC class I complex, i.e., each of the antibody moieties competes with the other for binding to the target HIV-1 RT/MHC class I complex.
  • the anti-RTMC antibody moiety competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247- 2
  • the anti-RTMC antibody moiety competes for binding to a target
  • HIV-1 RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of
  • SEQ ID NOs: 97-124 or a variant thereof comprising up to about 5 (for example about any of 1,
  • an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 164-189; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; an LC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 190-207; or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ
  • the anti-RTMC antibody moiety competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 97- 124; and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs:
  • the anti-RTMC antibody moiety competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC antibody moiety competes for binding to a target
  • HIV-1 RT/MHC class I complex with an antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and
  • SEQ ID NOs: 86, 109, 138, 173, 198, and 220 respectively, SEQ ID NOs: 80, 102, 139, 174, 199, and 221, respectively, SEQ ID NOs: 79, 110, 140, 164, 192, and 208,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114, 145, 179, 202, and 225, respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the anti-RTMC antibody moiety competes for binding to a target
  • HIV-1 RT/MHC class I complex with an antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • the anti-RTMC antibody moiety competes for binding to a target
  • HIV-1 RT/MHC class I complex with an antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and
  • SEQ ID NOs: 86, 109, 138, 173, 198, and 220 respectively, SEQ ID NOs: 80, 102, 139, 174, 199, and 221, respectively, SEQ ID NOs: 79, 110, 140, 164, 192, and 208,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114, 145, 179, 202, and 225, respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the anti-RTMC antibody moiety competes for binding to a target
  • HIV-1 RT/MHC class I complex with an antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ
  • SEQ ID NOs: 34 and 62 respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID NOs: 37 and 65, respectively, SEQ ID NOs: 38 and 66, respectively, SEQ ID NOs: 39 and 67, respectively, SEQ ID NOs: 40 and 68, respectively, SEQ ID NOs: 41 and 69, respectively, SEQ ID NOs: 42 and 70, respectively, SEQ ID NOs: 43 and 71, respectively, SEQ ID NOs: 44 and 72, respectively, SEQ ID NOs: 45 and 73, respectively, or SEQ ID NOs: 46 and 74, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC antibody moiety competes for binding to a target HIV-1 RT/MHC class I complex with an antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 26 and 54, respectively, SEQ ID NOs: 27 and 55, respectively, SEQ ID NOs: 28 and 56, respectively, SEQ ID NOs: 29 and 57, respectively, SEQ ID NOs: 30 and 58, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs
  • the anti-RTMC constructs in some embodiments are full-length antibodies comprising an anti-RTMC antibody moiety (also referred to herein as a "full-length anti-RTMC antibody").
  • the full-length antibody is a monoclonal antibody.
  • the full-length anti-RTMC antibody comprises an Fc sequence from an immunoglobulin, such as IgA, IgD, IgE, IgG, and IgM.
  • the full- length anti-RTMC antibody comprises an Fc sequence of IgG, such as any of IgGl, IgG2, IgG3, or IgG4.
  • the full-length anti-RTMC antibody comprises an Fc sequence of a human immunoglobulin.
  • the full-length anti-RTMC antibody comprises an Fc sequence of a mouse immunoglobulin.
  • the full-length anti-RTMC antibody comprises an Fc sequence that has been altered or otherwise changed so that it has enhanced antibody dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) effector function.
  • ADCC antibody dependent cellular cytotoxicity
  • CDC complement dependent cytotoxicity
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, and b) an Fc region.
  • the HIV-1 RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9) peptide and HLA-A*02:01, and b) an Fc region.
  • the Fc region comprises an IgGl Fc sequence. In some embodiments, the Fc region comprises a human IgGl Fc sequence. In some embodiments, the Fc region comprises a mouse IgGl Fc sequence.
  • the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID
  • the Fc region comprises an IgGl Fc sequence.
  • the Fc region comprises a human IgGl Fc sequence.
  • the Fc region comprises a mouse IgGl Fc sequence.
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-
  • CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of
  • the Fc region comprises an
  • the Fc region comprises a human IgGl Fc sequence.
  • the Fc region comprises a mouse IgGl Fc sequence.
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an
  • HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • LC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 164-189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-
  • the Fc region comprises an IgGl Fc sequence. In some embodiments, the Fc region comprises a human IgGl Fc sequence. In some embodiments, the Fc region comprises a mouse IgGl Fc sequence.
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75- 96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189; an LC-CDR2 comprising the amino acid sequence of
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75- 96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47- 74, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity; and b) an Fc region.
  • the Fc region comprises an IgGl Fc sequence.
  • the Fc region comprises a human IgGl Fc sequence.
  • the Fc region comprises a mouse IgGl F
  • a full-length anti-RTMC antibody comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74; and b) an Fc region.
  • the Fc region comprises an IgGl Fc sequence.
  • the Fc region comprises a human IgGl Fc sequence.
  • the Fc region comprises a mouse IgGl Fc sequence.
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-
  • SEQ ID NOs: 82, 114, 145, 179, 202, and 225 respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226, respectively, SEQ ID NOs: 90, 116, 147, 169, 191, and 227,
  • SEQ ID NOs: 91, 119, 151, 181, 191, and 230 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 93, 121, 154, 183, 204, and 233 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 85, 108, 157, 185, 200, and 235 respectively, SEQ ID NOs: 85, 108,
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-
  • CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC- CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 19 and 47, respectively
  • SEQ ID NOs: 34 and 62 respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID NOs: 37 and 65, respectively, SEQ ID NOs: 38 and 66, respectively, SEQ ID NOs: 39 and 67, respectively, SEQ ID NOs: 40 and 68, respectively, SEQ ID NOs: 41 and 69, respectively, SEQ ID NOs: 42 and 70, respectively, SEQ ID NOs: 43 and 71, respectively, SEQ ID NOs: 44 and 72, respectively, SEQ ID NOs: 45 and 73, respectively, or SEQ ID NOs: 46 and 74, respectively.
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the full- length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively.
  • the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the full-length anti-RTMC antibody moiety comprises heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively.
  • the full-length anti-RTMC antibody binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein with a IQ between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the full-length anti-RTMC antibody binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein with a K d between about 1 pM to about 250 pM (such as about any of 1, 10, 25, 50, 75, 100, 150, 200, or 250 pM, including any ranges between these values).
  • the anti-RTMC constructs in some embodiments comprise a multi- specific anti-RTMC molecule comprising an anti-RTMC antibody moiety and a second binding moiety (such as a second antigen-binding moiety).
  • the multi- specific anti-RTMC molecule comprises an anti-RTMC antibody moiety and a second antigen-binding moiety.
  • Multi- specific molecules are molecules that have binding specificities for at least two different antigens or epitopes (e.g., bispecific antibodies have binding specificities for two antigens or epitopes). Multi- specific molecules with more than two valencies and/or specificities are also contemplated. For example, trispecific antibodies can be prepared. Tutt et al. J.
  • a multi-specific ⁇ e.g., bispecific) anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, and b) a second binding moiety (such as an antigen-binding moiety).
  • the second binding moiety specifically binds to a complex comprising a different HIV-1 RT peptide bound to the MHC class I protein.
