Therapeutic antibodies
A pharmaceutical comprising a therapeutic protein that binds to a therapeutic target, the protein being modified with a compound that inhibits binding of the protein to the therapeutic target, the modified protein being effective for reducing an immune response against the protein and for producing a therapeutic effect by binding to the therapeutic target. The therapeutic protein may be an antibody that includes an antibody combining site that binds to the therapeutic target.
1. A modified therapeutic antibody comprising
an antibody comprising a light chain comprising the light chain V-region of alemtuzumab (CAMPATH-1H) and a heavy chain comprising the heavy chain V-region of alemtuzumab (CAMPATH-1H),
said antibody being linked at the N-terminus of the light chain to a peptide that inhibits binding of the antibody to the target antigen, wherein the peptide is the amino acid sequence QTSSPSAD (SEQ ID NO: 17) which is reversibly bound to the antibody combining site of the antibody,
said modified antibody being effective for reducing an immune response against the antibody and for producing a therapeutic effect by binding to the target antigen.
2. The modified therapeutic antibody of claim 1 wherein only one of the light chains of the antibody has a peptide linked thereto that binds to the antibody combining site.
3. The modified therapeutic antibody of claim 1 wherein the affinity of the modified antibody combined with the peptide for the target antigen is 5 fold less to 100 fold less than the affinity of the unmodified antibody for the target antigen.
4. The modified therapeutic antibody of claim 3 wherein the modified antibody has an affinity for the target antigen that is 20 fold less to 100 fold less than the affinity of the unmodified antibody for the target antigen.
5. The modified therapeutic antibody of claim 1 wherein the antibody is an aglycosylated antibody.
6. The modified therapeutic antibody of claim 1 wherein the Fc portion of the antibody is aglycosylated.
7. The modified therapeutic antibody of claim 1 wherein the antibody does not bind to the Fc receptor.
8. The modified therapeutic antibody of claim 1 , wherein the antibody has a peptide reversibly bound to the antibody combining site whereby said target antigen competes for and displaces the peptide from the antibody combining site, said peptide inhibiting binding of the antibody to the target antigen, said modified antibody initially binding to the target antigen in an amount that is lower than the unmodified antibody, with said binding to the target antigen increasing as a result of peptide being displaced from the antibody combining site as the antibody becomes bound to the target antigen.
9. The modified therapeutic antibody of claim 1 , wherein the antibody is an alemtuzumab (CAMPATH-1H) antibody.
10. The modified therapeutic antibody of claim 1 wherein the peptide is tethered to the light chain V-region of the antibody by a flexible Glycine4 Serine x2 Linker and the heavy chain of the antibody comprises a wild type human IgG1 constant region.
11. The modified therapeutic antibody of claim 10 , wherein the light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2.
12. The modified therapeutic antibody of claim 1 wherein the peptide is tethered to the light chain V-region of the antibody by a flexible Glycine4 Serine x2 Linker and the heavy chain of the antibody comprises an aglycosyl human IgG1 constant region.
13. The modified therapeutic antibody of claim 12 , wherein the light chain of the antibody tethered to the peptide comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2.
14. The modified therapeutic antibody of claim 1 wherein the peptide is tethered to the light chain V-region of the antibody by a flexible Glycine4 Serine x2 Linker and the heavy chain of the antibody comprises an Fc mutated human IgG1 constant region.
15. The modified therapeutic antibody of claim 14 , wherein the light chain of the antibody tethered to the peptide comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2.
16. A pharmaceutical composition comprising the modified therapeutic antibody of claim 1 .
17. The modified therapeutic antibody of claim 1 , wherein the peptide that is reversibly bound to the antibody combining site of the antibody is displaceable from the antibody combining site in the presence of the target antigen, whereby said target antigen when present displaces the peptide from the antibody combining site as a result of competitive binding.