US20210047417A1 - Mica/b antibodies and methods of use - Google Patents

Mica/b antibodies and methods of use Download PDF

Info

Publication number
US20210047417A1
US20210047417A1 US16/938,554 US202016938554A US2021047417A1 US 20210047417 A1 US20210047417 A1 US 20210047417A1 US 202016938554 A US202016938554 A US 202016938554A US 2021047417 A1 US2021047417 A1 US 2021047417A1
Authority
US
United States
Prior art keywords
monoclonal antibody
seq
amino acid
antigen
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/938,554
Other languages
English (en)
Inventor
Neil Gibson
Justin Chapman
Xin Du
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cullinan Mica Corp
Original Assignee
Cullinan Mica Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cullinan Mica Corp filed Critical Cullinan Mica Corp
Priority to US16/938,554 priority Critical patent/US20210047417A1/en
Assigned to PDI THERAPEUTICS, INC. reassignment PDI THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHAPMAN, JUSTIN, DU, XIN, GIBSON, NEIL
Assigned to Cullinan Mica Corporation reassignment Cullinan Mica Corporation CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: PDI THERAPEUTICS, INC.
Publication of US20210047417A1 publication Critical patent/US20210047417A1/en
Priority to US18/327,566 priority patent/US20240067731A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/844—Liver
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/70—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
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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