  • the second scFv specifically binds to a complex comprising the HIV-1 RT peptide bound to a different MHC class I protein.
  • the second binding moiety specifically binds to a different epitope on the complex comprising the HIV-1 RT peptide and the MHC class I protein. In some embodiments, the second binding moiety specifically binds to a different antigen. In some embodiments, the second binding moiety specifically binds to an antigen on the surface of a cell, such as a cytotoxic cell. In some embodiments, the second binding moiety specifically binds to an antigen on the surface of a lymphocyte, such as a T cell, an NK cell, a neutrophil, a monocyte, a macrophage, or a dendritic cell. In some embodiments, the second binding moiety specifically binds to an effector T cell, such as a cytotoxic T cell (also known as cytotoxic T lymphocyte (CTL) or T killer cell).
  • CTL cytotoxic T lymphocyte
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, and b) a second antigen-binding moiety that binds specifically to CD3.
  • the second antigen-binding moiety specifically binds to CD3s.
  • the second antigen-binding moiety specifically binds to an agonistic epitope of CD3s.
  • agonistic epitope means (a) an epitope that, upon binding of the multi- specific molecule, optionally upon binding of several multi- specific molecules on the same cell, allows said multi- specific molecules to activate T cell receptor (TCR) signaling and induce T cell activation, and/or (b) an epitope that is solely composed of amino acid residues of the epsilon chain of CD3 and is accessible for binding by the multi- specific molecule, when presented in its natural context on T cells ⁇ i.e. surrounded by the TCR, the CD3y chain, etc.), and/or (c) an epitope that, upon binding of the multi- specific molecule, does not lead to stabilization of the spatial position of CD3s relative to CD3y.
  • TCR T cell receptor
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an
  • HIV- 1 RT peptide and an MHC class I protein and b) a second antigen-binding moiety that binds specifically to an antigen on the surface of an effector cell, including for example CD3y,
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an
  • HIV- 1 RT peptide and an MHC class I protein and b) a second antigen-binding moiety that binds specifically to a component of the complement system, such as Clq.
  • Clq is a subunit of the CI enzyme complex that activates the serum complement system.
  • the second antigen-binding moiety specifically binds to an Fc receptor.
  • the second antigen-binding moiety specifically binds to an Fey receptor (FcyR).
  • the FcyR may be an FcyRIII present on the surface of natural killer (NK) cells or one of FcyRI, FcyRIIA, FcyRIIBI, FcyRIIB2, and FcyRIIIB present on the surface of macrophages, monocytes, neutrophils and/or dendritic cells.
  • the second antigen-binding moiety is an Fc region or functional fragment thereof.
  • a "functional fragment" as used in this context refers to a fragment of an antibody Fc region that is still capable of binding to an FcR, in particular to an FcyR, with sufficient specificity and affinity to allow an
  • FcyR bearing effector cell in particular a macrophage, a monocyte, a neutrophil and/or a dendritic cell, to kill the target cell by cytotoxic lysis or phagocytosis.
  • a functional Fc fragment is capable of competitively inhibiting the binding of the original, full-length Fc portion to an
  • a functional Fc fragment retains at least
  • the Fc region or functional fragment thereof is an enhanced Fc region or functional fragment thereof.
  • enhanced Fc region refers to an Fc region that is modified to enhance Fc receptor-mediated effector-functions, in particular antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity
  • CDC antibody-mediated phagocytosis.
  • This can be achieved as known in the art, for example by altering the Fc region in a way that leads to an increased affinity for an activating receptor (e.g. FcyRIIIA (CD 16 A) expressed on natural killer (NK) cells) and/or a decreased binding to an inhibitory receptor (e.g. FcyRIIB l/B2 (CD32B)).
  • an activating receptor e.g. FcyRIIIA (CD 16 A) expressed on natural killer (NK) cells
  • a decreased binding to an inhibitory receptor e.g. FcyRIIB l/B2 (CD32B
  • the second antigen-binding moiety is an antibody or antigen-binding fragment thereof that specifically binds to an FcR, in particular to an FcyR, with sufficient specificity and affinity to allow an FcyR bearing effector cell, in particular a macrophage, a monocyte, a neutrophil and/or a dendritic cell, to kill the target cell by cytotoxic lysis or phagocytosis.
  • the multi- specific anti-RTMC molecule allows killing of RTMC- presenting target cells and/or can effectively redirect CTLs to lyse RTMC-presenting target cells.
  • the multi- specific (e.g. , bispecific) anti-RTMC molecule of the present invention shows an in vitro EC 50 ranging from 10 to 500 ng/ml, and is able to induce redirected lysis of about 50% of the target cells through CTLs at a ratio of CTLs to target cells of from about 1 : 1 to about 50: 1 (such as from about 1: 1 to about 15: 1, or from about 2: 1 to about 10: 1).
  • the multi-specific (e.g. , bispecific) anti-RTMC molecule is capable of cross-linking a stimulated or unstimulated CTL and the target cell in such a way that the target cell is lysed. This offers the advantage that no generation of target- specific T cell clones or common antigen presentation by dendritic cells is required for the multi- specific anti- RTMC molecule to exert its desired activity.
  • the multi- specific anti- RTMC molecule of the present invention is capable of redirecting CTLs to lyse the target cells in the absence of other activating signals.
  • the second antigen-binding moiety of the multi- specific anti-RTMC molecule specifically binds to CD3 (e.g., specifically binds to CD3s), and signaling through CD28 and/or IL-2 is not required for redirecting CTLs to lyse the target cells.
  • Methods for measuring the preference of the multi- specific anti-RTMC molecule to simultaneously bind to two antigens are within the normal capabilities of a person skilled in the art.
  • the multi- specific anti-RTMC molecule may be contacted with a mixture of CD3 + /HIV- 1 RT " cells and CD37HIV- 1 RT + cells.
  • the number of multi- specific anti- RTMC molecule-positive single cells and the number of cells cross-linked by multi- specific anti-RTMC molecules may then be assessed by microscopy or fluorescence-activated cell sorting (FACS) as known in the art.
  • FACS fluorescence-activated cell sorting
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, and b) a second antigen-binding moiety.
  • the HIV- 1 RT peptide is HIV- 1 RT 181 (SEQ ID NO: 5), HIV- 1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01. In some embodiments, the second antigen-binding moiety specifically binds to a complex comprising a different HIV-1 RT peptide bound to the MHC class I protein. In some embodiments, the second antigen-binding moiety specifically binds to a complex comprising the HIV-1 RT peptide bound to a different MHC class I protein. In some
  • the second antigen-binding moiety specifically binds to a different epitope on the complex comprising the HIV-1 RT peptide and the MHC class I protein. In some embodiments, the second antigen-binding moiety specifically binds to another antigen. In some embodiments, the second antigen-binding moiety specifically binds to an antigen on the surface of a cell, such as an RTMC-presenting cell. In some embodiments, the second antigen-binding moiety specifically binds to an antigen on the surface of a cell that does not express HIV-1 RT. In some embodiments, the second antigen-binding moiety specifically binds to an antigen on the surface of a cytotoxic cell.
  • the second antigen-binding moiety specifically binds to an antigen on the surface of a lymphocyte, such as a T cell, an NK cell, a neutrophil, a monocyte, a macrophage, or a dendritic cell.
