WO2016182957A1 - Constructions ciblant les complexes mhc/peptide hpv16-e7 et leurs utilisations - Google Patents

Constructions ciblant les complexes mhc/peptide hpv16-e7 et leurs utilisations Download PDF

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WO2016182957A1
WO2016182957A1 PCT/US2016/031364 US2016031364W WO2016182957A1 WO 2016182957 A1 WO2016182957 A1 WO 2016182957A1 US 2016031364 W US2016031364 W US 2016031364W WO 2016182957 A1 WO2016182957 A1 WO 2016182957A1
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amino acid
seq
acid sequence
e7mc
variant
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PCT/US2016/031364
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English (en)
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Cheng Liu
Hong Liu
Pei Wang
Vivien Wai-Fan CHAN
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Eureka Therapeutics, Inc.
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Priority to MX2017014056A priority Critical patent/MX2017014056A/es
Priority to EP16793285.4A priority patent/EP3294328A1/fr
Priority to KR1020177035048A priority patent/KR20170141256A/ko
Priority to RU2017142716A priority patent/RU2017142716A/ru
Priority to CA2988397A priority patent/CA2988397A1/fr
Priority to AU2016261356A priority patent/AU2016261356A1/en
Priority to JP2017557069A priority patent/JP2018516879A/ja
Priority to SG11201708674XA priority patent/SG11201708674XA/en
Priority to CN201680039553.5A priority patent/CN107847570A/zh
Publication of WO2016182957A1 publication Critical patent/WO2016182957A1/fr
Priority to IL255228A priority patent/IL255228A0/en

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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
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/084—Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
    • A61K39/464—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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/59—Reproductive system, e.g. uterus, ovaries, cervix or testes
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/60—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 antibody constructs that specifically bind MHC molecules complexed with HPV16-E7 peptides, and uses thereof including treating and diagnosing diseases.
  • HPVs Human papillomaviruses
  • Persistent infections with high- risk HPV types can lead to more serious cytological abnormalities or lesions that, if untreated, may progress to cancer.
  • Annual incidence of HPV-associated cancers is >26,000 in the US (according to CDC) and >600,000 worldwide (Forman D. et al., Vaccine, 30: Suppl 5:F12-23, 2012).
  • Different types of HPV are responsible for causing almost all cases of cervical cancer (Doorbar J., Clin.
  • HPV human immunodeficiency virus
  • HNSCC head and neck squamous cell carcinomas
  • HPV-16 was found in 86.7% of the HPV-positive oropharyngeal SCCs, 68.2% of oral SCCs and 69.2% of laryngeal SCCs.
  • RNA-Seq RNA sequencing
  • E6 and E7 are intracellular proteins that have not been targeted by traditional drug development efforts using low molecular weight compounds or antibody approaches against cell surface proteins.
  • Recent studies in HPV16-positive high-grade vulvar intraepithelial neoplasia have demonstrated T cell and clinical responses in 50% of patients treated with vaccination approaches that utilized E6/E7 peptides (Kenter G.G. et al., N. Engl. J. Med. 361: 1838-1847, 2009; Welters M.J. et al, N. Engl. J. Med. 361: 1838-1847, 2010; Daayana S. et al, Br. J. Cancer
  • E7ii_i9 YMLDLQPET
  • HPV- 16 transformed HLA-A*02:01 expressing cell lines in vitro Riemer A.B. et al., J. Biol. Chem. 285(38):29608-29622, 2010.
  • This peptide is conserved in 16 out of 17 HPV-16 variants in the HPV database (Zhang G.L. et al, Database, 1-12, 2014).
  • constructs (such as isolated constructs) that bind to a complex comprising an HPV16-E7 peptide and an MHC class I protein
  • the constructs comprise an antibody moiety
  • an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • an anti-E7MC construct (such as an isolated anti-E7MC construct) comprising an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • the HPV16-E7/MHC class I complex is present on a cell surface. In some embodiments, the HPV16-E7/MHC class I complex is present on the surface of a cancer cell.
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the antibody moiety cross-reacts with a complex comprising the HPV16-E7 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 HPV16-E7 peptide comprising one amino acid substitution (such as a conservative amino acid substitution) and the MHC class I protein.
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the HPV16-E7 peptide is about 8 to about 12 (such as about any of 8, 9, 10, 11, or 12) amino acids in length.
  • the HPV16-E7 peptide has an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-14.
  • the HPV16-E7 peptide has the amino acid sequence YMLDLQPET (SEQ ID NO: 4).
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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, semi- synthetic with human antibody framework regions, or humanized.
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the antibody moiety binds to the HPV16-E7/MHC class I complex with an equilibrium dissociation constant (3 ⁇ 4) 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-E7MC construct binds to the HPV16-E7/MHC class I complex 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-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 G-F/G/Y-S/T-F-S/T-S-Y-A/G (SEQ ID NO: 183), 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 I-N/I-P-X-X-G-G/T/I-T/A/P or I-S-X-S/D- G/N-G/S-N-T/I/K (SEQ ID NO: 184 or 185), or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77, 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: 78-98, 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: 99-119, 244, and 245, or a variant thereof comprising up to
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77, an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 78-98, and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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 consist
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-35 and 233-237 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: 15-35 and 233-237; 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: 36-56 and 238-243 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: 36-56 and 238-243.
  • 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: 15- 35 and 233-237 and a light chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243.
  • the anti-E7MC construct comprises a first antibody moiety that competes for binding to a target HPV16-E7/MHC class I complex with a second antibody moiety according to any of the antibody moieties described above. In some embodiments, 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 HPV16-E7/MHC class I complex inhibits binding of the second antibody moiety to the target HPV16-E7/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 HPV16-E7/MHC class I complex, i.e., each of the first and second antibody moieties competes with the other for binding to the target HPV16-E7/MHC class I complex.
  • the isolated anti-E7MC construct is a full-length antibody.
  • the isolated anti-E7MC construct is monospecific.
  • the isolated anti-E7MC construct is multi- specific.
  • the isolated anti-E7MC construct is bispecific.
  • the isolated anti-E7MC 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 heteromultimeric antibody, or a heteroconjugate antibody.
  • the isolated anti-E7MC 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 GGGGS.
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the isolated anti-E7MC 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,
  • the second antigen is CD3s
  • the isolated anti-E7MC construct is a tandem scFv comprising an N-terminal scFv specific for the HPV16-E7/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-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the isolated anti-E7MC 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 intracellular signaling sequence.
  • the anti-E7MC construct comprises an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the isolated anti-E7MC 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 pharmaceutical composition comprising an anti-E7MC construct (such as an isolated anti-E7MC construct) according to any of the embodiments described above.
  • the pharmaceutical composition further comprises a cell (such as an effector cell) associated with the anti-E7MC construct.
  • a host cell expressing or associated with an anti-E7MC construct, or polypeptide component thereof.
  • a nucleic acid encoding an anti-E7MC construct, or polypeptide component thereof.
  • a vector comprising the nucleic acid.
  • an effector cell expressing or associated with an anti-E7MC construct.
  • the effector cell is a T cell.
  • a method of detecting a cell presenting a complex comprising an HPV16-E7 peptide and an MHC class I protein on its surface comprising contacting the cell with an anti-E7MC construct (such as an isolated anti-E7MC construct) according to any of the embodiments described above comprising a) an antibody moiety that specifically binds to a complex comprising the HPV16-E7 peptide and the MHC class I protein and b) a label, and detecting the presence of the label on the cell.
  • an anti-E7MC construct such as an isolated anti-E7MC construct
  • a method of treating an individual having an HPV16-E7-positive disease comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-E7MC construct (such as an isolated anti-E7MC 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-E7MC construct.
  • a method of treating an individual having an HPV16-E7-positive disease comprising administering to the individual an effective amount of an effector cell expressing any of the anti-E7MC CARs described above.
  • the effector cell is a T cell.
  • the HPV16-E7-positive disease is cancer.
  • the cancer is squamous cell carcinoma, cervical cancer, anal cancer, vaginal cancer, vulvar cancer, penile cancer, head and neck cancer, or oropharyngeal cancer.
  • the cancer is an HPV16-E7-positive squamous cell carcinoma (SCC).
  • a method of diagnosing an individual having an HPV16-E7-positive disease comprising: a) administering an effective amount of an isolated anti-E7MC 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
  • a method of diagnosing an individual having an HPV16-E7-positive disease comprising: a) contacting a sample derived from the individual with an isolated anti-E7MC construct comprising a label according to any of the embodiments described above; and b) determining the number of cells bound with the isolated anti-E7MC construct in the sample, wherein a value for the number of cells bound with the isolated anti-E7MC construct above a threshold level indicates that the individual has the HPV16-E7-positive disease.
  • HPV16-E7-positive disease is cancer.
  • the cancer is squamous cell carcinoma, cervical cancer, anal cancer, vaginal cancer, vulvar cancer, penile cancer, head and neck cancer, or oropharyngeal cancer.
  • the cancer is an HPV16- E7-positive squamous cell carcinoma (SCC).
  • FIG. 1 shows the size exclusion chromatography (SEC) chromatogram of HPV16-E7 11-19 peptide/HLA-A*02:01 complex following concentration by ultrafiltration.
  • SEC size exclusion chromatography
  • FIG. 2 shows the results of phage clone ELIS A for specific binding of biotinylated HPV16-E7 11-19 peptide/HLA-A*02:01 versus biotinylated C3 control peptide/HLA- A*02:01.
  • FIG. 3 shows the results of phage clone FACS binding assays for binding of HPV16- E7 11-19 peptide-loaded T2 cells versus C3 control peptide-loaded T2 cells.
  • 1 Cell only negative control
  • 2 2° antibody only control
  • 3 HPV16-E7 11-19 peptide/HLA-A*02:01- specific antibody phage clone.
  • FIG. 4 shows the results of phage clone #11 FACS binding assays for T2 cells loaded with HPV16-E7 11-19 peptides having a single alanine substitution at position 1, 5, or 8.
  • 1 Cell only negative control
  • 2 2° antibody only control
  • 3 HPV16-E7 11-19 peptide/HLA- A*02:01 -specific antibody phage clone #11.
  • FIG. 5 shows the results of phage clone FACS binding assays for binding of HPV16- E7 11-19 peptide-loaded T2 cells versus T2 cells loaded with peptides derived from normally expressed endogenous proteins.
  • the peptides loaded from left to right are HPV16-E7 11-19, A2E1, A2E2, A2E3, A2E4, A2E5, A2E6, A2E7, A2E8, A2E9, A2E11, and A2E17.
  • FIG. 6 shows SDS-PAGE analysis for determining purity of anti-HPV16-E7 11- 19/MHC bispecific antibodies.
  • FIG. 7 shows the T-cell killing of HPV16-E7 11-19 peptide-loaded T2 cells mediated by anti-HPV16-E7 11-19/HLA-A*02:01 bispecific antibodies prepared from various phage clones at 1 ⁇ g/ml and 0.2 ⁇ g/ml.
  • Negative controls include T2 cells loaded with AFP158 peptide and bispecific antibody specific for AFP158/HLA-A*02:01.
  • the peptides loaded from left to right are 1 ⁇ g/ml HPV16-E7 11-19, 1 ⁇ g/ml AFP158, 0.2 ⁇ g/ml HPV16-E7 11-19, and 0.2 ⁇ g/ml AFP158.
  • NC peptide AFP158 peptide; NC
  • Antibody anti-AFP158/HLA-A*02:01 bispecific antibody.
