CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.

Abstract

PURPOSE:

Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets.

EXPERIMENTAL DESIGN AND RESULTS:

By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined. GPNMB is predicted to be a transmembrane protein, thus making it a potential immunotherapeutic target in the treatment of this disease. A fully human monoclonal antibody, designated CR011, was generated to the extracellular domain of GPNMB and characterized for growth-inhibitory activity against melanoma. The CR011 monoclonal antibody showed surface staining of most melanoma cell lines by flow cytometry and reacted with a majority of metastatic melanoma specimens by immunohistochemistry. CR011 alone did not inhibit the growth of melanoma cells. However, when linked to the cytotoxic agent monomethylauristatin E (MMAE) to generate the CR011-vcMMAE antibody-drug conjugate, this reagent now potently and specifically inhibited the growth of GPNMB-positive melanoma cells in vitro. Ectopic overexpression and small interfering RNA transfection studies showed that GPNMB expression is both necessary and sufficient for sensitivity to low concentrations of CR011-vcMMAE. In a melanoma xenograft model, CR011-vcMMAE induced significant dose-proportional antitumor effects, including complete regressions, at doses as low as 1.25 mg/kg.

CONCLUSION:

These preclinical results support the continued evaluation of CR011-vcMMAE for the treatment of melanoma.

• Authors: Kam Fai Tse, Michael Jeffers, Vincent A Pollack, Denise A McCabe, Melanie L Shadish, Nikolai V Khramtsov, Craig S Hackett, Suresh G Shenoy, Bing Kuang, Ferenc L Boldog, John R MacDougall, Luca Rastelli, John Herrmann, Michael Gallo, Gadi Gazit-Bornstein, Peter D Senter, Damon L Meyer, Henri S Lichenstein, William J LaRochelle
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 4 Pg. 1373-82 (Feb 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16489096 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• CR011-vcMMAE
• GPNMB protein, human
• Immunoconjugates
• Membrane Glycoproteins
• Oligopeptides
• monomethyl auristatin E

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (chemistry, pharmacology, therapeutic use)
• Antibody Specificity
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• Immunohistochemistry
• Melanoma (drug therapy, genetics, pathology)
• Melanoma, Experimental (drug therapy, genetics, pathology)
• Membrane Glycoproteins (analysis, genetics, immunology)
• Mice
• Mice, Nude
• Oligopeptides (chemistry, pharmacology, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Treatment Outcome
• Xenograft Model Antitumor Assays (methods)