  • the second antigen-binding moiety specifically binds to an antigen on the surface of an effector T cell, such as a cytotoxic T cell.
  • the second antigen-binding moiety specifically binds to an antigen on the surface of an effector cell, including for example CD3y, CD35, CD3s, CD3 ⁇ , CD28, CD16a, CD56, CD68, and GDS2D.
  • the anti-RTMC antibody moiety is human, humanized, or semi- synthetic.
  • the second antigen-binding moiety is an antibody moiety.
  • the second antigen-binding moiety is a human, humanized, or semi- synthetic antibody moiety.
  • the multi- specific anti- RTMC molecule further comprises at least one (such as at least about any of 2, 3, 4, 5, or more) additional antigen-binding moieties.
  • the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9) peptide and HLA-A*02:01, and b) a second antigen-binding moiety.
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii) a light chain variable domain comprising an LC- CDR1 comprising a complex comprising an HIV-1 RT
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an
  • HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an
  • HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an
  • HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, and b) a second antigen-binding moiety.
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an
  • HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • a light chain variable domain comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and b) a second antigen-binding moiety.
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97- 124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125- 163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189; an LC-CDR2 comprising the amino acid
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97- 124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125- 163; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity; and b) a second scFv.
  • a multi-specific anti-RTMC molecule comprising a) an anti-RTMC antibody moiety comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74; and b) a second antigen-binding moiety.
  • the multi- specific anti-RTMC molecule is, for example, a diabody (Db), a single-chain diabody (scDb), a tandem scDb (Tandab), a linear dimeric scDb (LD-scDb), a circular dimeric scDb (CD-scDb), a di-diabody, a tandem scFv, a tandem di-scFv (e.g.
  • the multi-specific anti-RTMC molecule is a tandem scFv (e.g. , a tandem di-scFv,
  • the multi- specific anti-RTMC molecule in some embodiments is a tandem scFv comprising a first scFv comprising an anti-RTMC antibody moiety and a second scFv (also referred to herein as a "tandem scFv multi- specific anti-RTMC antibody").
  • a tandem scFv comprising a first scFv comprising an anti-RTMC antibody moiety and a second scFv (also referred to herein as a "tandem scFv multi- specific anti-RTMC antibody").
  • the tandem scFv multi- specific anti-RTMC antibody further comprises at least one (such as at least about any of 2, 3, 4, 5, or more) additional scFv.
  • additional scFv additional scFv.
  • a tandem scFv multi- specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, and b) a second scFv.
  • the HIV- 1 RT peptide is HIV- 1 RT 181 (SEQ ID NO: 5), HIV- 1 RT 181 M184V (SEQ ID NO: 6), HIV- 1 RT 181 M184I (SEQ ID NO: 7), HIV- 1 RT 181 Y181C (SEQ ID NO: 8), or HIV- 1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the MHC class I protein is HLA-A02.
  • the MHC class I protein is HLA-A*02:01.
  • the second scFv specifically binds to a complex comprising a different HIV- 1 RT peptide bound to the MHC class I protein.
  • the second scFv specifically binds to a complex comprising the HIV- 1 RT peptide bound to a different MHC class I protein. In some embodiments, the second scFv specifically binds to a different epitope on the complex comprising the HIV- 1 RT peptide and the MHC class I protein. In some embodiments, the second scFv specifically binds to another antigen. In some embodiments, the second scFv specifically binds to an antigen on the surface of a cell, such as an RTMC-presenting cell. In some embodiments, the second scFv specifically binds to an antigen on the surface of a cell that does not express HIV- 1 RT.
  • the second scFv specifically binds to an antigen on the surface of a cytotoxic cell. In some embodiments, the second scFv specifically binds to an antigen on the surface of a lymphocyte, such as a T cell, an NK cell, a neutrophil, a monocyte, a macrophage, or a dendritic cell. In some embodiments, the second scFv specifically binds to an antigen on the surface of an effector T cell, such as a cytotoxic T cell.
  • the second scFv specifically binds to an antigen on the surface of an effector cell, including for example CD3y, CD35, CD3s, ⁇ 3 ⁇ , CD28, CD16a, CD56, CD68, and GDS2D.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semi- synthetic. In some embodiments, the tandem scFv multi- specific anti-RTMC antibody further comprises at least one (such as at least about any of 2, 3, 4, 5, or more) additional scFv. In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV- 1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV- 1 RT peptide and a different subtype of the MHC class I protein.
  • at least one such as at least any of 2, 3, 4, or 5
  • a tandem scFv multi- specific e.g.
  • bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT 181 (SEQ ID NO: 5), FflV- 1 RT 181 M184V (SEQ ID NO: 6), FflV- 1 RT 181 M184I (SEQ ID NO: 7), HIV- 1 RT 181 Y181C (SEQ ID NO: 8), or HIV- 1 RT 181 Y181C, M184V (SEQ ID NO: 9) peptide and HLA-A*02:01, and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii)
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, and b) a second scFv.
  • a first scFv that specifically binds to a
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75- 96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97- 124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125- 163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3,
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97- 124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125- 163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NO:
  • a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239; and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity; and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74; and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, and b) a second scFv, wherein the tandem scFv multi- specific anti-RTMC antibody is a tandem di-scFv or a tandem tri-scFv.
  • the tandem scFv multi- specific anti-RTMC antibody is a tandem di-scFv.
  • the tandem scFv multi- specific anti-RTMC antibody is a bispecific T-cell engager.
  • tandem di-scFv bispecific anti- RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • the HIV- 1 RT peptide is HIV- 1 RT 181 (SEQ ID NO: 5), HIV- 1 RT 181 M184V (SEQ ID NO: 6), HIV- 1 RT 181 M184I (SEQ ID NO: 7), HIV- 1 RT 181 Y181C (SEQ ID NO: 8), or HIV- 1 RT 181 Y181C, M184V (SEQ ID NO: 9).
  • the MHC class I protein is HLA-A02.
  • the MHC class I protein is HLA-A*02:01.
  • the second scFv specifically binds to an antigen on the surface of an effector T cell, such as a cytotoxic T cell.
  • the second scFv specifically binds to an antigen selected, for example, from the group consisting of
  • the second scFv specifically binds to an agonistic epitope on an antigen on the surface of a T cell, wherein the binding of the second scFv to the antigen enhances T cell activation.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic.
  • both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9) peptide and HLA-A*02:01, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID
  • NOs: 245-246 or a variant thereof comprising up to about 3 (for example about any of 1, 2, or
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an
  • LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-
  • CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii)
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75- 96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189; an LC-CDR2 compris
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75- 96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of S
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47- 74, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, and b) a second scFv that specifically binds to CD3s.
  • the HIV-1 RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01. In some embodiments, the first scFv is fused to the second scFv through linkage with a peptide linker. In some embodiments, the peptide linker is between about 5 to about 20 (such as about any of 5, 10, 15, or 20, including any ranges between these values) amino acids in length. In some embodiments, the peptide linker comprises (and in some embodiments consists of) the amino acid sequence S RGGGGS GGGGSGGGGSLEMA (SEQ ID NO: 276).
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic.
