Development of potent monoclonal antibody auristatin conjugates for cancer therapy.

Abstract

We describe the in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylauristatin E (MMAE), linked to the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies). The linkers used for conjugate formation included an acid-labile hydrazone and protease-sensitive dipeptides, leading to uniformly substituted conjugates that efficiently released active drug in the lysosomes of antigen-positive (Ag+) tumor cells. The peptide-linked mAb-valine-citrulline-MMAE and mAb-phenylalanine-lysine-MMAE conjugates were much more stable in buffers and plasma than the conjugates of mAb and the hydrazone of 5-benzoylvaleric acid-AE ester (AEVB). As a result, the mAb-Val-Cit-MMAE conjugates exhibited greater in vitro specificity and lower in vivo toxicity than corresponding hydrazone conjugates. In vivo studies demonstrated that the peptide-linked conjugates induced regressions and cures of established tumor xenografts with therapeutic indices as high as 60-fold. These conjugates illustrate the importance of linker technology, drug potency and conjugation methodology in developing safe and efficacious mAb-drug conjugates for cancer therapy.

• Authors: Svetlana O Doronina, Brian E Toki, Michael Y Torgov, Brian A Mendelsohn, Charles G Cerveny, Dana F Chace, Ron L DeBlanc, R Patrick Gearing, Tim D Bovee, Clay B Siegall, Joseph A Francisco, Alan F Wahl, Damon L Meyer, Peter D Senter
• Journal: Nature biotechnology (Nat Biotechnol) Vol. 21 Issue 7 Pg. 778-84 (Jul 2003) ISSN: 1087-0156 [Print] United States
• PMID: 12778055 (Publication Type: Evaluation Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Immunotoxins
• Oligopeptides
• soblidotin

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antibodies, Monoclonal (adverse effects, chemistry, therapeutic use)
• Antineoplastic Agents (adverse effects, chemical synthesis, chemistry, therapeutic use)
• Cells, Cultured (drug effects)
• Drug Delivery Systems (methods)
• Drug Stability
• Humans
• Immunotoxins (adverse effects, chemistry, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, SCID
• Neoplasm Transplantation
• Oligopeptides (adverse effects, chemical synthesis, chemistry, therapeutic use)
• Protein Binding
• Treatment Outcome