  • FIG. 8A shows the T-cell killing of two cancer cell lines (CaSki and MS-751) mediated by anti-HPV16-E7 11-19/MHC bispecific antibodies (BsAb).
  • FIG. 8B shows the dose-dependence for T-cell killing of two cancer cell lines (CaSki and MS-751) mediated by anti-HPV16-E7 11-19/MHC bispecific antibodies (BsAb) at varying BsAb concentrations.
  • FIG. 9 shows a schematic representation of a chimeric antigen receptor construct.
  • FIGS. 10A and 10B show the results of BsAb FACS binding assays for T2 cells loaded with HPV16-E7 11-19 peptides having a WT sequence or a single alanine substitution at positions 1-9.
  • FIG. 10A shows results for BsAbs based on clones US-7, 7-1, 7-3, and 7-6.
  • FIG. 10B shows results for BsAbs based on clones 7-7 and 7-8.
  • FIGS. 1 lA-11C show flow cytometry analysis of T cells transduced with various CARs having an anti-HPV16-E7 affinity matured or parental scFv; cells were stained with HPV16-E7 11-19 peptide /HLA-A*02:01 tetramers and co-stained with anti-CD4 antibody and anti-CD8 antibody.
  • FIG. 11A shows flow cytometry analysis for US-7 4- IBB, 7-1 4- 1BB, 7-3 4-1BB, 7-6 4-1BB, 7-7 4-1BB, and 7-8 4-1BB CAR-T cells.
  • FIG. 11B shows flow cytometry analysis for 7-9 4-1BB, US-7 CD28, 7-1 CD28, 7-3 CD28, 7-6 CD28, and 7-7 CD28 CAR-T cells.
  • FIG. 11C show flow cytometry analysis for 7-8 CD28 and 7-9 CD28 CAR-T cells, and mock- transduced T cells.
  • FIG. 12 shows the killing of cancer cell lines positive for HLA-A*02:01 and either positive or negative for HPV16-E7, mediated by T cells expressing an anti-HPV16-E7/HLA- A*02:01 CAR having an affinity matured or parental scFv. Mock-transduced cells were included as controls.
  • anti-E7MC constructs that comprise an antibody moiety (referred to herein as an "anti-E7MC antibody moiety") that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein (referred to herein as an "HPV16-E7/MHC class I complex," or "E7MC").
  • the anti-E7MC constructs specifically recognize HPV16-E7/MHC class I complexes, such as MHC-presented HPV16-E7 peptides on the surface of cells expressing HPV16-E7.
  • Anti- E7MC constructs may specifically bind to the N-terminal portion, the C-terminal portion, or the middle portion of the HPV16-E7 peptide in the complex, and/or cross-react with at least one complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein (e.g. , the anti-E7MC construct binds to both an HPV16-E7 peptide/HLA-A*02:01 complex and an HPV16-E7 peptide/HLA-A*02:02 complex).
  • the anti-E7MC constructs allow for specific targeting of E7MC-presenting cells (i.e.
  • cells presenting on their surface an HPV16-E7 peptide bound to an MHC molecule such as disease cells expressing HPV16-E7.
  • This strategy provides a significant technical advantage over using antibodies directed against the HPV16-E7 protein, which cannot specifically target E7MC-presenting cells.
  • the anti-E7MC antibody moiety allows for diagnosis and prognosis of HPV16-E7-positive diseases or disorders with high sensitivity to changes in the number and distribution of E7MC-presenting cells, a potentially more relevant measure of disease progression than circulating HPV16-E7 levels.
  • the present application thus provides constructs (such as isolated constructs) comprising an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • the construct can be, for example, a full-length anti- E7MC antibody, a multi- specific anti-E7MC molecule (such as a bispecific anti-E7MC antibody), an anti-E7MC chimeric antigen receptor ("CAR”), or an anti-E7MC
  • nucleic acids encoding the anti-E7MC constructs or the anti-E7MC antibody moiety portion of the constructs.
  • compositions comprising an anti-E7MC construct comprising an antibody moiety that specifically binds to a complex comprising an HPV16-E7-peptide and an MHC class I protein.
  • the composition can be a pharmaceutical composition comprising an anti-E7MC construct or an effector cell expressing or associated with the anti-E7MC construct (for example a T cell expressing an anti-E7MC CAR).
  • 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. , preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g.
  • metastasis of the disease, preventing or delaying the recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving the quality of life, increasing weight gain, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of cancer (such as, for example, tumor volume).
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • recurrence refers to the return of a cancer or disease after clinical assessment of the disappearance of disease. A diagnosis of distant metastasis or local recurrence can be considered a relapse.
  • the term "refractory” or “resistant” refers to a cancer or disease that has not responded to treatment.
  • Activation refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions.
  • 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.
  • lgGl ⁇ heavy chain
  • lgG2 ⁇ 2 heavy chain
  • lgG3 ⁇ 3 heavy chain
  • lgG4 ⁇ 4 heavy chain
  • IgAl al heavy chain
  • 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 first antibody moiety "competes" for binding to a target E7MC with a second antibody moiety when the first antibody moiety inhibits target E7MC 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
  • 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 HPV16-E7 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 HPV16-E7 peptide/MHC class I protein complex
  • An "isolated" anti-E7MC construct as used herein refers to an anti-E7MC 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 nucleic acid of genomic, cDNA, or 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
  • V H CDR3 95- 102 96- 101 93- 101
  • 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 al., Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)).
  • si- 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-naturally 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 VJJ and VL antibody domains connected into a single polypeptide chain.
  • the scFv polypeptide further comprises a polypeptide linker between the Vf j and VL 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 VJJ and VL 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 VJJ and VL 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.
  • 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.
  • % amino acid sequence identity values are generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5): 1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1): 113, 2004).
  • 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 tyrosine-based activation motif (IT AM) in its cytoplasmic domain.
  • Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)).
  • FcyRIIIA allotypes FcYRIIIA-Phel58, FcYRIIIA-Vall58, FcyRIIA-R131 and/or FCYRIIA-H131.
  • FCRS are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et ah, Immunomethods 4:25-34 (1994); and de Haas et ah, J. Lab. Clin. Med. 126:330-41 (1995).
  • Other FcRs including those to be identified in the future, are
  • FcR neonatal receptor
  • FcRn the neonatal receptor
  • 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.
  • the "CHI 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 IgG).
  • a "functional Fc fragment” possesses an "effector function” of a native sequence Fc region.
  • effector functions include Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors ⁇ e.g. B cell receptor; BCR), etc.
  • Such 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 ADCC activity compared to a parent polypeptide or to a polypeptide comprising a native sequence Fc region.
  • 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, 150, 200, or up to 500 fold, or about 25% to 1000% improvement in binding.
  • the polypeptide variant which "exhibits decreased binding" to an FcR binds at least one FcR with lower affinity (e.g., higher apparent K d or higher IC 50 value) than a parent polypeptide.
  • 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
  • cytotoxic cells e.g. Natural Killer (NK) cells, neutrophils, and macrophages
  • NK cells Natural Killer cells
  • neutrophils neutrophils
  • macrophages cytotoxic cells
  • the antibodies “arm” the cytotoxic cells and are absolutely required for such killing.
  • the primary cells for mediating ADCC, NK cells express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII.
  • FcR expression on cytotoxic cells e.g. Natural Killer (NK) cells, neutrophils, and macrophages
  • ADCC activity of a molecule of interest is assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • 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.
  • 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 ah, 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 W099/51642. The contents of those patent publications are specifically incorporated herein by reference. See, also, Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • 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 intron(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-E7MC 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-E7MC construct or composition as disclosed herein, effective to "treat” a disease or disorder in an individual.
  • the therapeutically effective amount of the anti-E7MC construct or composition as disclosed herein can reduce the number of cancer cells; reduce the tumor size or weight; inhibit (i.e. , slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e. , slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the anti-E7MC construct or composition as disclosed herein can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic.
  • the therapeutically effective amount is a growth inhibitory amount.
  • the therapeutically effective amount is an amount that extends the survival of a patient.
  • the therapeutically effective amount is an amount that improves progression free 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-E7MC 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 cancer of type X means the method is used to treat cancer of types other than X.
  • the present invention provides HPV16-E7/MHC class I complex- specific constructs (anti-E7MC constructs) that comprise an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein ("HPV16- E7/MHC class I complex," or "E7MC").
  • anti-E7MC constructs that comprise an antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein
  • E7MC MHC class I protein
  • reference to a moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein means that the moiety binds to the E7MC 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 HPV16-E7, free HPV16-E7 peptide, MHC class I protein not bound to a peptide, and MHC class I protein bound to a non-HPV16-E7 peptide; or b) a K d 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
  • Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation assay (RIA).
  • K d 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-E7MC constructs include, for example, full-length anti-E7MC antibodies, multi- specific (such as bispecific) anti-E7MC molecules, anti-E7MC chimeric antigen receptors (CARs), and anti-E7MC immunoconjugates.
  • an anti-E7MC construct (such as an isolated anti-E7MC construct) comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02.
  • the MHC class I protein is HLA-A*02:01 (GenBank Accession No.: AAO20853).
  • the anti-E7MC construct is non-naturally occurring.
  • the anti-E7MC construct is a full-length antibody. In some embodiments, the anti-E7MC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti- E7MC construct is a chimeric antigen receptor. In some embodiments, the anti-E7MC construct is an immunoconjugate.
  • the anti-E7MC construct binds the E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising an anti- E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01.
  • the anti-E7MC construct is non-naturally occurring.
  • the anti-E7MC construct is a full-length antibody.
  • the anti-E7MC construct is a multi- specific (such as bispecific) molecule.
  • the anti-E7MC construct is a chimeric antigen receptor.
  • the anti-E7MC construct is an immunoconjugate.
  • the anti-E7MC construct binds the E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising an anti-
  • E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti-E7MC antibody moiety comprises: i) a heavy chain variable domain sequence comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188; 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 SEQ ID NO: 183, or
  • ID NO: 191 or a variant thereof comprising up to about 3 (for example about any of 1, 2, or
  • the anti-E7MC construct is non-naturally occurring. In some embodiments, the anti-E7MC construct is a full-length antibody. In some embodiments, the anti-E7MC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-E7MC construct is a chimeric antigen receptor. In some embodiments, the anti-E7MC construct is an immunoconjugate. In some embodiments, the anti-E7MC construct binds the E7MC with a K d between about 0.1 pM to about 500 nM
  • the anti-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-E7MC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising an anti- E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti-E7MC 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: 57-77; 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: 78-98; or a variant thereof comprising up to about 5 (for example 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: 99-119
  • the anti-E7MC construct is non-naturally occurring. In some embodiments, the anti-E7MC construct is a full-length antibody. In some embodiments, the anti-E7MC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-E7MC construct is a chimeric antigen receptor. In some embodiments, the anti-E7MC construct is an
  • the anti-E7MC construct binds the E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC construct cross- reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16- E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising an anti- E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti-E7MC 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: 57-77; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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 up to about 5 (for example about any of
  • the anti-E7MC construct is non-naturally occurring. In some embodiments, the anti-E7MC construct is a full-length antibody. In some embodiments, the anti-E7MC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-E7MC construct is a chimeric antigen receptor. In some embodiments, the anti-E7MC construct is an immunoconjugate.