  • both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6), HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT 181 Y181C, M184V (SEQ ID NO: 9) peptide and HLA-A*02:01, and b) a second scFv that specifically binds to CD3s.
  • the first scFv is fused to the second scFv through linkage with a peptide linker.
  • the peptide linker is between about 5 to about 20 (such as about any of 5, 10, 15, or 20, including any ranges between these values) amino acids in length.
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence of SEQ ID NO: 276.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID
  • NOs: 245-246 or a variant thereof comprising up to about 3 (for example about any of 1, 2, or
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and b) a second scFv that specifically binds to CD3s.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, and b) a second scFv that specifically binds to CD3s.
  • the first scFv is fused to the second scFv through linkage with a peptide linker.
  • the peptide linker is between about 5 to about 20 (such as about any of 5, 10, 15, or 20, including any ranges between these values) amino acids in length.
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence of SEQ ID NO: 276.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an
  • HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-
  • CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • a second scFv that specifically binds to CD3s.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • the first scFv is fused to the second scFv through linkage with a peptide linker.
  • the peptide linker is between about 5 to about 20 (such as about any of 5, 10, 15, or 20, including any ranges between these values) amino acids in length.
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence of SEQ ID NO: 276.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47- 74, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity, and b) a second scFv that specifically binds to CD3s.
  • tandem di-scFv bispecific anti-RTMC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, and b) a second scFv that specifically binds to CD3s.
  • the first scFv is fused to the second scFv through linkage with a peptide linker.
  • the peptide linker is between about 5 to about 20 (such as about any of 5, 10, 15, or 20, including any ranges between these values) amino acids in length.
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence of SEQ ID NO: 276.
  • the first scFv is human, humanized, or semi- synthetic.
  • the second scFv is human, humanized, or semi- synthetic.
  • both the first scFv and the second scFv are human, humanized, or semi- synthetic.
  • the tandem di-scFv bispecific anti-RTMC antibody binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein with a K d between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM, including any ranges between these values).
  • the tandem di-scFv bispecific anti-RTMC antibody binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein with a K d between about 0.1 pM to about 500 nM (such as about any of 0.1 pM, 1.0 pM, 10 pM, 50 pM, 100 pM, 500 pM, 1 nM, 10 nM, 50 nM, 100 nM, or 500 nM,
  • HIV-1 RT peptide comprising an HIV-1 RT peptide and an MHC class I protein with a IQ between about 1 nM to about 500 nM (such as about any of 1, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500 nM, including any ranges between these values).
  • tandem di-scFv bispecific anti-RTMC antibody is stable in a solution for at least about 1 month (such as at least about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer).
  • Stability can be expressed, for example, as the retention of target cell-killing activity by the tandem di-scFv bispecific anti-RTMC antibody in an aqueous formulation kept at a storage temperature, e.g., 4° C [0225]
  • the tandem di-scFv bispecific anti-RTMC antibody retains at least 40% (such as at least about any of 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or greater) target cell-killing activity in an aqueous formulation kept at a storage temperature for at least about 1 month (such as at least about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer).
  • the storage temperature is no greater than about 25° C (such as no greater than about any of 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2, 1, or 0° C, or less).
  • the tandem di-scFv bispecific anti-RTMC antibody retains at least 60% target cell-killing activity in an aqueous formulation kept at a storage temperature of 4° C for at least about 2 years.
  • the tandem di-scFv bispecific anti-RTMC antibody comprises a) a first scFv that specifically binds to a complex comprising an HIV-1 RT 181 peptide and an MHC class I protein, and b) a second scFv that specifically binds to CD3s.
  • the multi- specific anti-RTMC molecule (such as di- scFv) comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-
  • CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and 208, respectively, SEQ ID NOs: 76, 98, 126, 165, 191, and 209, respectively, SEQ ID NOs: 77, 99,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the multi- specific anti-RTMC molecule (such as di-scFv) comprises an anti-RTMC antibody moiety comprising HC-CDR1, HC-CDR2, HC-CDR3, LC- CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • SEQ ID NOs: 82, 114, 150, 176, 200, and 229 respectively, SEQ ID NOs: 91, 119, 151, 181, 191, and 230, respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231, respectively, SEQ ID NOs: 80, 102, 153, 164, 192, and 232, respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the multi- specific anti-RTMC molecule (such as di-scFv) comprises an anti-RTMC antibody moiety comprising HC-CDR1, HC-CDR2, HC-CDR3, LC- CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97,
  • SEQ ID NOs: 88, 113, 144, 178, 201, and 224 respectively, SEQ ID NOs: 82, 114,
  • SEQ ID NOs: 80, 102, 153, 164, 192, and 232 respectively, SEQ ID NOs: 93, 121, 154, 183, 204, and 233, respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214,
  • the multi-specific anti-RTMC molecule comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 26 and 54, respectively, SEQ ID NOs: 27 and 55, respectively, SEQ ID NOs: 28 and 56, respectively, SEQ ID NOs: 29 and 57, respectively, SEQ ID NOs: 30 and 58, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and
  • the multi-specific anti-RTMC molecule comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 26 and 54, respectively, SEQ ID NOs: 27 and 55, respectively, SEQ ID NOs: 28 and 56, respectively, SEQ ID NOs: 29 and 57, respectively, SEQ ID NOs: 30 and 58, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 19 and
  • SEQ ID NOs: 36 and 64 respectively, SEQ ID NOs: 37 and 65, respectively, SEQ ID NOs: 38 and 66, respectively, SEQ ID NOs: 39 and 67, respectively, SEQ ID NOs: 40 and 68, respectively, SEQ ID NOs: 41 and 69, respectively, SEQ ID NOs: 42 and 70, respectively, SEQ ID NOs: 43 and 71, respectively, SEQ ID NOs: 44 and 72, respectively, SEQ ID NOs: 45 and 73, respectively, or SEQ ID NOs: 46 and 74, respectively.
  • the multi-specific anti-RTMC molecule (such as di-scFv) comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the multi- specific anti-RTMC molecule (such as di-scFv) comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively.
  • the multi- specific anti-RTMC molecule (such as di- scFv) comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the multi- specific anti- RTMC molecule (such as di-scFv) comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively.
  • the anti-RTMC construct in some embodiments is a chimeric receptor comprising an anti-RTMC antibody moiety (also referred to herein as an "anti-RTMC chimeric receptor").
  • an effector cell e.g., T cell
  • an anti-RTMC chimeric receptor effector cell also referred to herein as an "anti-RTMC chimeric receptor effector cell”
  • the chimeric receptor is a chimeric antigen receptor (CAR), and the anti-RTMC chimeric receptor is an anti-RTMC CAR.
  • the anti-RTMC CAR comprises a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein and b) an intracellular signaling domain.
  • a transmembrane domain may be present between the extracellular domain and the intracellular domain.
  • the spacer domain can be any oligo- or polypeptide that functions to link the transmembrane domain to the extracellular domain or the intracellular domain in the polypeptide chain.
  • a spacer domain may comprise up to about 300 amino acids, including for example about 10 to about 100, or about 25 to about 50 amino acids.
  • the transmembrane domain may be derived either from a natural or from a synthetic source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein.
