Meditopes and meditope-binding antibodies and uses thereof
Antibodies and meditopes that bind to the antibodies are provided, as well as complexes, compositions and combinations containing the meditopes and antibodies, and methods of producing, using, testing, and screening the same, including therapeutic and diagnostic methods and uses.
1. A method comprising:
administering to a subject having cancer, a meditope-enabled antibody or antigen-binding fragment thereof and a meditope comprising a peptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 1, 2, 15, 16, 17, 18, 29, 31, 32, 36, 42, 43, 51, 54, and 55, wherein:
said meditope-enabled antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region; a heavy chain constant region (CH) or portion thereof; a light chain variable (VL) region comprising a threonine, serine, or aspartate at position 40, a residue other than glycine at position 41, a residue other than phenylalanine at position 83, and an aspartate or asparagine at position 85, according to Kabat numbering; and a light chain constant region (CL) or portion thereof;
said meditope-enabled antibody or antigen-binding fragment thereof is a meditope-enabled variant of a human or humanized template antibody or antigen-binding fragment thereof, said variant comprising a plurality of framework region (FR) modifications, compared to the template antibody or antigen-binding fragment thereof, according to Kabat numbering, being only at positions selected from the group consisting of positions 8, 9, 10, 38, 39, 40, 41, 42, 43, 44, 45, 82, 83, 84, 85, 86, 87, 99, 100, 101, 102, 103, 104, and 105 of the VL of said template antibody or antigen-binding fragment thereof, and positions 6, 9, 38, 39, 40, 41, 42, 43, 44, 45, 84, 86, 87, 88, 89, 90, 91, 103, 104, 105, 106, 107, 108, 109, and 110 of the VH of said template antibody or antigen-binding fragment thereof;
said meditope-enabled antibody or antigen-binding fragment thereof is capable of binding to an antigen expressed by the cancer, is capable of binding to a cyclic peptide comprising the amino acid sequence of SEQ ID NO 1 via a meditope binding site comprising residues 40, 41, 83, and 85 of the VL of the meditope-enabled antibody or antigen-binding fragment thereof, according to Kabat numbering, and/or residues 39, 89, 105, and 108 of the heavy chain VH of the meditope-enabled antibody or antigen-binding fragment thereof, according to Kabat numbering, and does not specifically bind to the epitope of EGFR that is specifically bound by cetuximab.
2. The method of claim 1 , wherein:
the meditope is coupled to a therapeutic agent selected from the group consisting of: chemotherapeutic agent, therapeutic antibody, toxin, radioisotope, enzyme, chelator, boron compound, photoactive agent, dye, metal, metal alloy, and nanoparticle; or
the meditope is coupled to a diagnostic agent comprising an imaging agent selected from the group consisting of fluorescent substance, luminescent substance, dye, indicator, and radioactive substance.
3. The method of claim 1 , wherein the meditope-enabled antibody or antigen-binding fragment thereof and the meditope are administered sequentially.
4. The method of claim 1 , wherein the meditope-enabled antibody or antigen-binding fragment thereof and the meditope are administered simultaneously.
5. The method of claim 4 , wherein the meditope-enabled antibody or antigen-binding fragment thereof and the meditope are administered as a complex comprising the meditope bound to the meditope binding site in the meditope-enabled antibody or antigen-binding fragment thereof.
6. The method of claim 1 , wherein the meditope is coupled to a chemotherapeutic agent.
7. The method of claim 1 , wherein the meditope is cyclic.
8. The method of claim 1 , wherein the meditope comprises the amino acid sequence of SEQ ID NO: 1.