Definitions

  • monoclonal antibodies that specifically bind to MICA/B and thereby modulating an immune response against disease cells.
  • a monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical an amino acid sequence set forth as SEQ ID NO: 7.
  • a monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical an amino acid sequence set forth as SEQ ID NO: 7.
  • a monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical an amino acid sequence set forth as SEQ ID NO: 7.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical an amino acid sequence set forth as SEQ ID NO: 7.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence 100% identical an amino acid sequence set forth as SEQ ID NO: 7.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • VL light chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • VL light chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • VL light chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • VL light chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a light chain variable domain (VL) comprising an amino acid sequence 100% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • VL light chain variable domain
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • VH heavy chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • VH heavy chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • VH heavy chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • VH heavy chain variable domain
  • monoclonal antibodies or an antigen-binding fragments thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • VH heavy chain variable domain
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 100% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 100% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 100% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 100% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 100% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 100% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 6.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • monoclonal antibodies or an antigen-binding fragments thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 3.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified.
  • the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • compositions comprising: a monoclonal antibody or an antigen-binding fragment thereof according to any of the disclosures herein; and a pharmaceutically acceptable carrier or excipient.
  • a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.
  • the cancer is hepatocellular carcinoma.
  • a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • VH heavy chain variable domain
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.
  • the cancer is hepatocellular carcinoma.
  • a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.
  • a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • VH heavy chain variable domain
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein.
  • the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both.
  • the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.
  • the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.
  • soluble MICA protein soluble MICB protein
  • methods of reducing level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • CDR1 light chain complementarity determining region 1
  • CDR2 light chain complementarity determining region 2
  • CDR3 light chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the MICA protein is soluble MICA protein. In some embodiments, the MICB protein is soluble MICB protein.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing level of soluble MICA protein, soluble MICB protein, or both in the individual.
  • the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.
  • the cancer is hepatocellular carcinoma.
  • a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6.
  • CDR1 heavy chain complementarity determining region 1
  • CDR2 heavy chain complementarity determining region 2
  • CDR3 heavy chain complementarity determining region 3
  • the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • VH heavy chain variable domain
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 7. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. In some embodiments, the MICA protein is soluble MICA protein. In some embodiments, the MICB protein is soluble MICB protein.
  • the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM.
  • the monoclonal antibody or fragment thereof is humanized or chimeric.
  • the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing level of soluble MICA protein, soluble MICB protein, or both in the individual.
  • the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.
  • the cancer is hepatocellular carcinoma.
  • monoclonal antibodies or an antigen-binding fragments thereof according to any of the disclosures herein for use in treating cancer in an individual in need thereof are also disclosed herein, in certain embodiments, are monoclonal antibodies or an antigen-binding fragments thereof according to any of the disclosures herein for use in preparation of a medicament for treating cancer in an individual in need thereof.
  • the cancer is hepatocellular carcinoma.
  • FIG. 1 illustrates kinetic measurements of antibody PDI-1 to MICA antigens (MICA*01 and MICA*08) by BioLayer Interferometry.
  • FIG. 2 exemplifies binding of antibody PDI-1 to MICA/B alleles by ELISA.
  • FIG. 3 exemplifies antibody PDI-1 binds to cell surface MICA, evaluated by cell staining of TRAMP C2 cell transfected with MICA*04.
  • FIG. 4 exemplifies antibody PDI-1 inhibits MICA shedding from PLC/PRF/5 cells.
  • FIG. 5 exemplifies PDI-1 enhances NK-92 cells mediated cytotoxicity of PLC/PRF/5 cells.