  • Transmembrane regions of particular use in this invention may be derived from (i.e. comprise at least the transmembrane region(s) of) the ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ chain of the T-cell receptor, CD28, CD3s, CD3 CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
  • the transmembrane regions of particular use in this invention may be derived from (i.e. comprise at least the transmembrane region(s) of) the ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ chain of the T-cell receptor, CD28, CD3s, CD3 CD45, CD4, CD5, CD8, CD9, CD16, CD22,
  • transmembrane domain may be synthetic, in which case it may comprise predominantly hydrophobic residues such as leucine and valine.
  • phenylalanine, tryptophan and valine may be found at each end of a synthetic transmembrane domain.
  • a short oligo- or polypeptide linker having a length of, for example, between about 2 and about 10 (such as about any of 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids in length may form the linkage between the transmembrane domain and the intracellular signaling domain of the anti-RTMC CAR.
  • the linker is a glycine- serine doublet.
  • the transmembrane domain that naturally is associated with one of the sequences in the intracellular domain of the anti-RTMC CAR is used (e.g. , if an anti-RTMC
  • the CAR intracellular domain comprises a CD28 co-stimulatory sequence
  • the transmembrane domain of the anti-RTMC CAR is derived from the CD28 transmembrane domain.
  • the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex.
  • the intracellular signaling domain of the anti-RTMC CAR is responsible for activation of at least one of the normal effector functions of the immune cell in which the anti-RTMC CAR has been placed in.
  • Effector function of a T cell for example, may be cytolytic activity or helper activity including the secretion of cytokines.
  • intracellular signaling domain refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain.
  • intracellular signaling sequence is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal.
  • intracellular signaling domains for use in the anti-RTMC CAR of the invention include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the same functional capability.
  • TCR T cell receptor
  • T cell activation can be said to be mediated by two distinct classes of intracellular signaling sequence: those that initiate antigen-dependent primary activation through the TCR (primary signaling sequences) and those that act in an antigen- independent manner to provide a secondary or co-stimulatory signal (co-stimulatory signaling sequences).
  • Primary signaling sequences regulate primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way.
  • Primary signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyro sine-based activation motifs or ITAMs.
  • ITAMs immunoreceptor tyro sine-based activation motifs
  • the anti-RTMC CAR constructs in some embodiments comprise one or more ITAMs.
  • IT AM containing primary signaling sequences examples include those derived from TCRC, FcRy, FcRp, CD3y, CD35, CD3s, CD5, CD22, CD79a, CD79b, and CD66d.
  • the anti-RTMC CAR comprises a primary signaling sequence derived from CD3 ⁇ .
  • the intracellular signaling domain of the CAR can comprise the CD3 ⁇ intracellular signaling sequence by itself or combined with any other desired intracellular signaling sequence(s) useful in the context of the anti-RTMC CAR of the invention.
  • the intracellular domain of the anti-RTMC CAR can comprise a CD3 ⁇ intracellular signaling sequence and a costimulatory signaling sequence.
  • the costimulatory signaling sequence can be a portion of the intracellular domain of a costimulatory molecule including, for example, CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and the like.
  • a costimulatory molecule including, for example, CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and the like.
  • the intracellular signaling domain of the anti-RTMC CAR comprises the intracellular signaling sequence of CD3 ⁇ and the intracellular signaling sequence of CD28. In some embodiments, the intracellular signaling domain of the anti-RTMC CAR comprises the intracellular signaling sequence of CD3 ⁇ and the intracellular signaling sequence of 4- IBB. In some embodiments, the intracellular signaling domain of the anti-RTMC CAR comprises the intracellular signaling sequence of CD3 ⁇ and the intracellular signaling sequences of CD28 and 4- IBB.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, b) a transmembrane domain, and c) an intracellular signaling domain.
  • HIV-1 RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6),
  • HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT
  • the MHC class I protein is HLA-
  • the MHC class I protein is HLA-A*02:01.
  • the intracellular signaling domain is capable of activating an immune cell.
  • the intracellular signaling domain comprises a primary signaling sequence and a co-stimulatory signaling sequence.
  • the primary signaling sequence comprises a CD3 ⁇ intracellular signaling sequence.
  • the co- stimulatory signaling sequence comprises a CD28 and/or 4- IBB intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a
  • the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV-1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV-1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO:
  • the intracellular signaling domain is capable of activating an immune cell.
  • the intracellular signaling domain comprises a primary signaling sequence and a co-stimulatory signaling sequence.
  • the primary signaling sequence comprises a CD3 ⁇ intracellular signaling sequence.
  • the co-stimulatory signaling sequence comprises a CD28 and/or 4- IBB intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- 1BB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1,
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID
  • the intracellular signaling domain is capable of activating an immune cell.
  • the intracellular signaling domain comprises a primary signaling sequence and a co-stimulatory signaling sequence.
  • the primary signaling sequence comprises a CD3 ⁇ intracellular signaling sequence.
  • the co- stimulatory signaling sequence comprises a CD28 and/or 4- IBB intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; b
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1,
  • a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the LC-CDR sequences; b) a transmembrane domain, and c) an intracellular signaling domain.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164- 189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208
  • the intracellular signaling domain is capable of activating an immune cell.
  • the intracellular signaling domain comprises a primary signaling sequence and a co-stimulatory signaling sequence.
  • the primary signaling sequence comprises a CD3 ⁇ intracellular signaling sequence.
  • the co-stimulatory signaling sequence comprises a CD28 and/or 4- IBB intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or
  • sequence identity and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity; b) a transmembrane domain, and c) an intracellular signaling domain.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-74; b) an intracellular signaling domain.
  • the intracellular signaling domain is capable of activating an immune cell.
  • the intracellular signaling domain comprises a primary signaling sequence and a co-stimulatory signaling sequence.
  • the primary signaling sequence comprises a CD3 ⁇ intracellular signaling sequence.
  • the co- stimulatory signaling sequence comprises a CD28 and/or 4- IBB intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein, b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • the extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein
  • b) a transmembrane domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • HIV-1 RT peptide is HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO: 6),
  • HIV-1 RT 181 M184I (SEQ ID NO: 7), HIV-1 RT 181 Y181C (SEQ ID NO: 8), or HIV-1 RT
  • the MHC class I protein is HLA-
  • the MHC class I protein is HLA-A*02:01.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT 181 (SEQ ID NO: 5), HIV-1 RT 181 M184V (SEQ ID NO:
  • HIV-1 RT 181 M184I SEQ ID NO: 7
  • HIV-1 RT 181 Y181C SEQ ID NO: 8
  • HIV-1 RT 181 M184I SEQ ID NO: 7
  • HIV-1 RT 181 Y181C SEQ ID NO: 8
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1,
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247- 249, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions
  • b) a transmembrane domain and
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247-249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250-253, b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signal
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions
  • an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 208-239, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions
  • b) a transmembrane domain and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; and ii) a light chain variable domain sequence comprising an LC- CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-189; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 190-207; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%,
  • intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • an anti-RTMC CAR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 19-46 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 47-
  • 74 b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28 and/or 4- IBB intracellular signaling sequence.