  • the anti-E7MC construct binds the E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising an anti- E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti-E7MC 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: 15-35 and 233-237, 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: 36-56 and 238-243, or a variant thereof having
  • the anti-E7MC construct is a multi- specific (such as bispecific) molecule. In some embodiments, the anti-E7MC construct is a chimeric antigen receptor. In some embodiments, the anti-E7MC construct is an immunoconjugate. In some embodiments, the anti-E7MC construct binds the E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-E7MC construct cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC construct comprising a first anti-E7MC antibody moiety that competes for binding to a target HPV16-E7/MHC class I complex with a second anti-E7MC antibody moiety according to any of the anti-E7MC antibody moieties described herein.
  • the first anti-E7MC antibody moiety binds to the same, or substantially the same, epitope as the second anti-E7MC antibody moiety.
  • binding of the first anti-E7MC antibody moiety to the target HPV16-E7/MHC class I complex inhibits binding of the second anti-E7MC antibody moiety to the target HPV16-E7/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-E7MC antibody moiety and the second anti-E7MC antibody moiety cross-compete for binding to the target HPV16-E7/MHC class I complex, i.e., each of the first and second antibody moieties competes with the other for binding to the target HPV16-E7/MHC class I complex.
  • an anti-E7MC construct comprising an anti-E7MC antibody moiety that competes for binding to a target HPV16- E7/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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188; 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
  • an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions.
  • an anti-E7MC construct comprising an anti-E7MC antibody moiety that competes for binding to a target HPV16-E7/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: 57-77; or a variant thereof comprising up to about
  • an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of
  • HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 99-119,
  • 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: 120-140 and 246; or a variant thereof comprising up to about 5
  • an LC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 141-161; 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: 162-182 and 247-250; 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-E7MC construct comprising an anti-E7MC antibody moiety that competes for binding to a target HPV16-E7/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: 57-77; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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
  • an anti-E7MC construct comprising an anti-E7MC antibody moiety that competes for binding to a target HPV16-E7/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: 15- 35 and 233-237, 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: 36-56 and 238-243, 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-E7MC constructs comprise an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • the anti-E7MC antibody moiety specifically binds to an E7MC present on the surface of a cell.
  • the cell is a cancer cell.
  • the cancer cell is in a solid tumor.
  • the cancer cell is a metastatic cancer cell.
  • the HPV16-E7 peptide is an MHC class I-restricted peptide. In some embodiments, the HPV16-E7 peptide is from about 8 to about 12 (such as about any of 8, 9, 10, 11, or 12) amino acids in length.
  • the HPV16-E7 peptide comprises (and in some embodiments consists of) the sequence of amino acids 7-15 of HPV16-E7 (TLHEYMLDL, SEQ ID NO: 3), amino acids 11-19 of HPV16-E7 (YMLDLQPET, SEQ ID NO: 4, also referred to herein as "HPV16-E7 11-19"), amino acids 16-25 of HPV16-E7 (QPETTDLYCY, SEQ ID NO: 5), amino acids 44-52 of HPV16-E7 (QAEPDRAHY, SEQ ID NO: 6), amino acids 46-55 of HPV16-E7 (EPDRAHYNIV, SEQ ID NO: 7), amino acids 49-57 of HPV16-E7
  • RAHYNIVTF amino acids 82-90 of HPV16-E7 (LLMGTLGIV, SEQ ID NO: 9), or amino acids 86-93 of HPV16-E7 (TLGIVCPI, SEQ ID NO: 10).
  • 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-E7MC antibody moiety is a full-length antibody.
  • the anti-E7MC 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-E7MC antibody moiety is an scFv.
  • the anti-E7MC antibody moiety is human, humanized, or semisynthetic.
  • the anti-E7MC antibody moiety specifically binds to the N- terminal portion of the HPV16-E7 peptide in the complex. In some embodiments, the anti-
  • E7MC antibody moiety specifically binds to the C-terminal portion of the HPV16-E7 peptide in the complex. In some embodiments, the anti-E7MC antibody moiety specifically binds to the middle portion of the HPV16-E7 peptide in the complex.
  • the anti-E7MC antibody moiety (or the anti-E7MC construct comprising the anti-E7MC antibody moiety) binds to the complex comprising the HPV16-E7 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 HPV16-E7, free HPV16-E7 peptide, MHC class I protein not bound to a peptide, and MHC class I protein bound to a non-HPV16- E7 peptide.
  • 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 HPV16-E7, free HPV16-E7 peptide, MHC class I protein not bound to a peptide, and MHC class
  • the anti-E7MC antibody moiety (or the anti-E7MC construct comprising the anti-E7MC antibody moiety) binds to the complex comprising the HPV16-E7 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, 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 HPV16-E7, free HPV16-E7 peptide, MHC class I protein not bound to a peptide, and MHC class I protein bound to a non-HPV16-E7 peptide.
  • a K d 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/
  • the anti-E7MC antibody moiety (or the anti-E7MC construct comprising the anti-E7MC antibody moiety) binds to the complex comprising the HPV16-E7 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-E7MC antibody moiety binds to the complex comprising the HPV16-E7 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,
  • E7MC antibody moiety (or the anti-E7MC construct comprising the anti-E7MC antibody moiety) binds to the complex comprising the HPV16-E7 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,
  • the anti-E7MC antibody moiety (or the anti-E7MC construct comprising the anti-E7MC antibody moiety) binds to the complex comprising the HPV16-E7 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,
  • the anti-E7MC antibody moiety specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti-
  • E7MC antibody moiety cross-reacts with at least one complex comprising the HPV16-E7 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- E7MC antibody moiety does not cross-react with any complex comprising the HPV16-E7 peptide and an allelic variant of the MHC class I protein.
  • the anti- E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • the anti-E7MC antibody moiety specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the anti- E7MC antibody moiety cross-reacts with at least one complex comprising the MHC class I protein and a variant of the HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-E7MC antibody moiety does not cross-react with any complex comprising the MHC class I protein and a variant of the HPV16-E7 peptide.
  • the anti-E7MC antibody moiety specifically binds to a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti- E7MC antibody moiety further binds to at least one (including at least about any of 2 or 3) of: a complex comprising an alanine-substituted HPV16-E7 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 HPV16-E7 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 HPV16-E7 peptide of SEQ ID NO: 14 and an MHC class I protein (such as HLA- A02, for example HLA-A*02:01).
  • a complex comprising an alanine-substituted HPV16-E7 peptide of SEQ ID NO: 12 and an MHC class I protein such as HLA-A02,
  • the anti-E7MC antibody moiety specifically binds to: a complex comprising an HPV16-E7 peptide of SEQ ID NO: 4 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HPV16-E7 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-substituted HPV16- E7 peptide of SEQ ID NO: 13 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-E7MC antibody moiety specifically binds to: a complex comprising an HPV16-E7 peptide of SEQ ID NO: 4 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); a complex comprising an alanine- substituted HPV16-E7 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-substituted HPV16- E7 peptide of SEQ ID NO: 14 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-E7MC antibody moiety specifically binds to: a complex comprising an HPV16-E7 peptide of SEQ ID NO: 4 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HPV16-E7 peptide of SEQ ID NO: 12 and an MHC class I protein (such as HLA- A02, for example HLA-A*02:01).
  • the anti-E7MC antibody moiety specifically binds to: a complex comprising an HPV16-E7 peptide of SEQ ID NO: 4 and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an alanine- substituted HPV16-E7 peptide of SEQ ID NO: 14 and an MHC class I protein (such as HLA- A02, for example HLA-A*02:01).
  • the anti-E7MC antibody moiety specifically binds to a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and HLA-A*02:01.
  • the anti-E7MC antibody moiety cross-reacts with at least one (including at least about any of 2, 3, 4, 5, or 6) of: a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and HLA-A*02:02 (GenBank Accession No.: AFL91480), a complex comprising HPV16- E7 11-19 (SEQ ID NO: 4) and HLA-A*02:03 (GenBank Accession No.: AAA03604), a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and HLA-A*02:05 (GenBank Accession No.: AAA03603), a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and HLA-A*02:06 (GenBank Accession No.: 4)
  • the anti-E7MC antibody moiety specifically binds to: a complex comprising HPV16-E7 11-19 (SEQ ID NO: 4) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01); and a complex comprising an HPV16-E7 11-19 variant having the amino acid sequence of YMLDVQPET (SEQ ID NO: 11) and an MHC class I protein (such as HLA-A02, for example HLA-A*02:01).
  • the anti-E7MC antibody moiety is a semi-synthetic antibody moiety comprising fully human sequences and one or more synthetic regions. In some embodiments, the anti-E7MC 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-E7MC 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-E7MC antibody moiety to bind the E7MC.
  • alterations that do not substantially reduce E7MC binding affinity may be made.
  • Alterations that substantially improve E7MC binding affinity or affect some other property, such as specificity and/or cross -reactivity with related variants of the E7MC, are also contemplated.
  • the anti-E7MC 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: 186-188 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-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions.
  • the anti-E7MC 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: 186-188; and ii) a light chain variable domain comprising an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191.
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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-CDRl comprising the amino acid sequence of SEQ ID NO: 189 or 190, 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
  • an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions.
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 183, 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 SEQ ID NO: 183, 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 SEQ ID NO:
  • 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: 186-188; and ii) a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 189 or 190, 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 SEQ ID NO: 191.
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; 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-CDRl comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191; 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-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191.
  • the sequences of the CDRs noted herein are provided in Table 2 below.
  • the anti-E7MC 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: 99-119, 244, and 245, 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: 162-182 and 247-250, 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-E7MC 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: 99-119, 244, and 245; and ii) a light chain variable domain comprising an LC- CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 162-182 and 247- 250.
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 57-77, 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: 78-98, 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: 99-119, 244, and 245, 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: 120-140 and 246, or a variant thereof comprising
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain comprising an HC-CDRl comprising the amino acid sequence of any one of SEQ ID NOs: 57-77, 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: 78-98, 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: 99-119, 244, and 245; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246, 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-CDR
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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-CDR1 or HC-CDR2; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising
  • the anti-E7MC antibody moiety comprises i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 162-182 and 247-250.
  • the sequences of the HC-CDRs noted herein are provided in Table 3 below and the LC-CDRs noted
  • SEQ ID NO: 64 SEQ ID NO: 85 SEQ ID NO: 106
  • LC-CDR1 40 SSNIGSNH LC-CDR2 40 NNN LC-CDR3 40 AAWDDSLNVPV
  • LC-CDR1 41 TLRSFY LC-CDR2 41 GKN LC-CDR3 41 NSRDSGGDPVV
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, 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: 36-56 and 238-243, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243.