  • FIG. 6 exemplifies measurement of soluble MICA levels in the serum of human liver cancer xenograft model using PDI-1 antibody.
  • MICA/B antibodies that bind specifically to MICA/B.
  • MICA/B antibodies herein bind to MICA/B proteins or fragments thereof and modulate immune response in an individual, thereby treating cancer (e.g. hepatocellular carcinoma).
  • MICA/B Major histocompatibility complex class I-related chain A and B
  • NK natural killer cell
  • Soluble MICA/B shed by diseased cells desensitizes NK and T cells through binding of NKG2D receptor, thereby suppressing the immune response.
  • modulation of MICA/B is useful in modulating an immune response in an individual, for example, in an individual suffering from cancer. Antibodies binding to MICA/B and modulating its activity are desirable for the development of novel therapeutics for treatment of cancer.
  • MICA/B refers to MICA protein, MICB protein or both MICA and MICB proteins, including their variants, isoforms, and species homologs of human MICA/B.
  • antibody refers to a glycoprotein which exhibits binding specificity to a specific antigen.
  • An antibody often comprises a variable domain and a constant domain in each of a heavy chain and a light chain. Accordingly, most antibodies have a heavy chain variable domain (VH) and a light chain variable domain (VL) that together form the portion of the antibody that binds to the antigen. Within each variable domain are three complementarity determining regions (CDR) which form loops in the heavy chain variable domain (VH) and light chain variable domain (VL) that contact the surface of the antigen.
  • CDR complementarity determining regions
  • Antibodies herein also include “antigen binding portion” or fragments of the antibody that are capable of binding to the antigen.
  • chimeric antibodies are antibodies having a portion of the heavy and/or light chain 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 the desired biological activity (see e.g., Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).
  • “Humanized antibodies” herein refers chimeric antibodies having human sequences substituted in the antibody sequence.
  • the terms “recipient”, “individual”, “subject”, “host”, and “patient”, are used interchangeably herein and in some cases, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human.
  • treatment refers to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of effecting a partial or complete cure for a disease and/or symptoms of the disease.
  • Treatment may include treatment of a disease or disorder (e.g.
  • cancer in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • Treating may refer to any indicia of success in the treatment or amelioration or prevention of a cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating.
  • the treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician.
  • treating includes the administration of the compounds or agents of the present invention to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with diseases (e.g. cancer).
  • therapeutic effect refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.
  • a “therapeutically effective amount” in some cases means the amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for that disease.
  • an antibody includes a plurality of antibodies and reference to “an antibody” in some embodiments includes multiple antibodies, and so forth.
  • references to a range of 90-100% includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.
  • reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.
  • “About” a number refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.
  • monoclonal antibodies that bind specifically to MICA/B.
  • MHC class I Chain-related gene A and gene B protein are glycosylated, polymorphic and membrane-anchored non-classical MHC class I proteins.
  • MICA/B are related to MHC class I and have similar domain structure comprising three extra-cellular Ig-like domains (alpha-1, alpha-2 and alpha-3), a transmembrane domain and a C-terminal cytoplasmic tail.
  • MICA/B do not associate with ⁇ 2-microglobulin, lack a CD8 binding site and do not present any antigens.
  • MICA/B are ligands to C-type lectin-like activating receptor Natural Killer Group 2D (NKG2D) on immune effector cells, including NK, NKT and both ⁇ and ⁇ CD8 + T cells.
  • NKG2D Natural Killer Group 2D
  • the interaction of MICA/B and NKG2D plays a role in tumor surveillance, and immune response.
  • MICA/B proteins are expressed normally at low levels in normal cells, but are induced to higher levels in stressed or transformed cells (e.g. cancer cells).
  • stressed or transformed cells e.g. cancer cells.
  • the interaction of NKG2D-bearing immune effector cells with stressed or diseased cells expressing MICA/B ligands on the cell surface creates a cellular immune response against the stressed/diseased cell that culminates in the death of the MICA/B expressing cells.
  • MICA/B proteins proteins that lack the transmembrane domain and cytoplasmic tail but retain the three extracellular domain comprising alpha- 1, -2 and -3 domains
  • MICA/B glycoproteins are produced intracellularly that are not routinely destined to become cell surface membrane-bound, but instead are incorporated within exosomes and released outside the cell where interaction with NKG2D receptors on immune cells occurs.
  • truncated or soluble MICA/B ligands shed from the surface of cancer cells function like decoy molecules and lead to down-modulation of the NKG2D receptor on immune effector cells such as NK, NKT and various CD8 + T cells.
  • immune effector cells such as NK, NKT and various CD8 + T cells.
