Monoclonal antibodies for use in diagnosis and therapy of cancers and autoimmune disease
The specification describes the sequences for antibodies that recognize the HLA-A2-restricted peptide PR-1 in the context of HLA presentation on the surface of cancer cells. Use of these antibodies in the diagnosis and treatment of cancer and immune-related diseases are also provided.
1. A humanized antibody that binds to VLQELNVTV (SEQ ID NO:45) when bound by an HLA-A2 receptor, said antibody comprises a heavy chain variable region comprising CDRs consisting of amino acid sequences SEQ ID NOS: 3, 60 and 5 respectively, and a light chain variable region comprising CDRs consisting of amino acid sequences SEQ ID NOS: 8, 9 and 10 respectively.
2. The antibody of claim 1 , wherein said antibody comprises a heavy chain variable region consisting of amino acid sequence SEQ ID NO: 16, and a light chain variable region consisting of amino acid sequences SEQ ID NOS: 19 or 20.
3. The antibody of claim 2 , wherein said antibody comprises a heavy chain constant region which is a human gamma-1 heavy chain constant region and a light chain constant region which is a human kappa light chain constant region.
4. The antibody of claim 3 , wherein the human gamma-1 heavy chain constant region is residues 144-473 in the amino acid sequence SEQ ID NO: 38, and the human kappa light chain constant region is residues 128-234 in the amino acid sequence SEQ ID NO: 42.
5. The antibody of claim 1 , wherein said antibody is fused to a non-antibody peptide or polypeptide segment.
6. The antibody of claim 1 , wherein said antibody is linked to a diagnostic reagent or a therapeutic reagent.
7. The antibody of claim 6 , wherein said diagnostic reagent is a fluorophore, a chromophore, a dye, a radioisotope, a chemilluminescent molecule, a paramagnetic ion, or a spin-trapping reagent.
8. The antibody of claim 6 , wherein the therapeutic reagent is a cytokine, a chemotherapeutic, a radiotherapeutic, a hormone, an antibody Fc fragment, a TLR agonist, a CpG-containing molecule, or an immune co-stimulatory molecule.
9. A humanized antibody that binds to VLQELNVTV (SEQ ID NO: 45) when bound by an HLA-A2 receptor, produced by a method comprising culturing, under conditions supporting expression of a humanized antibody:
(a) a host cell comprising an expression vector that comprises both a nucleic acid molecule comprising a sequence that encodes the heavy chain variable region of the antibody of claim 2 and a nucleic acid molecule comprising a sequence that encodes the light chain variable region of the antibody of claim 2 ; or
(b) a host cell comprising an expression vector comprising a nucleic acid molecule comprising a sequence that encodes the heavy chain variable region of the antibody of claim 2 and an expression vector comprising a nucleic acid molecule comprising a sequence that encodes the light chain variable region of the antibody of claim 2 .
10. The antibody of claim 3 , wherein the antibody comprises a heavy chain comprising a heavy chain variable region consisting of amino acid sequence SEQ ID NO: 16 and a heavy chain constant region which is a human gamma-1 heavy chain constant region, and a light chain comprising a light chain variable region consisting of amino acid sequences SEQ ID NO: 19 and a light chain constant region which is a human kappa light chain constant region.
11. The antibody of claim 10 , wherein the antibody comprises a heavy chain comprising a heavy chain variable region consisting of amino acid sequence SEQ ID NO: 16 and the heavy chain constant region consisting of residues 144-473 in the amino acid sequence SEQ ID NO: 38, and a light chain comprising a light chain variable region consisting of amino acid sequence SEQ ID NO: 19 and the light chain constant region consisting of residues 128-234 in amino acid sequence SEQ ID:NO: 42.
12. The antibody of claim 3 , wherein the antibody comprises a heavy chain comprising a heavy chain variable region consisting of amino acid sequence SEQ ID NO: 16 and a heavy chain constant region which is a human gamma-1 heavy chain constant region, and a light chain comprising a light chain variable region consisting of amino acid sequence SEQ ID NO: 20 and a light chain constant region which is a human kappa light chain constant region.
13. The antibody of claim 12 , wherein the antibody comprises a heavy chain comprising a heavy chain variable region consisting of amino acid sequence SEQ ID NO: 16 and the heavy chain constant region consisting of residues 144-473 in the amino acid sequence SEQ ID NO: 38, and a light chain comprising a light chain variable region consisting of amino acid sequence SEQ ID NO: 20 and the light chain constant region consisting of residues 128-234 in the amino acid sequence SEQ ID:NO: 42.