  • the heavy and light chain variable domains can be combined in various pair- wise combinations to generate a number of anti-E7MC antibody moieties.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 57, or a variant thereof comprising up to about 5 (for example about any of 1,
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, or a variant thereof comprising up to about 5 (for example about any of 1, 2,
  • an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, 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 the amino acid sequence of SEQ ID NO: 141, 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 SEQ ID NO: 162, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 57, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 99, 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 a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 141, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 57, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 78, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 99; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 141, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 162.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 58 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 79 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 100 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, 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 the amino acid sequence of SEQ ID NO: 142, 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 SEQ ID NO: 163, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 58, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 100, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 121, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 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 LC-CDR sequences.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 58, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 79, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 121, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 163.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 59 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 80 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 101 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 122, 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 the amino acid sequence of SEQ ID NO: 143, 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 SEQ ID NO: 164, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 80, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 101, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 122, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 164, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 59, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 80, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 101; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 122, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 164.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 60 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 81 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 102 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 123, 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 the amino acid sequence of SEQ ID NO: 144, 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 SEQ ID NO: 165, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 60, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 102, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 123, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 60, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 81, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 102; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 123, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 165.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 61 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 82 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 103 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 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 LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, 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 SEQ ID NO: 166, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 61, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 103, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 124, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 61, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 103; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 124, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 62 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 83 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 104 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 125, 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 the amino acid sequence of SEQ ID NO: 146, 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 SEQ ID NO: 167, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 62, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 104, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 125, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 167, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 62, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 83, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 125, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 167.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 63 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 84 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 105 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 126, 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 the amino acid sequence of SEQ ID NO: 147, 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 SEQ ID NO: 168, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 84, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 105, 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 a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 126, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 147, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 168, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 63, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 84, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 105; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 126, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 147, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 168.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 64 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 85 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 106 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, 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 the amino acid sequence of SEQ ID NO: 148, 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 SEQ ID NO: 169, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 106, 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 comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 148, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 169, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 106; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 148, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 169.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 65 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 86 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 107 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, 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 the amino acid sequence of SEQ ID NO: 149, 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 SEQ ID NO: 170, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 107, 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 comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 149, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 65, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 86, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 107; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 128, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 149, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 170.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 66 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 87 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 108 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 129, 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 the amino acid sequence of SEQ ID NO: 150, 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 SEQ ID NO: 171, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 87, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 108, 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 comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 129, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, and an LC-CDR3 comprising the amino acid sequence of SEQ
  • ID NO: 171 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 66, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 87, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 108; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 129, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 171.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 67, 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 the amino acid sequence of SEQ ID NO: 88, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 130, 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 the amino acid sequence of S
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 88, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 109, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 130, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 172, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 67, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 88, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 109; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 130, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 172.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 68, 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 the amino acid sequence of SEQ ID NO: 89, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 110, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 131, 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 the amino acid sequence of S
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 68, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 110, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 131, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 173, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 89, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 131, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 173.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 69, 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 the amino acid sequence of SEQ ID NO: 90, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 111, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 132, 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 the amino acid sequence of S
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 69, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 111, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 132, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 69, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 111; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 132, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 174.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 70, 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 the amino acid sequence of SEQ ID NO: 91, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 133, 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 the amino acid sequence of SEQ
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 70, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 91, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 112, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 133, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 91, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 133, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 71, 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 the amino acid sequence of SEQ ID NO: 92, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 134, 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 the amino acid sequence of
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 71, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 113, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 155, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 71, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 134, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 155, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 176.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 72, 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 the amino acid sequence of SEQ ID NO: 93, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 114, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 135, 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 the amino acid sequence of SEQ
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 72, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 114, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 135, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 156, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 177, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 72, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 114; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 135, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 156, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 177.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 73 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 136, 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 the amino acid sequence of SEQ ID NO: 157, 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 SEQ ID NO: 178, or a variant thereof comprising up to about 5 (such
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 73, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 115, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 136, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 157, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 73, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 94, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 115; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 136, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 157, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 74 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 95 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 116, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 137, 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 the amino acid sequence of SEQ ID NO: 158, 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 SEQ ID NO: 179, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 74, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 95, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 116, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 137, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 158, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 74, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 95, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 116; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 137, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 158, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 75 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 96 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 117 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 138, 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 the amino acid sequence of SEQ ID NO: 159, 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 SEQ ID NO: 180, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 75, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 96, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 117, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 138, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 159, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 180, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 75, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 96, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 117; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 138, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 159, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 180.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 76 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 97 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 118 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 139, 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 the amino acid sequence of SEQ ID NO: 160, 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 SEQ ID NO: 181, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 76, 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: 118, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 139, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 160, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 181, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 76, 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: 118; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 139, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 160, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 181.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 119 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 244 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 244, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 244; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 245, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 245; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 119 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 247, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 247.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 119 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 248, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 248, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 248.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 119 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 246, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 246, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 246, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • NO: 77 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • NO: 98 or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or
  • ID NO: 119 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • amino acid substitutions and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of SEQ ID NO: 161, 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 SEQ ID NO: 249, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-
  • CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ
  • ID NO: 249 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 249.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, 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 the amino acid sequence of SEQ ID NO: 98, or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3, 4, or 5) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 119, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions; and a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, 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 the amino acid sequence of S
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119, 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 a light chain variable domain comprising an LC-CDRl comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250, 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-E7MC antibody moiety comprises a heavy chain variable domain comprising an HC-CDR 1 comprising the amino acid sequence of SEQ ID NO: 77, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 250.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 15, 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 set forth in SEQ ID NO: 36, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 15 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 36.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 16, 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 set forth in SEQ ID NO: 37, or a variant thereof having at least about 95%
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 16 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 37.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 17, 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 set forth in SEQ ID NO: 38, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 38.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 18, 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 set forth in SEQ ID NO: 39, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 18 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 39.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 19, 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 set forth in SEQ ID NO: 40, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 19 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 40.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 20, 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 set forth in SEQ ID NO: 41, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 20 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 41.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 21, 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 set forth in SEQ ID NO: 42, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 42.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 22, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 22 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 43.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 23, 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 set forth in SEQ ID NO: 44, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 23 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 44.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 24, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 24 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 45.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25, 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 set forth in SEQ ID NO: 46, or a variant thereof having at least about 95%
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 46.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 26 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 47.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 27 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 48.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 49.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 29 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 50.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 30 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 51.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 31, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 31 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 52.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 32 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 53.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 33 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 54.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 34, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 34 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 55.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 56.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 233, 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 set forth in SEQ ID NO: 56, or a variant thereof having at least about
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 233 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 56.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 234, or a variant thereof having at least about 95% (including for example at least about any of 96%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 234 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 56.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 235, or a variant thereof having at least about 95% (including for example at least about any of 96%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 235 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 56.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 238. [0249] In some embodiments, the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 239.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 240.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 241.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%,
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 242.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 236, 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 set forth in SEQ ID NO: 243, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 236 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 243.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 237, 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 set forth in SEQ ID NO: 56, or a variant thereof having at least about 95% (including for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • the anti-E7MC antibody moiety comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 237 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 56.
  • the anti-E7MC antibody moiety competes for binding to a target HPV16-E7/MHC class I complex with a second anti-E7MC antibody moiety according to any of the anti-E7MC antibody moieties described herein. In some embodiments, the anti- E7MC antibody moiety binds to the same, or substantially the same, epitope as the second anti-E7MC antibody moiety.
  • binding of the anti-E7MC antibody moiety to the target HPV16-E7/MHC class I complex inhibits binding of the second anti- E7MC antibody moiety to the target HPV16-E7/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-E7MC antibody moiety and the second anti-E7MC antibody moiety cross-compete for binding to the target HPV16-E7/MHC class I complex, i.e., each of the antibody moieties competes with the other for binding to the target HPV16-E7/MHC class I complex.
  • the anti-E7MC antibody moiety competes for binding to a target HPV16-E7/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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188; 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-CDRl comprising the amino acid sequence of SEQ ID NO: 189 or 190,
  • the anti-E7MC antibody moiety competes for binding to a target HPV16-E7/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: 57-77; 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: 78-98; or a variant thereof comprising up to about 5 (for example 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: 99-119, 244, and 245; or a variant thereof comprising up to about 5 (for example about any of 1, 2, 3,
  • the anti-E7MC antibody moiety competes for binding to a target HPV16-E7/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: 57-77; an HC-CDR2 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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-E7MC antibody moiety competes for binding to a target HPV16-E7/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: 15-35 and 233-237, 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: 36-56 and 238-243, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 98%, or 99%) sequence identity.
  • a heavy chain variable domain comprising (and in some embodiments consisting of) the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%
  • the anti-E7MC constructs in some embodiments are full-length antibodies comprising an anti-E7MC antibody moiety (also referred to herein as a "full-length anti- E7MC antibody").
  • the full-length antibody is a monoclonal antibody.
  • the full-length anti-E7MC antibody comprises an Fc sequence from an immunoglobulin, such as IgA, IgD, IgE, IgG, and IgM.
  • the full-length anti-E7MC antibody comprises an Fc sequence of IgG, such as any of IgGl, IgG2, IgG3, or IgG4.
  • the full-length anti-E7MC antibody comprises an Fc sequence of a human immunoglobulin. In some embodiments, the full-length anti-E7MC antibody comprises an Fc sequence of a mouse immunoglobulin. In some embodiments, the full-length anti-E7MC 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) an Fc region.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01, 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 anti-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • at least one such as at least any of 2, 3, 4, 5, or 6
  • a variant of the HPV16-E7 peptide having one amino acid substitution such as a conservative amino acid substitution.
  • the anti-E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • a full-length anti-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 183, 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 SEQ ID NO: 183, 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 SEQ ID NO:
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, and b) an Fc region.
  • the Fc region comprises an
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 NO: 1
  • NOs: 57-77 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • an HC-CDR2 comprising the amino acid sequence of any one of
  • SEQ ID NOs: 78-98 or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245, or a variant thereof comprising up to about 5
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of
  • the Fc region comprises an
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of
  • 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-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-35 and 233-237, 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: 36-56 and 238-243, 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.
  • a full-length anti-E7MC antibody comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243; 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-E7MC antibody binds to a complex comprising an HPV16-E7 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 full-length anti-E7MC antibody binds to a complex comprising an HPV16-E7 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).
  • Multi-Specific anti-E7MC molecules binds to a complex comprising an HPV16-E7 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-E7MC constructs in some embodiments comprise a multi- specific anti- E7MC molecule comprising an anti-E7MC antibody moiety and a second binding moiety (such as a second antigen-binding moiety).
  • the multi- specific anti- E7MC molecule comprises an anti-E7MC 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. Immunol. 147: 60 (1991). It is to be appreciated that one of skill in the art could select appropriate features of individual multi- specific molecules described herein to combine with one another to form a multi-specific anti-E7MC molecule of the invention.
  • a multi-specific (e.g. , bispecific) anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 HPV16-E7 peptide bound to the MHC class I protein.
  • the second scFv specifically binds to a complex comprising the HPV16-E7 peptide bound to a different MHC class I protein.
  • the second binding moiety specifically binds to a different epitope on the complex comprising the HPV16-E7 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-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 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.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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, CD35, CD3s, CD3C, CD28, CD16a, CD56, CD68, and GDS2D.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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.
  • “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 FcR such as the activating FcyRI.
  • a functional fragment is capable of competitively inhibiting the binding of the original, full- length Fc portion to an FcR such as the activating FcyRI.
  • Fc fragment retains at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of its affinity to an activating FcyR.
  • 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), and 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.
  • 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-E7MC molecule allows killing of E7MC-presenting target cells and/or can effectively redirect CTLs to lyse E7MC-presenting target cells.
  • the multi- specific (e.g. , bispecific) anti-E7MC 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-E7MC 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-E7MC molecule to exert its desired activity.
  • the multi- specific anti-E7MC 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-E7MC 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-E7MC molecule to simultaneously bind to two antigens are within the normal capabilities of a person skilled in the art.
  • the multi- specific anti-E7MC molecule may be contacted with a mixture of CD3 + /HPV16-E7 " cells and CD37HPV16-E7 + cells.