  • the formation of soluble MICA/B leads to the unusual situation where the effectors of the innate defense system, whose natural role is to seek and destroy transformed cells, are shut down by the immunosuppressive actions of these decoy ligand molecules, thereby enabling the cancer cells to hide from the immune system and to grow unchecked.
  • HCC Hepatocellular Carcinoma
  • MICA/B antibodies disclosed herein bind to MICA/B proteins or fragments thereof and modulate immune response in an individual, thereby treating cancer (e.g. hepatocellular carcinoma).
  • cancer e.g. hepatocellular carcinoma
  • Hepatocellular carcinoma is a primary malignancy of the liver and occurs predominantly in individuals with underlying chronic liver disease and cirrhosis. Tumors progress with local expansion, intrahepatic spread, and distant metastases. Hepatitis B and Hepatitis C predisposes individuals to the development of chronic liver disease and subsequent development of HCC. Obesity, diabetes, and alcohol abuse are some other causes that predispose individuals to the subsequent development of HCC.
  • MICA/B antibodies comprise at least one heavy chain comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL).
  • VH heavy chain variable domain
  • VL light chain variable domain
  • Each VH and VL comprises three complementarity determining regions (CDR).
  • CDR complementarity determining regions
  • the antibodies specifically bind to a MICA protein. In some embodiments, the antibodies specifically bind to a MICB protein. In some embodiments, the antibodies specifically bind to both MICA and MICB protein. In some embodiments, the antibodies bind to an alpha-3 domain of a MICA protein. In some embodiments, the antibodies bind to an alpha-3 domain of a MICB protein. In some embodiments, the antibodies bind to an alpha-3 domain of both MICA and MICB protein. In some embodiments, the antibodies bind to a MICA protein that is membrane-bound MICA protein. In some embodiments, the antibodies bind to a MICA protein that is soluble MICA protein.
  • the antibodies bind to a MICA protein that is both membrane-bound MICA protein and soluble MICA protein. In some embodiments, the antibodies bind to a MICB protein that is membrane-bound MICB protein. In some embodiments, the antibodies bind to a MICB protein that is soluble MICB protein. In some embodiments, the antibodies bind to a MICB protein that is both membrane-bound MICB protein and soluble MICB protein.
  • antibodies that specifically bind to MICA/B are monoclonal antibodies.
  • the antibody is an antigen binding fragment.
  • the antibody is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the antibody is an IgG or an IgM.
  • the antibody is humanized. In some embodiments, the antibody is chimeric.
  • antibodies binding to MICA/B comprise a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the VL has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • antibodies binding to MICA/B comprise a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VH has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • antibodies binding to MICA/B comprising a light chain variable domain (VL) and a heavy chain variable domain (VH).
  • antibodies binding to MICA/B comprise a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 7 and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 7 and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VL has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7 and the VH has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9.
  • the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the light chain comprises an amino acid sequence wherein at least 1 amino acid of amino acid sequence set forth as SEQ ID NO: 9 is modified.
  • the light chain comprises an amino acid sequence wherein at least 2 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 3 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 4 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 5 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 6 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified.
  • the light chain comprises an amino acid sequence wherein at least 7 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 8 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 9 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the light chain comprises an amino acid sequence wherein at least 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10.
  • the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 1 amino acid of amino acid sequence set forth as SEQ ID NO: 10 is modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 2 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 3 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 4 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified.
  • the heavy chain comprises an amino acid sequence wherein at least 5 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 6 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 7 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 8 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 9 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. In some embodiments, the heavy chain comprises an amino acid sequence wherein at least 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified.
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 3.
  • antibodies binding to MICA/B comprise at least one of a light chain a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 3.
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 92%
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprising a light chain complementarity determining region (CDR) and a heavy chain complementarity determining region (CDR).