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising HC-
  • CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NOs: 75, 97, 125, 164, 190, and 208, respectively, SEQ ID NOs: 76, 98,
  • SEQ ID NOs: 91, 119, 151, 181, 191, and 230 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 93, 121, 154, 183, 204, and 233 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 85, 108, 157, 185, 200, and 235 respectively, SEQ ID NOs: 85, 108,
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2,
  • HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NO: 1
  • SEQ ID NOs: 85, 108, 142, 176, 192, and 208 respectively, SEQ ID NOs: 80, 112, 143, 177, 191, and 223, respectively, SEQ ID NOs: 88, 113, 144, 178, 201, and 224,
  • SEQ ID NOs: 82, 114, 145, 179, 202, and 225 respectively, SEQ ID NOs: 89, 115, 146, 175, 200, and 226, respectively, SEQ ID NOs: 90, 116, 147, 169, 191, and 227,
  • SEQ ID NOs: 91, 119, 151, 181, 191, and 230 respectively, SEQ ID NOs: 92, 120, 152, 182, 203, and 231, respectively, SEQ ID NOs: 80, 102, 153, 164, 192, and 232,
  • SEQ ID NOs: 93, 121, 154, 183, 204, and 233 respectively, SEQ ID NOs: 92, 120, 155, 184, 191, and 214, respectively, SEQ ID NOs: 80, 102, 156, 164, 192, and 234,
  • SEQ ID NOs: 85, 108, 157, 185, 200, and 235 respectively, SEQ ID NOs: 85, 108, 158, 186, 191, and 218, respectively, SEQ ID NOs: 79, 110, 159, 187, 205, and 236,
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising HC-CDR1, HC-CDR2,
  • HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 comprising the amino acid sequences of SEQ ID NO: 1
  • SEQ ID NOs: 91, 119, 151, 181, 191, and 230 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 93, 121, 154, 183, 204, and 233 respectively, SEQ ID NOs: 92, 120,
  • SEQ ID NOs: 85, 108, 157, 185, 200, and 235 respectively, SEQ ID NOs: 85, 108,
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of
  • SEQ ID NOs: 19 and 47 respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively, SEQ ID NOs: 21 and 49, respectively, SEQ ID NOs: 22 and 50, respectively, SEQ ID NOs: 23 and 51, respectively, SEQ ID NOs: 24 and 52, respectively, SEQ ID NOs: 25 and 53, respectively, SEQ
  • SEQ ID NOs: 31 and 59 respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID NOs: 37 and 65, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID NOs: 37 and 65, respectively, SEQ ID NOs: 31 and 59, respectively, SEQ ID NOs: 32 and 60, respectively, SEQ ID NOs: 33 and 61, respectively, SEQ ID NOs: 34 and 62, respectively, SEQ ID NOs: 35 and 63, respectively, SEQ ID NOs: 36 and 64, respectively, SEQ ID
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 19 and 47, respectively, SEQ ID NOs: 20 and 48, respectively,
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 27 and 55, respectively.
  • the anti-RTMC CAR comprises an anti- RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively, or variants thereof having, individually, at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-RTMC CAR comprises an anti-RTMC antibody moiety comprising heavy chain and light chain variable domains comprising the amino acid sequence of SEQ ID NOs: 30 and 58, respectively.
  • the chimeric receptor is a chimeric antibody/T cell receptor construct (referred to herein as "abTCR"), and the anti-RTMC chimeric receptor is an anti- RTMC abTCR.
  • the anti-RTMC abTCR comprises a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein and b) a T cell receptor module (TCRM) capable of recruiting at least one TCR-associated signaling module.
  • TCRM T cell receptor module
  • the anti-RTMC abTCR comprises a first polypeptide chain and a second polypeptide chain.
  • the first and second polypeptide chains are linked, such as by a covalent linkage ⁇ e.g., peptide or other chemical linkage) or non-covalent linkage.
  • the anti-RTMC abTCR is a heterodimer comprising the first polypeptide chain and the second polypeptide chain.
  • the first polypeptide chain and the second polypeptide chain are linked by at least one disulfide bond.
  • the specificity of the anti-RTMC abTCR derives from an antibody moiety that confers binding specificity to the RTMC.
  • the antibody moiety is a Fab-like antigen-binding module. In some embodiments, the antibody moiety is an Fv-like antigen-binding module. In some embodiments, the antibody moiety is an scFv.
  • the capability of the anti-RTMC abTCR to recruit a TCR-associated signaling module derives from a T cell receptor module (TCRM).
  • the TCRM comprises the transmembrane module of a TCR (such as an aPTCR or a y5TCR).
  • the TCRM further comprises one or both of the connecting peptides or fragments thereof of a TCR.
  • the anti-RTMC abTCR further comprises at least one intracellular domain. In some embodiments, one or more of the at least one intracellular domain of the anti-RTMC abTCR comprises a sequence from the intracellular domain of a TCR. In some embodiments, one or more of the at least one
  • intracellular domain of the anti-RTMC abTCR comprises a T cell costimulatory signaling sequence.
  • the costimulatory signaling sequence can be a portion of the intracellular domain of a costimulatory molecule including, for example, CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, ICOS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and the like.
  • the antibody moiety is contained in an extracellular domain of the anti-RTMC abTCR.
  • the anti-RTMC abTCR further comprises one or more peptide linkers between the antibody moiety and the TCRM to optimize the length of the extracellular domain.
  • the antibody moiety is a Fab-like antigen-binding module comprising a) a first polypeptide chain comprising a first antigen-binding domain comprising a V H antibody domain and a C H I antibody domain and b) a second polypeptide chain comprising a second antigen-binding domain comprising a V L antibody domain and a C L antibody domain.
  • the first antigen-binding domain comprises the V H antibody domain amino- terminal to the C H I antibody domain and/or the second antigen-binding domain comprises the V L antibody domain amino-terminal to the C L antibody domain.
  • the V L and C L antibody domains there is a peptide linker between the V L and C L antibody domains and/or a peptide linker between the V H and C H I antibody domains.
  • all of the V L antibody domain and V H antibody domain CDRs are derived from the same antibody moiety.
  • the V L antibody domain and the V H antibody domain comprise antibody CDRs derived from more than one antibody moiety.
  • the first and second polypeptide chains are linked, such as by a covalent linkage (e.g. , peptide or other chemical linkage) or non-covalent linkage.
  • the first and second antigen-binding domains are linked by a disulfide bond.
  • the first and second antigen-binding domains are linked by a disulfide bond between a residue in the CHI domain and a residue in the CL domain.
  • the CHI domain is derived from an IgG (e.g, IgGl, IgG2, IgG3, or IgG4) heavy chain, optionally human.
  • the CHI domain is a variant comprising one or more modifications (e.g. , amino acid substitutions, insertions, and/or deletions) compared to the sequence from which it is derived.
  • the CL domain is derived from a kappa or lambda light chain, optionally human.
  • the CL domain is a variant comprising one or more modifications (e.g., amino acid substitutions, insertions, and/or deletions) compared to the sequence from which it is derived.
  • the CHI and/or CL domains comprise one or more modifications that do not substantially alter their binding affinities for one another.
  • the CHI and/or CL domains comprise one or more modifications that increase their binding affinities for one another and/or introduce a non-naturally occurring disulfide bond.
  • the Fab-like antigen-binding module is human, humanized, chimeric, semi-synthetic, or fully synthetic.