  • the number of multi- specific anti-E7MC molecule-positive single cells and the number of cells cross-linked by multi- specific anti-E7MC 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-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) a second antigen- binding moiety.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • the second antigen-binding moiety specifically binds to a complex comprising a different HPV16-E7 peptide bound to the MHC class I protein. In some embodiments, the second antigen-binding moiety specifically binds to a complex comprising the HPV16-E7 peptide bound to a different MHC class I protein. In some embodiments, the second antigen-binding moiety specifically binds to a different epitope on the complex comprising the HPV16-E7 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 E7MC-presenting cell. In some
  • the second antigen-binding moiety specifically binds to an antigen on the surface of a cell that does not express HPV16-E7. In some embodiments, the second antigen- binding moiety specifically binds to an antigen on the surface of a cytotoxic cell. In some embodiments, 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
  • the second antigen-binding moiety specifically binds to an antigen on the surface of an effector T cell, such as a cytotoxic T cell. In some embodiments, 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. In some embodiments, the anti-E7MC antibody moiety is human, humanized, or semi- synthetic. In some embodiments, 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-E7MC 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-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01, and b) a second antigen- binding moiety.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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-C
  • an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, 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 antigen-binding moiety.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 1
  • an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, and b) a second antigen-binding moiety.
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77, 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: 78-98, 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: 99-119, 244, and 245, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid substitutions;
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161 ; and an LC-CDR3 comprising the amino
  • a multi-specific anti-E7MC molecule comprising a) an anti-E7MC antibody moiety comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, 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: 36-56 and 238-243, 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-E7MC molecule comprising a) an anti-E7MC antibody moiety comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243; and b) a second antigen-binding moiety.
  • the multi- specific anti-E7MC 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. , a bispecific T cell engager)
  • a tandem tri-scFv a tri(a)body, a bispecific Fab2, a di-miniantibody, a tetrabody, an scFv-Fc-scFv fusion, a dual-affinity retargeting (DART) antibody, a dual variable domain (DVD) antibody
  • IgG-scFab an scFab-ds-scFv
  • an Fv2- variable domain
  • the multi- specific anti-E7MC molecule is a tandem scFv (e.g. , a tandem di- scFv, such as a bispecific T cell engager).
  • the multi- specific anti-E7MC molecule in some embodiments is a tandem scFv comprising a first scFv comprising an anti-E7MC antibody moiety and a second scFv (also referred to herein as a "tandem scFv multi- specific anti-E7MC antibody").
  • the tandem scFv multi- specific anti-E7MC antibody further comprises at least one (such as at least about any of 2, 3, 4, 5, or more) additional scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) a second scFv.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • the second scFv specifically binds to a complex comprising a different HPV16-E7 peptide bound to the MHC class I protein. In some embodiments, the second scFv specifically binds to a complex comprising the HPV16- E7 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 HPV16-E7 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 E7MC-presenting cell.
  • the second scFv specifically binds to an antigen on the surface of a cell that does not express HPV16-E7. In some embodiments, 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
  • 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.
  • both the first scFv and the second scFv are human, humanized, or semisynthetic.
  • the tandem scFv multi- specific anti-E7MC antibody further comprises at least one (such as at least about any of 2, 3, 4, 5, or more) additional scFv.
  • the anti-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 11- 19 peptide (SEQ ID NO: 4) and HLA-A*02:01, and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, and b) a second scFv.
  • a first scFv that specifically binds to a complex comprising an HPV16
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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: 57-77, 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: 78-98, or a variant thereof comprising up to about 5
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99- 119, 244, and 245, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246, 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: 141- 161, 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: 141- 161, 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
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99- 119, 244, and 245; 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 S
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99- 119, 244, and 245; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-16
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, 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: 36-56 and 238-243, 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 first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, or a variant thereof having at least about 95% (for example at least about any of 96%, 97%, 9
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243; and b) a second scFv.
  • tandem scFv multi-specific (e.g. , bispecific) anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) a second scFv, wherein the tandem scFv multi- specific anti-E7MC antibody is a tandem di-scFv or a tandem tri-scFv.
  • the tandem scFv multi- specific anti-E7MC antibody is a tandem di-scFv.
  • the tandem scFv multi- specific anti-E7MC antibody is a bispecific T-cell engager.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 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 HPV16- E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02. In some embodiments, 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 CD3y, CD35, CD3s, CD3C, CD28, OX40, GITR, CD137, CD27, CD40L, and HVEM.
  • 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, 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 SEQ ID NO: 191, 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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:
  • HC-CDR2 comprising the amino acid sequence of any one of
  • SEQ ID NOs: 78-98 or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245, or a variant thereof comprising up to about 5
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161, 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: 162-182 and 247-250, 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 an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs:
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 compris
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, 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: 36-56 and 238-243, 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-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243, and b) a second scFv that specifically binds to an antigen on the surface of a T cell.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) a second scFv that specifically binds to CD3s.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • 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 GGGGS.
  • 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) 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 GGGGS.
  • 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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 SEQ ID NO: 189 or 190, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and an
  • 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 GGGGS.
  • the first scFv is human, humanized, or semi-synthetic.
  • the second scFv is human, humanized, or semi-synthetic. In some
  • both the first scFv and the second scFv are human, humanized, or semisynthetic.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-
  • CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of
  • 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,
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence GGGGS.
  • 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 semisynthetic.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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:
  • HC-CDR2 comprising the amino acid sequence of any one of
  • SEQ ID NOs: 78-98 or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245, or a variant thereof comprising up to about 5
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161, 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: 162-182 and 247-250, 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.
  • 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. In some embodiments, the peptide linker comprises (and in some embodiments consists of) the amino acid sequence GGGGS.
  • 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-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 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: 1
  • 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 GGGGS.
  • the first scFv is human, humanized, or semisynthetic.
  • the second scFv is human, humanized, or semi-synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semisynthetic.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv that specifically binds to a complex comprising an
  • HPV16-E7 peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NO: 1
  • LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and
  • 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,
  • the peptide linker comprises (and in some embodiments consists of) the amino acid sequence GGGGS.
  • 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 semisynthetic.
  • tandem di-scFv bispecific anti-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237, 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: 36-56 and 238-243, 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.
  • 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 GGGGS.
  • 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-E7MC antibody comprising a) a first scFv comprising a heavy chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243, 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. In some embodiments, the peptide linker comprises (and in some embodiments consists of) the amino acid sequence GGGGS.
  • the first scFv is human, humanized, or semisynthetic.
  • the second scFv is human, humanized, or semi-synthetic. In some embodiments, both the first scFv and the second scFv are human, humanized, or semisynthetic.
  • the tandem di-scFv bispecific anti-E7MC antibody binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein with a K d between about 0.1 M 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-E7MC antibody binds to a complex comprising an HPV16-E7 peptide and an 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-E7MC construct in some embodiments is a chimeric antigen receptor (CAR) comprising an anti-E7MC antibody moiety (also referred to herein as an "anti-E7MC CAR").
  • CAR chimeric antigen receptor
  • anti-E7MC CAR an anti-E7MC antibody moiety
  • a CAR effector cell e.g. , T cell
  • an anti-E7MC CAR effector cell also referred to herein as an "anti-E7MC CAR effector cell"
  • the anti-E7MC CAR comprises a) an extracellular domain comprising an anti- E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein and b) an intracellular signaling domain.
  • 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 a, ⁇ , ⁇ , ⁇ , or ⁇ chain of the T-cell receptor, CD28, CD3s, ⁇ 3 ⁇ , CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
  • the transmembrane domain may be synthetic, in which case it may comprise predominantly hydrophobic residues such as leucine and valine.
  • a triplet of 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-E7MC 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-E7MC CAR is used (e.g. , if an anti-E7MC CAR intracellular domain comprises a CD28 co-stimulatory sequence, the transmembrane domain of the anti-E7MC 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-E7MC CAR is responsible for activation of at least one of the normal effector functions of the immune cell in which the anti-E7MC 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. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal.
  • 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-E7MC 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
  • co-receptors that act in concert to initiate signal transduction following antigen receptor engagement
  • 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 tyrosine-based activation motifs or ITAMs.
  • ITAMs immunoreceptor tyrosine-based activation motifs
  • the anti-E7MC CAR constructs in some embodiments comprise one or more ITAMs.
  • IT AM containing primary signaling sequences examples include those derived from TCR ⁇ , FcRy, FcRp, CD3y, CD35, CD3s, CD5, CD22, CD79a, CD79b, and CD66d.
  • the anti-E7MC 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-E7MC CAR of the invention.
  • the intracellular domain of the anti-E7MC 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.
  • the intracellular signaling domain of the anti-E7MC 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- E7MC 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-E7MC CAR comprises the intracellular signaling sequence of CD3 ⁇ and the intracellular signaling sequences of CD28 and 4- IBB.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, b) a transmembrane domain, and c) an intracellular signaling domain.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02.
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • the anti-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution).
  • the anti-E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01, b) a transmembrane domain, and c) 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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
  • ID NO: 191 or a variant thereof comprising up to about 3 (for example about any of 1, 2, or
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191; 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77, 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: 78-98, or a variant thereof comprising up to about 5
  • an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246, 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: 141-161, 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: 141-161, 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
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a
  • CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence are CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an extracellular domain comprising an anti-E7MC
  • CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC- CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 162-182 and 247-
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a
  • CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence are CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-
  • 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 intracellular signaling sequence.
  • the intracellular domain comprises a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 intracellular signaling sequence.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO: 4).
  • the MHC class I protein is HLA-A02. In some embodiments, the MHC class I protein is HLA-A*02:01.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01, b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77, 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: 78-98, 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: 99-119, 244, and 245, or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or 5) amino acid
  • a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246, 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: 141-161, 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: 162-182 and 247-250, 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 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an extracellular domain comprising an anti-E7MC
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; and ii) a light chain variable domain sequence comprising an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15- 35 and 233-237, 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: 36-56 and 238-243, 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 comprising a CD3 ⁇ intracellular signaling sequence and a CD28 intracellular signaling sequence.
  • an anti-E7MC CAR comprising a) an extracellular domain comprising an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15- 35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243; b) a transmembrane domain, and c) an intracellular signaling domain comprising a CD3 ⁇ intracellular signaling sequence and a CD28
  • effector cells such as lymphocytes, e.g., T cells
  • effector cells expressing an anti-E7MC CAR.
  • Also provided is a method of producing an effector cell expressing an anti-E7MC CAR comprising introducing a vector comprising a nucleic acid encoding the anti-E7MC CAR into the effector cell.
  • introducing the vector into the effector cell comprises transducing the effector cell with the vector.
  • introducing the vector into the effector cell comprises transfecting the effector cell with the vector. Transduction or transfection of the vector into the effector cell can be carried about using any method known in the art.
  • the anti-E7MC constructs in some embodiments comprise an immunoconjugate comprising an anti-E7MC antibody moiety attached to an effector molecule (also referred to herein as an "anti-E7MC immunoconjugate").
  • an effector molecule also referred to herein as an "anti-E7MC immunoconjugate”
  • the effector molecule is a therapeutic agent, such as a cancer therapeutic agent, which is either cytotoxic, cytostatic or otherwise provides some therapeutic benefit.
  • the effector molecule is a label, which can generate a detectable signal, either directly or indirectly.
  • an anti-E7MC immunoconjugate comprising an anti-E7MC antibody moiety and a therapeutic agent (also referred to herein as an "antibody-drug conjugate", or "ADC").
  • the therapeutic agent is a toxin that is either cytotoxic, cytostatic or otherwise prevents or reduces the ability of the target cells to divide.
  • ADCs for the local delivery of cytotoxic or cytostatic agents, i.e., drugs to kill or inhibit tumor cells in the treatment of cancer (Syrigos and Epenetos, Anticancer Research 19:605-614 (1999); Niculescu-Duvaz and Springer, Adv. Org. Del. Rev.