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 92%
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • cancer e.g. hepatocellular carcinoma
  • methods of treating cancer comprising administration of an MICA/B antibody disclosed herein.
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 3.
  • antibodies binding to MICA/B comprise at least one of a light chain a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 3.
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 92%
  • antibodies binding to MICA/B comprise at least one of a heavy chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 5, a heavy chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprising a light chain complementarity determining region (CDR) and a heavy chain complementarity determining region (CDR).
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 92%
  • antibodies binding to MICA/B comprise at least one of a light chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 6.
  • antibodies binding to MICA/B comprise a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • the VL has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7.
  • antibodies binding to MICA/B comprise a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VH has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • antibodies binding to MICA/B comprising a light chain variable domain (VL) and a heavy chain variable domain (VH).
  • antibodies binding to MICA/B comprise a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 7 and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 7 and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the VL has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7 and the VH has an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8.
  • the antibodies specifically bind to a MICA protein. In some embodiments, the antibodies specifically bind to a MICB protein. In some embodiments, the antibodies specifically bind to both MICA and MICB protein. In some embodiments, the antibodies bind to an alpha-3 domain of a MICA protein. In some embodiments, the antibodies bind to an alpha-3 domain of a MICB protein. In some embodiments, the antibodies bind to an alpha-3 domain of both MICA and MICB protein. In some embodiments, the antibodies bind to a MICA protein that is membrane-bound MICA protein. In some embodiments, the antibodies bind to a MICA protein that is soluble MICA protein.
  • the antibodies bind to a MICA protein that is both membrane-bound MICA protein and soluble MICA protein. In some embodiments, the antibodies bind to a MICB protein that is membrane-bound MICB protein. In some embodiments, the antibodies bind to a MICB protein that is soluble MICB protein. In some embodiments, the antibodies bind to a MICB protein that is both membrane-bound MICB protein and soluble MICB protein.
  • antibodies that specifically bind to MICA/B are monoclonal antibodies.
  • the antibody is an antigen binding fragment.
  • the antibody is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab′) 2 , or a disulfide linked Fv.
  • the antibody is an IgG or an IgM.
  • the antibody is humanized. In some embodiments, the antibody is chimeric.
  • the antibodies disclosed herein reduce level of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce level of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce level of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICB protein.
  • the antibodies disclosed herein inhibit shedding of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce or inhibit shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing level of soluble MICA protein, soluble MICB protein, or both.
  • the antibody is administered by intravenous administration. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, the antibody is administered locally. In some embodiments, the antibody is administered systemically (e.g., intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, sublingually). In some embodiments, the antibody is formulated as a salve, lotion or emulsion. In some embodiments, the antibody is formulated as a solution. In some embodiments, the antibody is formulated for topical, oral, buccal, or nasal administration.
  • the individual is monitored prior to administration of the antibody. Symptoms are identified and their severity is assessed. An antibody as described herein is administered alone or in combination with additional treatments, singly or multiply over time as discussed herein or known to one of skill in the art. In some embodiments, the individual is monitored such that the efficacy of the treatment regimen is determined. In some embodiments, a treatment regimen is modified in response to preliminary treatment outcomes, such that treatment dose or frequency or dose and frequency is altered so as to attain a desired level of subject response in light of symptom alleviation, side effect reduction, or a combination of symptom alleviation and side effect reduction.
  • Therapeutically effective amounts or dosages are contemplated to include dosages of about 0.01 mg/kg to about 20 mg/kg, about for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg
  • Methods of treatment herein comprise one or more administrations of MICA/B antibodies in doses disclosed herein.
  • methods comprise one administration of MICA/B antibodies.
  • methods comprise two administrations of MICA/B antibodies.
  • methods comprise three administrations of MICA/B antibodies.
  • methods comprise four administrations of MICA/B antibodies.
  • methods comprise five administrations of MICA/B antibodies.
  • methods comprise six administrations of MICA/B antibodies.
  • one or more administrations of MICA/B antibodies are administered daily.