  • the antibody moiety is a Fab-like antigen-binding module comprising a) a first polypeptide chain comprising a first antigen-binding domain comprising a
  • the first antigen-binding domain comprises the VL antibody domain amino- terminal to the CHI antibody domain and/or the second antigen-binding domain comprises the
  • VH antibody domain amino-terminal to the CL antibody domain.
  • all of the VL antibody domain and VH antibody domain CDRs are derived from the same antibody moiety.
  • VL antibody domain and the VH antibody domain comprise antibody CDRs derived from more than one antibody moiety.
  • the first and second polypeptide chains are linked, such as by a covalent linkage (e.g. , peptide or other chemical linkage) or non-covalent linkage.
  • the first and second antigen-binding domains are linked by a disulfide bond.
  • the first and second antigen-binding domains are linked by a disulfide bond between a residue in the CHI domain and a residue in the CL domain.
  • the CHI domain is derived from an IgG (e.g, IgGl, IgG2, IgG3, or IgG4) heavy chain, optionally human.
  • the CHI domain is a variant comprising one or more modifications (e.g. , amino acid substitutions, insertions, and/or deletions) compared to the sequence from which it is derived.
  • the CL domain is derived from a kappa or lambda light chain, optionally human.
  • the CL domain is a variant comprising one or more modifications (e.g., amino acid substitutions, insertions, and/or deletions) compared to the sequence from which it is derived.
  • the CHI and/or CL domains comprise one or more modifications that do not substantially alter their binding affinities for one another.
  • the CHI and/or CL domains comprise one or more modifications that increase their binding affinities for one another and/or introduce a non-naturally occurring disulfide bond.
  • the Fab-like antigen-binding module is human, humanized, chimeric, semi-synthetic, or fully synthetic.
  • the antibody moiety is an Fv-like antigen-binding module comprising a) a first polypeptide chain comprising a first antigen-binding domain comprising a
  • VH antibody domain and optionally a first TCR constant domain from a T cell receptor subunit and b) a second polypeptide chain comprising a second antigen-binding domain comprising a VL antibody domain and optionally a second TCR constant domain from a T cell receptor subunit.
  • the first antigen-binding domain comprises the VH antibody domain amino-terminal to the first TCR constant domain and/or the second antigen-binding domain comprises the VL antibody domain amino-terminal to the second TCR constant domain.
  • the CDRs are derived from the same antibody moiety.
  • the VL antibody domain and the VH antibody domain comprise antibody CDRs derived from more than one antibody moiety.
  • the first and second polypeptide chains are linked, such as by a covalent linkage (e.g. , peptide or other chemical linkage) or non-covalent linkage.
  • the first and second antigen-binding domains are linked by a disulfide bond.
  • the first and second antigen-binding domains are linked by a disulfide bond between a residue in the first TCR constant domain and a residue in the second TCR constant domain.
  • the first TCR constant domain is derived from a TCR a subunit, optionally human, and/or the second TCR constant domain is derived from a TCR ⁇ subunit, optionally human.
  • the first TCR constant domain is derived from a TCR a subunit comprising the amino acid sequence of SEQ ID NO: 281
  • the second TCR constant domain is derived from a TCR ⁇ subunit, comprising the amino acid sequence of SEQ ID NO: 282.
  • the first TCR constant domain is derived from a TCR ⁇ subunit, optionally human, and/or the second TCR constant domain is derived from a TCR ⁇ subunit, optionally human.
  • the first TCR constant domain is derived from a TCR ⁇ subunit comprising the amino acid sequence of SEQ ID NO: 283, and/or the second TCR constant domain is derived from a TCR ⁇ subunit, comprising the amino acid sequence of SEQ ID NO: 282.
  • the first and/or second TCR constant domain is a variant comprising one or more modifications (e.g., amino acid substitutions, insertions, and/or deletions) compared to the sequence from which it is derived.
  • the first and/or second TCR constant domains comprise one or more modifications that do not substantially alter their binding affinities for one another. In some embodiments, the first and/or second TCR constant domains comprise one or more modifications that increase their binding affinities for one another and/or introduce a non-naturally occurring disulfide bond. In some embodiments, the Fv-lrke antigen-binding module is human, humanized, chimeric, semisynthetic, or fully synthetic.
  • the antibody moiety is an scFv comprising a) a polypeptide chain comprising a VH antibody domain and a VL antibody domain.
  • the scFv comprises the VH antibody domain amino-terminal to the VL antibody domain.
  • the scFv comprises the VL antibody domain amino-terminal to the VH antibody domain.
  • all of the VL antibody domain and VH antibody domain CDRs are derived from the same antibody moiety.
  • the VL antibody domain and the VH antibody domain comprise antibody CDRs derived from more than one antibody moiety.
  • the scFv is human, humanized, chimeric, semisynthetic, or fully synthetic.
  • the TCRM comprises a) a first polypeptide chain comprising a first T cell receptor domain (TCRD) comprising a first transmembrane domain and b) a second polypeptide chain comprising a second TCRD comprising a second transmembrane domain.
  • TCRD T cell receptor domain
  • the first transmembrane domain is the transmembrane domain of a first T cell receptor domain
  • the TCR subunit and/or the second transmembrane domain is the transmembrane domain of a second TCR subunit.
  • the first TCR subunit is a TCR a chain (e.g. ,
  • the second TCR subunit is a TCR ⁇ chain (e.g. ,
  • the first TCR subunit is a TCR ⁇ chain
  • the second TCR subunit is a TCR a chain.
  • the first TCR subunit is a TCR ⁇ chain (e.g. , GenBank Accession No: AGE91788)
  • the second TCR subunit is a TCR ⁇ chain (e.g. , GenBank Accession No: AAQ57272).
  • the first TCR subunit is a TCR ⁇ chain
  • the second TCR subunit is a TCR ⁇ chain.
  • the first and/or second transmembrane domains comprise (such as consist of), individually, a transmembrane domain contained in any one of the TCR subunit amino acid sequences of SEQ ID NOs: 281-284. In some embodiments, the first and/or second
  • transmembrane domains comprise (such as consist of), individually, any one of the amino acid sequences of SEQ ID NOs: 285-288.
  • the first TCRD further comprises a first connecting peptide amino-terminal to the transmembrane domain and/or the second TCRD further comprises a second connecting peptide amino-terminal to the transmembrane domain.
  • the first connecting peptide comprises all or a portion of the connecting peptide of the first TCR subunit and/or the second connecting peptide comprises all or a portion of the connecting peptide of the second TCR subunit.
  • the first and/or second connecting peptides comprise (such as consist of), individually, all or a portion of a connecting peptide contained in any one of the TCR subunit amino acid sequences of SEQ ID
  • first and/or second connecting peptides comprise
  • the first TCRD further comprises a first TCR intracellular domain carboxy-terminal to the first transmembrane domain and/or the second TCRD further comprises a second TCR intracellular domain carboxy-terminal to the second transmembrane domain.
  • the first TCR intracellular domain comprises all or a portion of the intracellular domain of the first TCR subunit and/or the second TCR intracellular domain comprises all or a portion of the intracellular domain of the second TCR subunit.
  • the first and/or second TCR intracellular domains comprise (such as consist of), individually, all or a portion of an intracellular sequence contained in any one of the TCR subunit amino acid sequences of SEQ ID NOs: 281-284.