  • Therapeutic agents used in anti-E7MC immunoconjugates include, for example, daunomycin, doxorubicin, methotrexate, and vindesine (Rowland et al. , Cancer Immunol. Immunother. 21: 183-187 (1986)).
  • Toxins used in anti-E7MC immunoconjugates include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as geldanamycin (Mandler et al, J.Nat. Cancer Inst. 92(19): 1573-1581 (2000); Mandler et al., Bioorganic & Med. Chem.
  • cytotoxic drugs may exert their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands.
  • Enzymatically active toxins and fragments thereof that can be used include, for example, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,a- sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. See, e.g., WO 93/21232 published October 28, 1993.
  • Anti-E7MC immunoconjugates of an anti-E7MC antibody moiety and one or more small molecule toxins are also contemplated herein.
  • small molecule toxins such as a calicheamicin, maytansinoids, dolastatins, aurostatins, a trichothecene, and CC1065, and the derivatives of these toxins that have toxin activity, are also contemplated herein.
  • an anti-E7MC immunoconjugate comprising a therapeutic agent that has an intracellular activity.
  • the anti-E7MC immunoconjugate is internalized and the therapeutic agent is a cytotoxin that blocks the protein synthesis of the cell, therein leading to cell death.
  • the therapeutic agent is a cytotoxin comprising a polypeptide having ribosome-inactivating activity including, for example, gelonin, bouganin, saporin, ricin, ricin A chain, bryodin, diphtheria toxin, restrictocin, Pseudomonas exotoxin A and variants thereof.
  • the anti-E7MC immunoconjugate must be internalized upon binding to the target cell in order for the protein to be cytotoxic to the cells.
  • an anti-E7MC immunoconjugate comprising a therapeutic agent that acts to disrupt DNA.
  • the therapeutic agent that acts to disrupt DNA is, for example, selected from the group consisting of enediyne (e.g. , calicheamicin and esperamicin) and non-enediyne small molecule agents (e.g. , bleomycin, methidiumpropyl-EDTA-Fe(II)).
  • cancer therapeutic agents useful in accordance with the present application include, without limitation, daunorubicin, doxorubicin, distamycin A, cisplatin, mitomycin C, ecteinascidins, duocarmycin/CC-1065, and bleomycin/pepleomycin.
  • the present invention further contemplates an anti-E7MC immunoconjugate formed between the anti-E7MC antibody moiety and a compound with nucleolytic activity (e.g. , a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; DNase).
  • a compound with nucleolytic activity e.g. , a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; DNase.
  • the anti-E7MC immunoconjugate comprises an agent that acts to disrupt tubulin.
  • agents may include, for example, rhizoxin/maytansine, paclitaxel, vincristine and vinblastine, colchicine, auristatin dolastatin 10 MMAE, and peloruside A.
  • the anti-E7MC immunoconjugate comprises an alkylating agent including, for example, Asaley NSC 167780, AZQ NSC 182986, BCNU NSC 409962,
  • Busulfan NSC 750 carboxyphthalatoplatinum NSC 271674, CBDCA NSC 241240, CCNU
  • NSC 95441 mitomycin C NSC 26980, mitozolamide NSC 353451 , nitrogen mustard NSC
  • NSC 296934 tetraplatin NSC 363812, thio-tepa NSC 6396, triethylenemelamine NSC 9706, uracil nitrogen mustard NSC 34462, and Yoshi-864 NSC 102627.
  • the cancer therapeutic agent portion of the anti-E7MC immunoconjugate of the present application may comprise an antimitotic agent including, without limitation, allocolchicine NSC 406042, Halichondrin B NSC 609395, colchicine NSC 757, colchicine derivative NSC 33410, dolastatin 10 NSC 376128 (NG - auristatin derived), maytansine NSC 153858, rhizoxin NSC 332598, taxol NSC 125973, taxol derivative NSC 608832, thiocolchicine NSC 361792, trityl cysteine NSC 83265, vinblastine sulfate NSC 49842, and vincristine sulfate NSC 67574.
  • an antimitotic agent including, without limitation, allocolchicine NSC 406042, Halichondrin B NSC 609395, colchicine NSC 757, colchicine derivative NSC 33410, dolastatin 10 NSC 376128 (NG -
  • the anti-E7MC immunoconjugate comprises a topoisomerase
  • camptothecin NSC 94600 camptothecin, Na salt NSC 100880, aminocamptothecin NSC 603071 , camptothecin derivative NSC 95382, camptothecin derivative NSC 107124, camptothecin derivative NSC 643833, camptothecin derivative NSC 629971 , camptothecin derivative NSC 295500, camptothecin derivative NSC 249910, camptothecin derivative NSC 606985, camptothecin derivative NSC 374028, camptothecin derivative NSC 176323, camptothecin derivative NSC 295501 , camptothecin derivative NSC 606172, camptothecin derivative NSC 606173, camptothecin derivative NSC 610458, camptothecin derivative NSC 618939, camptothecin derivative NSC 610457, camptothecin derivative NSC 610459, camptothecin derivative NSC 606499, camptothecin
  • the anti-E7MC immunoconjugate comprises a topoisomerase
  • doxorubicin NSC 123127 amonafide NSC 308847, m-AMSA NSC 249992, anthrapyrazole derivative NSC 355644, pyrazoloacridine NSC 366140, bisantrene HCL NSC 337766, daunorubicin NSC 82151 , deoxydoxorubicin NSC 267469, mitoxantrone NSC 301739, menogaril NSC 269148, ⁇ , ⁇ -dibenzyl daunomycin NSC 268242, oxanthrazole NSC 349174, rubidazone NSC 164011 , VM-26 NSC 122819, and VP-16 NSC 141540.
  • the anti-E7MC immunoconjugate comprises an RNA or
  • DNA antimetabolite including, without limitation, L-alanosine NSC 153353, 5-azacytidine
  • NSC 102816 5-fluorouracil NSC 19893, acivicin NSC 163501 , aminopterin derivative NSC
  • aminopterin derivative NSC 184692 aminopterin derivative NSC 134033, an antifol
  • NSC 633713 an antifol NSC 623017, Baker's soluble antifol NSC 139105, dichlorallyl lawsone NSC 126771 , brequinar NSC 368390, ftorafur (pro-drug) NSC 148958, 5,6- dihydro-5-azacytidine NSC 264880, methotrexate NSC 740, methotrexate derivative NSC
  • N-(phosphonoacetyl)-L-aspartate (PALA) NSC 224131 N-(phosphonoacetyl)-L-aspartate (PALA) NSC 224131 , pyrazofurin NSC 143095, trimetrexate NSC 352122, 3-HP NSC 95678, 2'-deoxy-5-fluorouridine NSC 27640, 5-HP
  • the anti-E7MC immunoconjugate comprises a highly radioactive atom.
  • a variety of radioactive isotopes are available for the production of radioconjugated antibodies. Examples include 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi,
  • the anti-E7MC antibody moiety can be conjugated to a "receptor” (such as streptavidin) for utilization in tumor pre-targeting wherein the antibody- receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand” (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide).
  • a "receptor” such as streptavidin
  • a ligand e.g., avidin
  • cytotoxic agent e.g., a radionucleotide
  • an anti-E7MC immunoconjugate may comprise an anti- E7MC antibody moiety conjugated to a prodrug-activating enzyme. In some such
  • a prodrug-activating enzyme converts a prodrug (e.g. , a peptidyl
  • chemotherapeutic agent see WO 81/01145
  • an active drug such as an anti-cancer drug.
  • anti-E7MC immunoconjugates are useful, in some embodiments, in antibody-dependent enzyme-mediated prodrug therapy ("ADEPT").
  • Enzymes that may be conjugated to an antibody include, but are not limited to, alkaline phosphatases, which are useful for converting phosphate-containing prodrugs into free drugs; arylsulfatases, which are useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase, which is useful for converting non-toxic 5-fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), which are useful for converting peptide-containing prodrugs into free drugs; D-alanylcarboxypeptidases, which are useful for converting prodrugs that contain D- amino acid substituents; carbohydrate-cleaving enzymes such as ⁇ -galactosidase and neuraminidase, which are useful for converting glycosylated
  • the therapeutic portion of the anti-E7MC immunoconjugates may be a nucleic acid.
  • Nucleic acids that may be used include, but are not limited to, anti- sense RNA, genes or other polynucleotides, including nucleic acid analogs such as thioguanine and thiopurine.
  • the present application further provides anti-E7MC immunoconjugates comprising an anti-E7MC antibody moiety attached to an effector molecule, wherein the effector molecule is a label, which can generate a detectable signal, indirectly or directly.
  • These anti- E7MC immunoconjugates can be used for research or diagnostic applications, such as for the in vivo detection of cancer.
  • the label is preferably capable of producing, either directly or indirectly, a detectable signal.
  • the label may be radio-opaque or a radioisotope, such as 3 H, 14 C, 32 P, 35 S, 123 I, 125 I, 131 I; a fluorescent (fluorophore) or chemiluminescent (chromophore) compound, such as fluorescein isothiocyanate, rhodamine or luciferin; an enzyme, such as alkaline phosphatase,P-galactosidase or horseradish peroxidase; an imaging agent; or a metal ion.
  • a radioisotope such as 3 H, 14 C, 32 P, 35 S, 123 I, 125 I, 131 I
  • a fluorescent (fluorophore) or chemiluminescent (chromophore) compound such as fluorescein isothiocyanate, rhodamine or luciferin
  • an enzyme such as alkaline phosphatase,P-galactosidase or horseradish
  • the label is a radioactive atom for scintigraphic studies, for example 99 Tc or 123 I, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as zirconium-89, iodine-
  • NMR nuclear magnetic resonance
  • MRI magnetic resonance imaging
  • Zirconium-89 may be complexed to various metal chelating agents and conjugated to antibodies, e.g., for PET imaging (WO 2011/056983).
  • the anti-E7MC immunoconjugate is detectable indirectly.
  • a secondary antibody that is specific for the anti-E7MC immunoconjugate and contains a detectable label can be used to detect the anti-E7MC immunoconjugate.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, and b) an effector molecule.
  • the HPV16-E7 peptide is HPV16-E7 11-19 (SEQ ID NO:
  • the MHC class I protein is HLA-A02. In some embodiments, the
  • MHC class I protein is HLA-A*02:01.
  • the effector molecule is covalently attached to the anti-E7MC antibody moiety.
  • the effector molecule is a therapeutic agent selected, for example, from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.
  • the effector molecular is a cancer therapeutic agent.
  • the cancer therapeutic agent is a chemotherapeutic.
  • the cancer therapeutic agent is a highly radioactive atom selected, for example, from the group consisting of 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, and 212 Pb.
  • the effector molecule is a label that can generate a detectable signal, either directly or indirectly.
  • the label is a radioisotope selected, for example, from the group consisting of 3 H, 14 C, 32 P,
  • the anti-E7MC antibody moiety is an scFv. In some embodiments, the anti-E7MC antibody moiety is human, humanized, or semi- synthetic. In some embodiments, the anti-E7MC 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 HPV16-E7 peptide having one amino acid substitution (such as a conservative amino acid substitution). In some embodiments, the anti-E7MC antibody moiety cross-reacts with at least one (such as at least any of 2, 3, 4, or 5) complex comprising the HPV16-E7 peptide and a different subtype of the MHC class I protein.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 11-19 peptide (SEQ ID NO: 4) and HLA-A*02:01, and b) an effector molecule.