  • one or more administrations of MICA/B antibodies are administered weekly.
  • one or more administrations of MICA/B antibodies are administered biweekly.
  • one or more administrations of MICA/B antibodies are administered monthly. In some embodiments, one or more administrations of MICA/B antibodies are administered every three months. In some embodiments, one or more administrations of MICA/B antibodies are administered every six months. In some embodiments, one or more administrations of MICA/B antibodies are administered yearly.
  • compositions comprising MICA/B antibodies disclosed herein and a pharmaceutically acceptable carrier or excipient.
  • excipients for use with the compositions disclosed herein include maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, histidine, glycine, sodium chloride, potassium chloride, calcium chloride, zinc chloride, water, dextrose, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and surfactant polyoxyethylene-sorbitan monooleate.
  • the compositions further comprise an additional therapeutic agent.
  • the therapeutic agent is a chemotherapeutic agent.
  • the chemotherapeutic agents can include, among others, cytotoxic agents, anti-metabolite agents (e.g., folate antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenedione, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), anti-microtubule agents (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethylenimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, and
  • the antibody and the therapeutic agent are in the same formulation. In some embodiments, the antibody and the therapeutic agent are in different formulation. In some embodiments, antibody described herein is used prior to the administration of the other therapeutic agent. In some embodiments, antibody described herein is used concurrently with the administration of the other therapeutic agent. In some embodiments, antibody described herein is used subsequent to the administration of the other therapeutic agent.
  • compositions are made to be compatible with a particular local, regional or systemic administration or delivery route.
  • pharmaceutical formulations include carriers, diluents, or excipients suitable for administration by particular routes.
  • routes of administration for compositions herein are parenteral, e.g., intravenous, intra-arterial, intradermal, intramuscular, subcutaneous, intra-pleural, transdermal (topical), transmucosal, intra-cranial, intra-spinal, intra-ocular, rectal, oral (alimentary), mucosal administration, and any other formulation suitable for the treatment method or administration protocol.
  • solutions or suspensions used for parenteral application include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • pH is adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS).
  • the carrier is a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), or suitable mixtures thereof.
  • Fluidity is maintained, in some embodiments, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal.
  • Isotonic agents for example, sugars; polyalcohols such as mannitol or sorbitol; or sodium chloride, in some embodiments, are included in the composition.
  • an agent which delays absorption in some embodiments, for example, aluminum monostearate or gelatin prolongs absorption of injectable compositions.
  • sterile injectable formulations are prepared by incorporating the active composition in the required amount in an appropriate solvent with one or a combination of above ingredients.
  • dispersions are prepared by incorporating the active composition into a sterile vehicle containing a basic dispersion medium and any other ingredient.
  • methods of preparation include, for example, vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously prepared solution thereof
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • transmucosal administration is accomplished through the use of nasal sprays, inhalation devices (e.g., aspirators) or suppositories.
  • the active compounds are formulated into ointments, salves, gels, creams or patches.
  • the pharmaceutical formulations are prepared with carriers that protect against rapid elimination from the body, such as a controlled release formulation or a time delay material such as glyceryl monostearate or glyceryl stearate.
  • the formulations in some embodiments, are also delivered using articles of manufacture such as implants and microencapsulated delivery systems to achieve local, regional or systemic delivery or controlled or sustained release.
  • the antibodies are prepared using conventional techniques known in the art, for example, Kohler and Milstein, 1975, Nature 256(5517):495-7; Coligan et al., supra, sections 2.5.1-2.6.7; Current Protocols in Immunology, John Wiley & Sons, Inc. (1992); and Antibodies: A Laboratory Manual, Harlow and Lane, eds., Cold Spring Harbor Press, New York (1988); Monoclonal Antibodies: Methods and Protocols in Methods Mol Biol., Vol. 378, Albitar M., ed., Humana Press (2007), which are hereby incorporated herein by reference. Monoclonal antibodies are generated in mice by administration of the immunogen and subsequent isolation of B-cells that make antibodies.
  • the B-cells are then immortalized by fusion to another, stable cell type of the same species of the B-cell to create a hybridoma.
  • the hybridoma clones are screened using ELISA for their ability to bind the antigen (MICA/B).
  • An individual B-cell makes one specific antibody (i.e., is clonally monospecific) which is defined by its primary amino acid sequence and its underlying gene sequence.
