Method of treating CD30 positive lymphomas
View Patent ↗Methods for treating lymphomas characterized by expression of CD30 using anti-CD30 antibodies and proteasome inhibitors in combination are disclosed.
1. A method of treating Hodgkin's disease (HD) in a subject, comprising administering (a) a monoclonal antibody that binds CD30 and (b) a proteasome inhibitor to the subject, wherein the antibody induces CD30 signaling, activates NF-κB, and increases expression of the caspase inhibitor, c-flip, in the HD-derived cells.
2. A method of treating Hodgkin's disease (HD) in a subject, comprising (a) selecting a monoclonal antibody that binds CD30, induces CD30 signaling, activates NF-KB, and increases expression of the caspase inhibitor, c-flip, in the HD-derived cells and (b) administering the antibody and a proteasome inhibitor to the subject.
3. The method of claim 1 , wherein the proteasome inhibitor inhibits chymotrypsin-like activity of the 26S proteasome.
4. The method of claim 1 , wherein the proteasome inhibitor is selected from bortezomib, ALLnL (N-acetyl-leucinyl-leucynil-norleucynal, MG101), LLM (N-acetyl-leucinyl-leucynil-methional), Z-LLnV (carbobenzoxyl-leucinyl-leucynil-norvalinal,MG115), Z-LLL (carbobenzoxyl-leucinyl-leucynil-leucynal, MG132), Lactacystine, b-lactone, Boronic Acid Peptides, Ubiquitin Ligase Inhibitors, Cyclosporin A, FK506 (Tacrolimus) and Deoxyspergualin.
5. The method of claim 1 wherein the proteasome inhibitor is bortezomib.
6. The method of claim 1 , wherein the antibody comprises a human IgG heavy chain and a human kappa light chain.
7. The method of claim 1 , wherein the antibody comprises a human IgG1 or IgG3 heavy chain.
8. The method of claim 1 , wherein the antibody binds to human CD30 with an affinity constant of at least 10 8 M −1 .
9. The method of claim 1 , wherein the antibody binds to human CD30 with an affinity constant of at least 10 9 M −1 .
10. The method of claim 1 , wherein the antibody is human, chimeric, or humanized.
11. The method of claim 1 , wherein the antibody is non-fucosylated.
12. The method of claim 1 wherein the antibody comprises heavy chain and light chain variable regions comprising the amino acid sequences shown in SEQ ID NO:2 and SEQ ID NO:4, respectively, or an antibody which competes for binding to CD30 with an antibody comprising heavy chain and light chain variable regions comprising the amino acid sequences shown in SEQ ID NO:2 and SEQ ID NO:4, respectively.
13. The method of claim 1 wherein the antibody comprises a heavy chain and a light chain variable regions comprising the amino acid sequences shown in SEQ ID NO: 6 and SEQ ID NO:8, respectively, or an antibody which competes for binding to CD30 with an antibody comprising heavy chain and light chain variable regions comprising the amino acid sequences shown in SEQ ID NO:6 and SEQ ID NO:4, respectively.
14. The method of claim 1 , wherein the antibody comprises a heavy chain and a light chain variable regions comprising the amino acid sequences shown in SEQ ID NO: 10 and SEQ ID NO:12, respectively, or an antibody which competes for binding to CD30 with an antibody comprising heavy chain and light chain variable regions comprising the amino acid sequences shown in SEQ ID NO:10 and SEQ ID NO:12, respectively.
15. The method of claim 1 , where the antibody is produced by a hybridoma, wherein the hybridoma is prepared from a B cell obtained from a transgenic non-human animal having a genome comprising a human heavy chain transgene or transchromosome and a human light chain transgene or transchromosome, fused to an immortalized cell.
16. The method of claim 1 , wherein the antibody is administered prior to, or simultaneous with, administration of the proteasome inhibitor.