  • the effector molecule is covalently attached to the anti- E7MC antibody moiety.
  • the effector molecule is a therapeutic agent selected, for example, from the group consisting of a drug, a toxin, a radioisotope, a protein, a peptide, and a nucleic acid.
  • the effector molecular is a cancer therapeutic agent.
  • the cancer therapeutic agent is a chemotherapeutic.
  • the cancer therapeutic agent is a highly radioactive atom selected, for example, from the group consisting of 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, and
  • the effector molecule is a label that can generate a detectable signal, either directly or indirectly.
  • the label is a radioisotope selected, for example, from the group consisting of 3 H, 14 C, 32 P, 35 S, 123 I, 125 I, and 131 I.
  • the anti-E7MC antibody moiety is an scFv. In some embodiments, the anti-
  • E7MC antibody moiety is human, humanized, or semi- synthetic.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, 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 SEQ ID NO: 184 or 185, 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: 186-188, 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
  • an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising up to about 3 (for example about any of 1, 2, or 3) amino acid substitutions, and b) an effector molecule.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 183, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184 or 185, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 186-188; and ii) a light chain variable domain comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 189 or 190, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 191, and b) an effector molecule.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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 NO:
  • NOs: 57-77 or a variant thereof comprising up to about 5 (such as about any of 1, 2, 3, 4, or
  • an HC-CDR2 comprising the amino acid sequence of any one of
  • SEQ ID NOs: 78-98 or a variant thereof comprising up to about 5 (such as about any of 1, 2,
  • HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245, or a variant thereof comprising up to about 5
  • an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161, 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: 162-182 and 247-250, 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) an effector molecule.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-C
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein comprising i) a heavy chain variable domain sequence comprising an HC-CDR 1 comprising the amino acid sequence of any one of SEQ ID NOs: 57-77; an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 78-98; and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 99-119, 244, and 245; 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: 120-140 and 246; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 141-161; and an LC-CDR3 comprising the amino acid sequence of
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-35 and 233-237, 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: 36-56 and 238-243, 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) an effector molecule.
  • an anti-E7MC immunoconjugate comprising a) an anti-E7MC antibody moiety that specifically binds to a complex comprising an HPV16-E7 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: 15-35 and 233-237 and a light chain variable domain comprising the amino acid sequence of any one of SEQ ID NOs: 36-56 and 238-243, b) an effector molecule.
  • Nucleic acid molecules encoding the anti-E7MC constructs or anti-E7MC antibody moieties are also contemplated.
  • a nucleic acid (or a set of nucleic acids) encoding a multi- specific anti-E7MC molecule e.g. , a multi- specific anti-E7MC antibody, a bispecific anti-E7MC antibody, or a bispecific T-cell engager anti-E7MC antibody
  • polypeptide portion thereof e.g. , a multi- specific anti-E7MC antibody, a bispecific anti-E7MC antibody, or a bispecific T-cell engager anti-E7MC antibody
  • nucleic acid or a set of nucleic acids encoding an anti- E7MC CAR. In some embodiments, there is provided a nucleic acid (or a set of nucleic acids) encoding an anti-E7MC immunoconjugate, or polypeptide portion thereof.
  • the present application also includes variants to these nucleic acid sequences.
  • the variants include nucleotide sequences that hybridize to the nucleic acid sequences encoding the anti-E7MC constructs or anti-E7MC antibody moieties of the present application under at least moderately stringent hybridization conditions.
  • the present invention also provides vectors in which a nucleic acid of the present invention is inserted.
  • an anti-E7MC construct e.g. , anti-E7MC CAR
  • polypeptide portion thereof by a natural or synthetic nucleic acid encoding the anti-E7MC construct or polypeptide portion thereof
  • an appropriate expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, including for example a promoter (e.g., a lymphocyte- specific promoter) and a 3' untranslated region (UTR).
  • the vectors can be suitable for replication and integration in eukaryotic host cells.
  • Typical cloning and expression vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence.
  • nucleic acids of the present invention may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties.
  • the invention provides a gene therapy vector.
  • the nucleic acid can be cloned into a number of types of vectors.
  • the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.
  • the expression vector may be provided to a cell in the form of a viral vector.
  • Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals.
  • Viruses which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno- associated viruses, herpes viruses, and lentiviruses.
  • a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers (see, e.g. , WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • a selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo.
  • retroviral systems are known in the art.
  • adenovirus vectors are used.
  • a number of adenovirus vectors are known in the art.
  • lentivirus vectors are used. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells.
  • Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity.
  • Additional promoter elements e.g. , enhancers, regulate the frequency of transcriptional initiation.
  • these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well.
  • the spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence.
  • CMV immediate early cytomegalovirus
  • This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto.
  • Another example of a suitable promoter is Elongation Growth Factor- la (EF- la).
  • EF- la Elongation Growth Factor- la
  • other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus
  • MMTV human immunodeficiency virus
  • LTR long terminal repeat
  • MoMuLV avian leukemia virus promoter
  • ELR Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter.
  • the invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention.
  • an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired.
  • inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter.
  • the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors.
  • the selectable marker may be carried on a separate piece of DNA and used in a co- transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells.
  • Useful selectable markers include, for example, antibiotic -resistance genes, such as neo and the like.
  • Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences.
  • a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells.
  • Suitable reporter genes may include genes encoding luciferase, ⁇ -galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tel et ah, 2000 FEBS Letters 479: 79-82).
  • Suitable expression systems are well known and may be prepared using known techniques or obtained commercially.
  • the construct with the minimal 5' flanking region showing the highest level of expression of reporter gene is identified as the promoter.
  • Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription.
  • the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art.
  • the expression vector can be transferred into a host cell by physical, chemical, or biological means.
  • Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, the introduction of a polynucleotide into a host cell is carried out by calcium phosphate transfection.
  • Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors.
  • Viral vectors, and especially retroviral vectors have become the most widely used method for inserting genes into mammalian, e.g., human cells.
  • Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus 1, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.
  • Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
  • colloidal dispersion systems such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
  • An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).
  • an exemplary delivery vehicle is a liposome.
  • lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo).
  • the nucleic acid may be associated with a lipid.
  • the nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid.
  • Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution.
  • Lipids are fatty substances which may be naturally occurring or synthetic lipids.
  • lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
  • assays include, for example, "molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR;
  • biochemical assays such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention.
  • ELISAs and Western blots immunological means
  • assays described herein to identify agents falling within the scope of the invention.
  • MHC class I proteins are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on nearly every nucleated cell of the body. Their function is to display fragments of proteins from within the cell to T cells; healthy cells will be ignored, while cells containing foreign proteins will be attacked by the immune system. Because MHC class I proteins present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway. Class I MHC molecules bind peptides generated mainly from degradation of cytosolic proteins by the proteasome. The MHC Lpeptide complex is then inserted into the plasma membrane of the cell.
  • MHC major histocompatibility complex
  • class I MHC cytotoxic T cells
  • CTLs cytotoxic T cells
  • class I MHC can also present peptides generated from exogenous proteins, in a process known as cross-presentation.
  • MHC class I proteins consist of two polypeptide chains, a and p2-microglobulin ( ⁇ 2 ⁇ ). The two chains are linked noncovalently via interaction of b2m and the a3 domain. Only the a chain is polymorphic and encoded by a HLA gene, while the b2m subunit is not polymorphic and encoded by the ⁇ -2 microglobulin gene. The a3 domain is plasma membrane- spanning and interacts with the CD8 co-receptor of T-cells.
  • the a3-CD8 interaction holds the MHC I molecule in place while the T cell receptor (TCR) on the surface of the cytotoxic T cell binds its al-a2 heterodimer ligand, and checks the coupled peptide for antigenicity.
  • TCR T cell receptor
  • the al and a2 domains fold to make up a groove for peptides to bind.
  • MHC class I proteins bind peptides that are 8-10 amino acid in length.
  • the human leukocyte antigen (HLA) genes are the human versions of the MHC genes.
  • the three major MHC class I proteins in humans are HLA-A, HLA-B, and HLA-C, while the 3 minor ones are HLA-E, HLA-F, and HLA-G.
  • HLA-A is ranked among the genes in humans with the fastest-evolving coding sequence. As of December 2013, there were 2432 known HLA-A alleles coding for 1740 active proteins and 117 null proteins.
  • the HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, a-chain, constituent of HLA-A. Variation of HLA-A a-chain is key to HLA function. This variation promotes genetic diversity in the population.
  • HLA-A Since each HLA has a different affinity for peptides of certain structures, greater variety of HLAs means greater variety of antigens to be 'presented' on the cell surface, enhancing the likelihood that a subset of the population will be resistant to any given foreign invader. This decreases the likelihood that a single pathogen has the capability to wipe out the entire human population.
  • Each individual can express up to two types of HLA-A, one from each of their parents. Some individuals will inherit the same HLA-A from both parents, decreasing their individual HLA diversity; however, the majority of individuals will receive two different copies of HLA-A. This same pattern follows for all HLA groups. In other words, a person can only express either one or two of the 2432 known HLA-A alleles.
  • All alleles receive at least a four digit classification, e.g. , HLA-A*02: 12.
  • the A signifies which HLA gene the allele belongs to.
  • the next pair of digits indicates this assignment.
  • HLA-A*02:02, HLA-A*02:04, and HLA-A*02:324 are all members of the A2 serotype (designated by the *02 prefix). This group is the primary factor responsible for HLA compatibility. All numbers after this cannot be determined by serotyping and are designated through gene sequencing.
  • the second set of digits indicates what HLA protein is produced. These are assigned in order of discovery and as of December
  • HLA-A*02:456 The shortest possible HLA name includes both of these details. Each extension beyond that signifies a nucleotide change that may or may not change the protein.
  • the anti-E7MC antibody moiety specifically binds to a complex comprising an HPV16-E7 peptide and an MHC class I protein, wherein the MHC class I protein is HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G.
  • MHC class I protein is HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G.
  • the MHC class I protein is HLA-A, HLA-B, or HLA-C. In some embodiments, the MHC class I protein is HLA-A. In some embodiments, the MHC class I protein is HLA-C
  • the MHC class I protein is HLA-C. In some embodiments, the
  • MHC class I protein is HLA-A01, HLA-A02, HLA-A03, HLA-A09, HLA-A 10, HLA-A11,
  • HLA-A 19 HLA-A23, HLA-A24, HLA-A25, HLA-A26, HLA-A28, HLA-A29, HLA-A30,
  • the MHC class I protein is HLA-A69, HLA-A74, or HLA-A80.
  • the MHC class I protein is HLA-
  • the MHC class I protein is any one of HLA-A*02:01-555, such as HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:01-555, such as HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-
  • the MHC class I protein is HLA-A*02:01.
  • HLA- A*02:01 is expressed in 39-46% of all Caucasians, and therefore represents a suitable choice of MHC class I protein for use in the present invention.
  • HPV16-E7 peptides suitable for use in generating anti-E7MC antibody moieties can be determined, for example, based on the presence of HLA-A*02:01 -binding motifs and cleavage sites for proteasomes and immune-proteasomes using computer prediction models known to those of skill in the art.
  • models include, but are not limited to, IEDB (Vita et al., The immune epitope database (IEDB) 3.0. Nucleic Acids Res. 2014 Oct 9. pii: gku938), ProPredl (described in more detail in Singh and Raghava, ProPred: prediction ofHLA-DR binding sites.