  • Monoclonal antibodies showing specific binding to MICA/B are isolated and purified from hybridoma cultures using conventional methodology such as affinity chromatography with Protein-A Sepharose, size-exclusion chromatography, and ion-exchange chromatography (see, e.g., Coligan, et al., supra, sections 2.7.1-2.7.12 and sections 2.9.1-2.9.3; Barnes, et al., Purification of Immunoglobulin G (IgG), in Methods Mol. Biol., Vol. 10, pages 79- 104, Humana Press (1992)).
  • Affinity kinetics was determined on a ForteBio Octet Red96 analyzer. Briefly, PDI-1 (30 ⁇ g/ml) was captured on Dip and ReadTM Anti-mouse IgG Fc Capture (AMC) Biosensors (ForteBio) at room temperature in an assay buffer of PBS+0.1% BSA+0.02% Tween-20 (pH 7.2). Sensors were washed in assay buffer and then incubated with purified 6xHis-MICA*08 and 6xHis-MICA*01 proteins (100 nM), respectively, in 2-fold dilution series for 5 minutes in assay buffer to determine association kinetics of the antibody with the protein antigen. Sensors were then incubated in assay buffer for 10 minutes to determine dissociation kinetics. The resulting kinetics parameters were calculated with ForteBio analysis suite 8.0 using a 1:1 model. Results for these assays are shown in FIG. 1 .
  • Recombinant MICA*01, MICA*02, MICA*04, MICA*08, MICA*09, and MICB proteins were diluted to 1 ⁇ g/ml in 50 mM sodium carbonate buffer, pH 9.6, and coated onto high binding 96-well microplates (Corning #9018), 100 ng in 100 ⁇ l per well. The following morning, coated ELISA plates were washed three times with TBS-Tween-20, pH 7.4 and then blocked in SuperBlock T20 Blocking Buffer (Pierce #37536). After blocking, ELISA plates were washed once with TBS-T and incubated with serially diluted PDI-1 antibody (0-1 ⁇ g/ml) for approximately two hours at room temperature.
  • ELISA plates were washed three times with TBS-T and then incubated with Goat anti-Mouse IgG (H+L)-HRP conjugate (ThermoFisher Scientific #626520) for 45 minutes at room temperature with shaking ( ⁇ 400 rpm). After the incubation, ELISA plates were washed three times with TBS-T and incubated with Super Sensitive Liquid Substrate TMB (Sigma #T4444), 100 ul per well, until color development was sufficient. The reaction was stopped with IN sulfuric acid, 100 ul per well. Optical density (OD) values were measured at 450 nm using a microplate reader. The result of this assay is shown in FIG. 2 .
  • TC2 Mouse prostate adenocarcinoma TRAMP-C2 cells (TC2) (ATCC, Manassas, Va.) was used to generate a stable cell line expressing MICA*04 allele (TC2-MICA-04). Binding of PDI-1 to TC2-MICA-04 was analyzed by flow cytometry. Briefly, cells were first stained with LIVE/DEAD Near IR Stain (Thermo) for 30 min at 4° C., and then washed once by centrifugation with FACS Buffer (1 mM EDTA, 25 mM HEPES, 2% FBS in 1 ⁇ PBS).
  • LIVE/DEAD Near IR Stain Thermo
  • TC2-MICA-04 cells were incubated with 100 ⁇ l of FACS Buffer containing 500 ng PDI-1 antibody at 4° C. for 30 min, followed by incubation with 100 ⁇ g/ml PE conjugated goat-anti-mouse IgG (Biolegend, San Diego, Calif.) secondary Ab at 4° C. for 30 min. Cells were then washed once and cell pellet resuspended with FACS Buffer for FACS analysis gated on live cells. Significantly higher PE fluorescence signal was observed with TC2-MICA-04 cells compared to parental TC2 cells indicated binding of PDI-1 to surface expressed MICA. Result for this assay is shown in FIG. 3 .
  • PLC/PRF/5 cells Hepatocellular Carcinoma
  • ATCC Manassas, Va.
  • Cells were then treated with 100 ⁇ 1 Complete Media (MEM+10% FBS, Thermo, Grand Island, N.Y.) containing PDI-1 and negative control antibodies, respectively, and incubated at 37° C. for another day.
  • Cell supernatants containing shed MICA were used to determine the level of soluble MICA by ELISA. Briefly, 96-well plate was coated with 100 ⁇ g/ml capture Ab anti-human MICA/MICB, clone 6D4 (Biolegend, San Diego, Calif.) overnight at 4° C.
  • PDI-1 Antibody Enhances NK-92 Cells Mediated Cytotoxicity to PLC/PRF/5 Cells
  • PLC/PRF/5 (Target) cells were suspended in RPMI-1640 with 10% FBS, and plated into 96-well flat bottom plates (Costar) at 6000 cells/well. Cells were then incubated with PDI-1 antibody (10 ⁇ g/ml) for 24 hours before being labeled with calcein AM (1 ⁇ M) for 3 hours at 37° C., 5% CO 2 . Wells were washed, and NK-92 cells (Effector) suspended in RPMI-1640 with 10% FBS were then added to wells at various Effector-to-Target (E:T) ratios as indicated and cocultured with target cells for 4 hours.
  • E:T Effector-to-Target
  • 96-well high binding plates (Costar #9018) were coated overnight at 4° C. with 200 ng/well anti-MICA capture antibody in sodium carbonate buffer (50 mM pH 9.6) in 100 ⁇ l volume, then blocked with SuperBlock T20 (Pierce #37536) and washed with TBS-T.
  • serum samples from human liver cancer xenograft model diluted 1:3 in SuperBlock T20 or recombinant MICA*08 standard were added to the plate and incubated for 2 hours at RT. After 2 hours incubation, the plate was washed three times with TBS-T and then incubated with biotinylated PDI-1 detection antibody diluted to 1 ⁇ g/ml in SuperBlock T20.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US16/938,554 2018-01-25 2020-07-24 Mica/b antibodies and methods of use Abandoned US20210047417A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/938,554 US20210047417A1 (en) 2018-01-25 2020-07-24 Mica/b antibodies and methods of use
US18/327,566 US20240067731A1 (en) 2018-01-25 2023-06-01 Mica/b antibodies and methods of use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862621892P 2018-01-25 2018-01-25
PCT/US2019/015025 WO2019147863A2 (en) 2018-01-25 2019-01-24 Mica/b antibodies and methods of use
US16/938,554 US20210047417A1 (en) 2018-01-25 2020-07-24 Mica/b antibodies and methods of use

