ANTI-HLA-E ANTIBODIES, THERAPEUTIC IMMUNOMODULATORY ANTIBODIES TO HUMAN HLA-E HEAVY CHAIN, USEFUL AS IVIG MIMETICS AND METHODS OF THEIR USE
Provided herein are compositions comprising antibodies immunoreactive to human leukocyte antigen E (HLA-E) and HLA Ia alleles, methods of their use, for example, as therapeutic IVIg mimetics, methods of their preparation and methods of their immunomodulatory benefits and applications. In particular embodiments provided herein are compositions and methods for treating an inflammatory condition or graft rejection.
1 . A pharmaceutical composition comprising purified antibodies in a pharmaceutically acceptable carrier, wherein said purified antibodies are chimeric, humanized or human anti-HLA-E antibodies immunoreactive to the polypeptide heavy chain of HLA-E and are not immunoreactive to the polypeptide heavy chain of HLA-F or HLA-G or to β2-microglobulin.
2 . The pharmaceutical composition of claim 1 , wherein said anti HLA E antibodies are immunoreactive to the polypeptide heavy chains of one or more HLA-A alleles and a plurality of HLA-B and HLA-Cvv alleles.
3 . The pharmaceutical composition of claim 1 wherein each said polypeptide heavy chain is free, or associated with β2-microglobulin or associated with another polypeptide heavy chain of the same alleles, and wherein each polypeptide heavy chain is expressed on a cell surface or present in circulation or a body fluid.
4 . The pharmaceutical composition of any of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by the peptide sequences QFAYDGKDY (SEQ ID NO: 5) and DTAAQI (SEQ ID NO: 8).
5 . The pharmaceutical composition of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by any peptide according to one of the sequences QFAYDGKDY (SEQ ID NO: 5), LNEDLRSWTA (SEQ ID NO: 7) and DTAAQI (SEQ ID NO: 8).
6 . The pharmaceutical composition of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by a peptide according to the sequence EYWDRETR (SEQ ID NO: 2).
7 . The pharmaceutical composition of claim 1 wherein the immunoreactivity of said and HLA-E antibodies is blocked by a peptide according to the sequence EPPKTHVT (SEQ ID NO: 12).
8 . The pharmaceutical composition of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by a peptide according to the sequence RAY LED (SEQ ID NO: 10).
9 . The pharmaceutical composition of any of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by a peptide according to the sequence 65 RSARDTA 71 (SEQ ID NO: 13).
10 . The pharmaceutical composition of claim 1 wherein the immunoreactivity of said anti HLA-E antibodies is blocked by a peptide according to the sequence 143 SEQKSNDASE 152 (SEQ ID NO: 14).
11 . The pharmaceutical composition of claim 1 wherein said anti HLA-E antibodies are purified monoclonal antibodies, purified polyclonal antibodies, recombinantly produced antibodies, Fab fragments, F(ab′) fragments or epitope-binding fragments.
12 . The pharmaceutical composition of claim 1 wherein the composition is suitable for subcutaneous, intravenous, or intramuscular administrations.
13 . The pharmaceutical composition of claim 1 wherein the composition is capable of modulating naïve and/or activated CD3+/CD4+ T-cells in a recipient of the pharmaceutical composition.
14 . The pharmaceutical composition of claim 1 wherein the composition is capable of immunomodulating naïve and/or activated CD3+/CD8+ T-cells in a recipient of the pharmaceutical composition.
15 . The pharmaceutical composition of claim 1 wherein the composition is capable of inducing cell death of naïve and/or activated CD3+/CD4+ T-cells in a recipient of the pharmaceutical composition.
16 . The pharmaceutical composition of claim 1 wherein the composition is capable of suppressing formation of T-cell dependent HLA antibodies in a recipient.
17 . The pharmaceutical composition of claim 1 wherein the composition is capable of blocking or neutralizing a proinflammatory or adverse effect of said polypeptide heavy chain by interfering with the binding of said polypeptide heavy chain to a lymphocyte bound receptor, wherein said polypeptide is soluble and in circulation or a body fluid.
18 . The pharmaceutical composition of claim 1 wherein the composition is capable of clearing one or more of said HLA-E, HLA-A, HLA-B or HLA-Cw polypeptide heavy chain from circulation or a body fluid, wherein said polypeptide heavy chain is soluble.
19 . The pharmaceutical composition of claim 1 wherein said anti HLA E antibodies are immunoreactive to HLA Ia antigens similar to therapeutically administered commercial preparations of Intravenous immunoglobulin (IVIg).
20 . The pharmaceutical composition of claim 1 wherein said anti-HLA-E antibodies have immunomodulatory activity comparable to Intravenous immunoglobulin (IVIg).
21 . The pharmaceutical composition of claim 1 wherein the composition is therapeutically effective for the treatment of one or more inflammatory diseases treatable by a therapeutically administered commercial preparation of Intravenous immunoglobulin (IVIg).
22 . The pharmaceutical composition of any one of claim 1 wherein said anti HLA-E antibodies are purified IgG antibodies.
23 . The pharmaceutical composition of any one of claim 1 wvherein said anti HLA-E antibodies are purified IgG1 antibodies.
24 . A method of preventing, managing, treating and/or ameliorating graft rejection, the method comprising administering to a human an effective amount of the pharmaceutical composition of claim 1 .
25 . The method of claim 24 , wherein the graft is a tissue graft.
26 . The method of claim 24 , wherein the graft is an organ graft.
27 . The method of claim 24 , wherein the organ graft is a heart, kidney or liver graft.
28 . The method of claim 24 , wherein the graft is a cell graft.
29 . The method of claim 24 , wherein the cell graft is bone marrow transplantation or a blood transfusion.
30 . A method of managing, treating and/or ameliorating an inflammatory condition selected from the group consisting of: a hematological disease, nephropathy, neuropathy, a bacterial infection, a viral infection, an autoimmune disease, cardiomyopathy, an eye or ear disease, a lung disease, recurring pregnancy loss, Behget syndrome, chronic fatigue syndrome, congenital heart block, diabetes mellitus, acute idiopathic dysautonomia, opsoclonus-myoclonus, Rasmussen syndrome, Reiter syndrome, or Vogt-Koyanagi-Harada syndrome, the method comprising administering to a mammal an effective amount of the pharmaceutical composition of claim 1 .
31 . The method of claim 24 wherein at least 99% of said antibodies are purified anti-HLA-E antibodies.