  • the first and/or second TCR intracellular domains comprise (such as consist of), individually, any one of the amino acid sequences of SEQ ID NOs: 297-298.
  • the first TCRD is a fragment of the first TCR subunit and/or the second TCRD is a fragment of the second TCR chain.
  • the first and second polypeptide chains are linked, such as by a covalent linkage (e.g. , peptide or other chemical linkage) or non-covalent linkage.
  • the first and second TCRDs are linked by a disulfide bond.
  • the first and second TCRDs are linked by a disulfide bond between a residue in the first connecting peptide and a residue in the second connecting peptide.
  • the TCRM is capable of recruiting at least one TCR-associated signaling module selected from the group consisting of CD35s, CD3y8, and ⁇ .
  • the TCRM is capable of recruiting each of CD35s, CD3y8, and ⁇ to form an octameric anti-RTMC abTCR-CD3 complex (i.e., promotes anti-RTMC abTCR-CD3 complex formation).
  • the anti-RTMC abTCR is a molecule comprising a fusion of the antibody moiety to the TCRM.
  • the anti-RTMC abTCR comprises a fusion of the first polypeptide chain of the Fab-like or Fv-like antigen-binding module amino- terminal to the first polypeptide chain of the TCRM, thereby forming a first polypeptide chain of the anti-RTMC abTCR, and a fusion of the second polypeptide chain of the Fab-like or Fv-like antigen-binding module amino-terminal to the second polypeptide chain of the TCRM, thereby forming a second polypeptide chain of the anti-RTMC abTCR.
  • the anti- RTMC abTCR comprises a fusion of the scFv amino-terminal to the first or second polypeptide chain of the TCRM. In some embodiments, the anti-RTMC abTCR further comprises a peptide linker between the first polypeptide chain of the Fab-like or Fv-like antigen-binding module and the first polypeptide chain of the TCRM and/or a peptide linker between the second polypeptide chain of the Fab-like or Fv-like antigen-binding module and the second polypeptide chain of the TCRM.
  • the anti-RTMC abTCR further comprises a peptide linker between the scFv and the first or second polypeptide chain of the TCRM.
  • the peptide linker is between about 5 to about 70 (such as about any of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70, including any ranges between these values) amino acids in length.
  • the first polypeptide chain of the anti-RTMC abTCR further comprises an amino-terminal first signal peptide and/or the second polypeptide chain of the anti-RTMC abTCR further comprises an amino-terminal second signal peptide.
  • the first and/or second signal peptides comprise (such as consist of) the amino acid sequence of SEQ ID NO: 299.
  • the first polypeptide chain of the anti-RTMC abTCR further comprises a first accessory intracellular domain carboxy-terminal to the first transmembrane domain and/or the second polypeptide chain of the anti-RTMC abTCR further comprises a second accessory intracellular domain carboxy-terminal to the second transmembrane domain.
  • the first and/or second accessory intracellular domains comprise a TCR costimulatory domain.
  • the TCR costimulatory domain comprises all or a portion of the amino acid sequence of SEQ ID NO: 300.
  • the first and second polypeptide chains of the anti-RTMC abTCR are linked, such as by a covalent linkage (e.g., peptide or other chemical linkage) or non-covalent linkage.
  • the anti-RTMC abTCR is a heterodimer.
  • an anti-RTMC abTCR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein, and b) a T cell receptor module (TCRM) capable of recruiting at least one TCR-associated signaling module.
  • the HIV-1 RT peptide is HIV- 1 RT 181 (SEQ ID NO:
  • the antibody moiety is a Fab-like antigen-binding module. In some embodiments, the antibody moiety is an Fv-like antigen-binding module. In some embodiments, the antibody moiety is an scFv. In some embodiments, the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, 5, or 6) complex comprising the MHC class I protein and a variant of the HIV- 1 RT peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-RTMC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HIV- 1 RT peptide and a different subtype of the MHC class I protein.
  • an anti-RTMC abTCR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV- 1 RT 181 (SEQ ID NO: 5), HIV- 1 RT 181 M184V (SEQ ID NO:
  • the antibody moiety is a Fab-like antigen-binding module. In some embodiments, the antibody moiety is an Fv-like antigen-binding module. In some embodiments, the antibody moiety is an scFv.
  • an anti-RTMC abTCR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV- 1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 240, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions; and ii) a light chain variable domain comprising an LC-
  • an anti- RTMC abTCR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of SEQ ID NO: 240, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 241-244, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 245-246; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 247- 249, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 250- 253; and b) a T cell receptor module (TCRM) capable of recruiting at least one TCR-associated signaling module.
  • TCRM T cell receptor module
  • an anti-RTMC abTCR comprising a) an extracellular domain comprising an anti-RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96, or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124, or a variant thereof comprising up to about 5 (such as about any of
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 164-
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 189, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID
  • an anti-RTMC abTCR comprising a) an extracellular domain comprising an anti-
  • RTMC antibody moiety that specifically binds to a complex comprising an HIV-1 RT peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 75-96; an HC-
  • CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 97-124; and an HC-
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 125-163; or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions in the HC-CDR sequences; and ii) a light chain variable domain sequence comprising an LC-

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Abstract

La présente invention concerne des constructions comprenant une fraction anticorps qui se lie spécifiquement à un complexe comprenant un peptide de transcriptase inverse (RT) du virus de l'immunodéficience humaine 1 (VIH-1) et une protéine du CMH de classe I. L'invention concerne également des procédés de production et d'utilisation de ces constructions.
PCT/US2017/053073 2016-09-23 2017-09-22 Constructions ciblant des complexes peptide du vih/cmh et leurs utilisations WO2018057967A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021073927A (ja) * 2019-11-11 2021-05-20 株式会社Ｇｓｐエンタープライズ 抗ヒトＣｒｉｐｔｏ−１抗体
CN114195898A (zh) * 2021-12-13 2022-03-18 南京凯地医疗技术有限公司 人源化抗cd33的单域抗体及其构建体制备方法和应用
US11965021B2 (en) 2017-04-26 2024-04-23 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US11976105B2 (en) 2015-10-23 2024-05-07 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6992176B2 (en) * 2002-02-13 2006-01-31 Technion Research & Development Foundation Ltd. Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease
WO2006124408A2 (fr) * 2005-05-12 2006-11-23 Merck & Co., Inc. Systeme et methode permettant de selectionner automatiquement des epitopes des lymphocytes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11976105B2 (en) 2015-10-23 2024-05-07 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US11965021B2 (en) 2017-04-26 2024-04-23 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
JP2021073927A (ja) * 2019-11-11 2021-05-20 株式会社Ｇｓｐエンタープライズ 抗ヒトＣｒｉｐｔｏ−１抗体
WO2021095703A1 (fr) * 2019-11-11 2021-05-20 株式会社Ｇｓｐエンタープライズ Anticorps anti-cripto-1 humain
CN114729372A (zh) * 2019-11-11 2022-07-08 Gsp企业株式会社 抗人Cripto-1抗体
CN114195898A (zh) * 2021-12-13 2022-03-18 南京凯地医疗技术有限公司 人源化抗cd33的单域抗体及其构建体制备方法和应用

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