  • BIOINFORMATICS 17(12): 1236- 1237, 2001), and SYFPEITHI see Schuler et al. SYFPEITHI, Database for Searching and T-Cell Epitope Prediction, in Immunoinformatics Methods in Molecular Biology, vol 409(1): 75-93, 2007).
  • peptide synthesis may be done in accordance with protocols well known to those of skill in the art. Because of their relatively small size, the peptides of the invention may be directly synthesized in solution or on a solid support in accordance with conventional peptide synthesis techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. The synthesis of peptides in solution phase has become a well-established procedure for large-scale production of synthetic peptides and as such is a suitable alternative method for preparing the peptides of the invention (See for example, Solid Phase Peptide Synthesis by John Morrow Stewart and Martin et al. Application of Almez-mediated Amidation Reactions to Solution Phase Peptide Synthesis, Tetrahedron Letters Vol. 39, pages 1517-1520, 1998).
  • the binding activity of candidate HPV16-E7 peptides can be tested using the antigen -processing-deficient T2 cell line, which increases expression of HLA-A when stabilized by a peptide in the antigen-presenting groove.
  • T2 cells are pulsed with the candidate peptide for a time sufficient to stabilize HLA-A expression on the cell surface, which can be measured using any methods known in the art, such as by immuno staining with a fluorescently labeled monoclonal antibody specific for HLA-A (for example, BB7.2) followed by fluorescence-activated cell-sorting (FACS) analysis.
  • FACS fluorescence-activated cell-sorting
  • the anti-E7MC antibody or anti-E7MC antibody moiety is a monoclonal antibody.
  • Monoclonal antibodies can be prepared, e.g., using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975) and Sergeeva et al, Blood, 117(16):4262-4272, using the phage display methods described herein and in the Examples below, or using recombinant DNA methods ⁇ see, e.g., US Patent No. 4,816,567).
  • a hamster, mouse, or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.
  • the lymphocytes can be immunized in vitro.
  • the immunizing agent can include a polypeptide or a fusion protein of the protein of interest, or a complex comprising at least two molecules, such as a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • PBLs peripheral blood lymphocytes
  • the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell.
  • Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Usually, rat or mouse myeloma cell lines are employed.
  • the hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium”), which prevents the growth of HGPRT-deficient cells.
  • HGPRT hypoxanthine guanine phosphoribosyl transferase
  • the immortalized cell lines fuse efficiently, support stable high-level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium.
  • the immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al. Monoclonal Antibody Production Techniques and
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide.
  • the binding specificity of monoclonal antibodies produced by the hybridoma cells can be determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art.
  • the binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • the clones can be sub cloned by limiting dilution procedures and grown by standard methods. Goding, supra. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
  • the monoclonal antibodies secreted by the sub clones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • the anti-E7MC antibodies or antibody moieties may also be identified by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics.
  • phage display methods repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen -binding phage as described in Winter et al. , Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments, either as single- chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • PCR polymerase chain reaction
  • naive repertoire can be cloned ⁇ e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al, EMBO J, 12: 725-734 (1993).
  • naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol, 227: 381-388 (1992).
  • Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
  • the antibodies or antigen-binding fragments thereof can be prepared using phage display to screen libraries for antibodies specific to a complex comprising an HPV16-E7 peptide and an MHC class I protein.
  • the library can be a human scFv phage display library having a diversity of at least one x 10 9 (such as at least about any of 1 x 10 9 , 2.5 x 10 9 , 5 x 10 9 , 7.5 x 10 9 , 1 x 10 10 , 2.5 x 10 10 , 5 x 10 10 , 7.5 x 10 10 , or 1 x 10 11 ) unique human antibody fragments.
  • the library is a naive human library constructed from DNA extracted from human PMBCs and spleens from healthy donors, encompassing all human heavy and light chain subfamilies.
  • the library is a naive human library constructed from DNA extracted from PBMCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases.
  • the library is a semi-synthetic human library, wherein heavy chain CDR3 is completely randomized, with all amino acids (with the exception of cysteine) equally likely to be present at any given position ⁇ see, e.g., Hoet, R.M. et al, Nat. Biotechnol. 23(3):344-348, 2005).
  • the heavy chain CDR3 of the semi- synthetic human library has a length from about 5 to about 24 (such as about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids.
  • the library is a non-human phage display library.
  • Phage clones that bind to the E7MC with high affinity can be selected by iterative binding of phage to the E7MC, which is bound to a solid support (such as, for example, beads for solution panning or mammalian cells for cell panning), followed by removal of non- bound phage and by elution of specifically bound phage.
  • a solid support such as, for example, beads for solution panning or mammalian cells for cell panning
  • the E7MC can be biotinylated for immobilization to a solid support.
  • the biotinylated E7MC is mixed with the phage library and a solid support, such as strep tavidin-conjugated
  • Dynabeads M-280, and then E7MC-phage-bead complexes are isolated.
  • the bound phage clones are then eluted and used to infect an appropriate host cell, such as E. coli XLl-Blue, for expression and purification.
  • an appropriate host cell such as E. coli XLl-Blue
  • T2 cells a TAP-deficient, HLA-A*02:01 + lymphoblast cell line
  • the HPV16-E7 peptide of the E7MC are mixed with the phage library, after which the cells are collected and the bound clones are eluted and used to infect an appropriate host cell for expression and purification.
  • the panning can be performed for multiple (such as about any of 2, 3, 4, 5, 6 or more) rounds with either solution panning, cell panning, or a combination of both, to enrich for phage clones binding specifically to the E7MC.
  • Enriched phage clones can be tested for specific binding to the E7MC by any methods known in the art, including for example ELISA and FACS.
  • Monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567.
  • DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).
  • Hybridoma cells as described above or E7MC- specific phage clones of the invention can serve as a source of such DNA.
  • the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • the DNA also can be modified, for example, by substituting the coding sequence for human heavy- and light-chain constant domains and/or framework regions in place of the homologous non-human sequences (U.S. Patent No. 4,816,567;
  • non- immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
  • the antibodies can be monovalent antibodies.
  • Methods for preparing monovalent antibodies are known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy-chain crosslinking.
  • cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using any method known in the art.
  • Antibody variable domains with the desired binding specificities can be fused to immunoglobulin constant-domain sequences.
  • the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions.
  • the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding is present in at least one of the fusions.
  • DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co- transfected into a suitable host organism.
  • the anti-E7MC antibodies or antibody moieties can be humanized antibodies or human antibodies.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 , scFv, or other antigen-binding subsequences of antibodies) that typically contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity.
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non- human residues.
  • Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non- human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain.

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Abstract

La présente invention concerne des constructions comprenant une fraction d'anticorps qui se lie spécifiquement à un complexe comprenant un peptide HPV16-E7 et une protéine CMH de classe I. L'invention porte en outre sur des procédés de production et d'utilisation desdites constructions.
PCT/US2016/031364 2015-05-08 2016-05-06 Constructions ciblant les complexes mhc/peptide hpv16-e7 et leurs utilisations WO2016182957A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
MX2017014056A MX2017014056A (es) 2015-05-08 2016-05-06 Construcciones dirigidas a complejos de peptido e7 del subtipo 16 del virus de papiloma humano (hpv16-e7)/complejo principal de histocompatibilidad (mhc) y sus usos.
EP16793285.4A EP3294328A1 (fr) 2015-05-08 2016-05-06 Constructions ciblant les complexes mhc/peptide hpv16-e7 et leurs utilisations
KR1020177035048A KR20170141256A (ko) 2015-05-08 2016-05-06 Hpv16-e7 펩티드/mhc 복합체를 표적화하는 구축물 및 그의 용도
RU2017142716A RU2017142716A (ru) 2015-05-08 2016-05-06 Конструкции, направленные на комплексы пептида hpv16-e7/мнс, и виды их использования
CA2988397A CA2988397A1 (fr) 2015-05-08 2016-05-06 Constructions ciblant les complexes mhc/peptide hpv16-e7 et leurs utilisations
AU2016261356A AU2016261356A1 (en) 2015-05-08 2016-05-06 Constructs targeting HPV16-E7 peptide/MHC complexes and uses thereof
JP2017557069A JP2018516879A (ja) 2015-05-08 2016-05-06 Ｈｐｖ１６−ｅ７ペプチド／ｍｈｃ複合体を標的化する構築物およびその使用
SG11201708674XA SG11201708674XA (en) 2015-05-08 2016-05-06 Constructs targeting hpv16-e7 peptide/mhc complexes and uses thereof
CN201680039553.5A CN107847570A (zh) 2015-05-08 2016-05-06 靶向hpv16‑e7肽/mhc复合体的构建体及其用途
IL255228A IL255228A0 (en) 2015-05-08 2017-10-24 Targeted structures of hpv16 - e7 peptide/mhc complexes and their uses

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US11976105B2 (en) 2015-10-23 2024-05-07 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US10822413B2 (en) 2017-04-26 2020-11-03 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
WO2018200583A1 (fr) 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cellules exprimant des récepteurs d'activation chimériques et des récepteurs de stimulation chimériques et utilisations associées
US11965021B2 (en) 2017-04-26 2024-04-23 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US11613573B2 (en) 2017-04-26 2023-03-28 Eureka Therapeutics, Inc. Chimeric antibody/T-cell receptor constructs and uses thereof
JP7401312B2 (ja) 2017-06-28 2023-12-19 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 抗ヒトパピローマウイルス（ｈｐｖ）抗原結合性タンパク質およびその使用方法
JP2020529835A (ja) * 2017-06-28 2020-10-15 リジェネロン・ファーマシューティカルズ・インコーポレイテッドＲｅｇｅｎｅｒｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 抗ヒトパピローマウイルス（ｈｐｖ）抗原結合性タンパク質およびその使用方法
US10806780B2 (en) 2017-06-28 2020-10-20 Regeneron Pharmaceuticals, Inc. Anti-human papillomavirus (HPV) antigen-binding proteins and methods of use thereof
US11559576B2 (en) 2017-06-28 2023-01-24 Regeneran Pharmaceuticals, Inc. Anti-human papillomavirus (HPV) antigen-binding proteins and methods of use thereof
US11952408B2 (en) 2017-10-03 2024-04-09 Juno Therapeutics, Inc. HPV-specific binding molecules
WO2021158073A1 (fr) 2020-02-06 2021-08-12 아주대학교산학협력단 Anticorps de fusion permettant la présentation d'un épitope d'antigène de lymphocyte t dérivé d'un antigène ou d'un peptide le contenant sur une surface cellulaire, et composition le comprenant
US11479599B2 (en) 2020-02-26 2022-10-25 Vir Biotechnology, Inc. Antibodies against SARS-CoV-2 and methods of using the same
US11168128B2 (en) 2020-02-26 2021-11-09 Vir Biotechnology, Inc. Antibodies against SARS-CoV-2 and methods of using the same
WO2021170115A1 (fr) * 2020-02-28 2021-09-02 香雪生命科学技术（广东）有限公司 Récepteur de lymphocytes t reconnaissant le hpv
US11883432B2 (en) 2020-12-18 2024-01-30 Century Therapeutics, Inc. Chimeric antigen receptor system with adaptable receptor specificity
WO2023133193A1 (fr) * 2022-01-05 2023-07-13 Memorial Sloan-Kettering Cancer Center Anticorps anti-hpv et leurs utilisations
WO2024050399A1 (fr) * 2022-09-01 2024-03-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anticorps à domaine unique ciblant des complexes peptide/cmh oncogènes hpv e6/e7

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