1. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.
- Author
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Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, Hackett CS, Shenoy SG, Kuang B, Boldog FL, MacDougall JR, Rastelli L, Herrmann J, Gallo M, Gazit-Bornstein G, Senter PD, Meyer DL, Lichenstein HS, and LaRochelle WJ
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal pharmacology, Antibody Specificity, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoconjugates pharmacology, Immunohistochemistry, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Melanoma, Experimental genetics, Melanoma, Experimental pathology, Membrane Glycoproteins analysis, Membrane Glycoproteins genetics, Mice, Mice, Nude, Oligopeptides chemistry, Oligopeptides pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Treatment Outcome, Xenograft Model Antitumor Assays methods, Antibodies, Monoclonal therapeutic use, Immunoconjugates therapeutic use, Melanoma, Experimental drug therapy, Membrane Glycoproteins immunology, Oligopeptides therapeutic use
- 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.
- Published
- 2006
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