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/015025 Continuation WO2019147863A2 (en) 2018-01-25 2019-01-24 Mica/b antibodies and methods of use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/327,566 Continuation US20240067731A1 (en) 2018-01-25 2023-06-01 Mica/b antibodies and methods of use

Publications (1)

Publication Number Publication Date
US20210047417A1 true US20210047417A1 (en) 2021-02-18

Family

ID=67396240

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/938,554 Abandoned US20210047417A1 (en) 2018-01-25 2020-07-24 Mica/b antibodies and methods of use
US18/327,566 Pending US20240067731A1 (en) 2018-01-25 2023-06-01 Mica/b antibodies and methods of use

Family Applications After (1)

Application Number Title Priority Date Filing Date
US18/327,566 Pending US20240067731A1 (en) 2018-01-25 2023-06-01 Mica/b antibodies and methods of use

Country Status (12)

Country Link
US (2) US20210047417A1 (ko)
EP (1) EP3743109A4 (ko)
JP (2) JP7458993B2 (ko)
KR (1) KR20200115545A (ko)
CN (1) CN112566659A (ko)
AU (1) AU2019211411A1 (ko)
BR (1) BR112020015142A2 (ko)
CA (1) CA3089478A1 (ko)
IL (1) IL276187A (ko)
MX (1) MX2020007880A (ko)
RU (1) RU2020128010A (ko)
WO (1) WO2019147863A2 (ko)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2019236865A1 (en) 2018-03-23 2020-10-01 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2020035345A1 (en) 2018-08-14 2020-02-20 Innate Pharma Treatment of colorectal cancer by a combination of an anti-mica antibody and an anti-nkg2a antibody
CN114369161B (zh) * 2021-12-28 2023-06-23 合肥天港免疫药物有限公司 Mica抗体及其应用
CN114369162B (zh) * 2021-12-28 2023-05-30 合肥天港免疫药物有限公司 抗体及其应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1857116A1 (en) * 2006-05-19 2007-11-21 Novoplant GmbH Antigen binding polypeptides against spike glycoprotein (S2) of bovine coronavirus
US8753640B2 (en) * 2011-05-31 2014-06-17 University Of Washington Through Its Center For Commercialization MIC-binding antibodies and methods of use thereof
RS55822B1 (sr) * 2011-09-30 2017-08-31 Dana-Farber Cancer Institute Inc Terapijski peptidi
EP2970490A4 (en) * 2013-03-15 2017-04-26 Novelogics Biotechnology, Inc. Antibodies to mica and micb proteins
WO2015003114A1 (en) * 2013-07-05 2015-01-08 University Of Washington Through Its Center For Commercialization Soluble mic neutralizing monoclonal antibody for treating cancer
KR102206029B1 (ko) * 2014-01-27 2021-01-20 삼성전자주식회사 Ang-2에 특이적으로 결합하는 항체 및 그의 용도
CN115029362A (zh) * 2015-02-06 2022-09-09 新加坡国立大学 核酸、包含其的工程免疫细胞及其生产方法和用途
EP3471761A2 (en) * 2016-06-21 2019-04-24 University Of Oslo Hla binding vaccine moieties and uses thereof

Also Published As

Publication number Publication date
CN112566659A (zh) 2021-03-26
KR20200115545A (ko) 2020-10-07
JP2021511387A (ja) 2021-05-06
AU2019211411A1 (en) 2020-08-20
WO2019147863A2 (en) 2019-08-01
JP7458993B2 (ja) 2024-04-01
EP3743109A2 (en) 2020-12-02
BR112020015142A2 (pt) 2021-01-05
WO2019147863A3 (en) 2019-10-24
MX2020007880A (es) 2021-05-14
EP3743109A4 (en) 2021-11-10
US20240067731A1 (en) 2024-02-29
CA3089478A1 (en) 2019-08-01
JP2024038169A (ja) 2024-03-19
IL276187A (en) 2020-09-30
RU2020128010A (ru) 2022-02-25

Similar Documents

Publication Publication Date Title
US20240067731A1 (en) Mica/b antibodies and methods of use
TWI640536B (zh) 抗體
US11498972B2 (en) Anti-OX40 antibody and use thereof
US10696745B2 (en) Anti-PD-L1 antibodies
US20210253711A1 (en) Anti-mica/b antibodies that block mica/b shedding and methods of use
KR102422411B1 (ko) Pd-l1-특이적 항체 및 이를 사용하는 방법
CN111133004A (zh) 抗ctla-4抗体和其用途
US20240026007A1 (en) Antibodies targeting a complex comprising non-classical hla-i and neoantigen and their methods of use
US20220411498A1 (en) Binding molecule specifically for cd39 and use thereof
US20210253713A1 (en) Antibodies targeting a complex comprising non-classical hla-i and neoantigen and their methods of use
CN111886252A (zh) 促进胰岛细胞生长的方法
RU2815101C2 (ru) Антитела против mica/b, блокирующие шеддинг mica/b, и способы их применения
AU2022420151A1 (en) Anti-tnfr2 antibodies and uses thereof
CN114375305A (zh) Cr2结合蛋白及其在医学疗法中的用途

Legal Events

Date Code Title Description
AS Assignment

Owner name: PDI THERAPEUTICS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GIBSON, NEIL;CHAPMAN, JUSTIN;DU, XIN;SIGNING DATES FROM 20190211 TO 20190220;REEL/FRAME:053347/0356

AS Assignment

Owner name: CULLINAN MICA CORPORATION, MASSACHUSETTS

Free format text: CHANGE OF NAME;ASSIGNOR:PDI THERAPEUTICS, INC.;REEL/FRAME:053383/0420

Effective date: 20200528

STPP Information on status: patent application and granting procedure in general

Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION