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

KAM FAI TSE ; JEFFERS, Michael ; MACDOUGALL, John R ; RASTELLI, Luca ; HERRMANN, John ; GALLO, Michael ; GAZIT-BORNSTEIN, Gadi ; SENTER, Peter D ; MEYER, Damon L ; LICHENSTEIN, Henri S ; LAROCHELLE, William J ; POLLACK, Vincent A ; MCCABE, Denise A ; SHADISH, Melanie L ; KHRAMTSOV, Nikolai V ; HACKETT, Craig S ; SHENOY, Suresh G ; BING KUANG ; BOLDOG, Ferenc L

Clinical cancer research, 2006-02, Vol.12 (4), p.1373-1382 [Periódico revisado por pares]

Philadelphia, PA: American Association for Cancer Research

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Título:
CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma
Autor: KAM FAI TSE ; JEFFERS, Michael ; MACDOUGALL, John R ; RASTELLI, Luca ; HERRMANN, John ; GALLO, Michael ; GAZIT-BORNSTEIN, Gadi ; SENTER, Peter D ; MEYER, Damon L ; LICHENSTEIN, Henri S ; LAROCHELLE, William J ; POLLACK, Vincent A ; MCCABE, Denise A ; SHADISH, Melanie L ; KHRAMTSOV, Nikolai V ; HACKETT, Craig S ; SHENOY, Suresh G ; BING KUANG ; BOLDOG, Ferenc L
Assuntos: Amino Acid Sequence ; Animals ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal - therapeutic use ; Antibody Specificity ; Antineoplastic agents ; Biological and medical sciences ; Cell Line ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dermatology ; Dose-Response Relationship, Drug ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoconjugates - pharmacology ; Immunoconjugates - therapeutic use ; Immunohistochemistry ; Medical sciences ; Melanoma - drug therapy ; Melanoma - genetics ; Melanoma - pathology ; Melanoma, Experimental - drug therapy ; Melanoma, Experimental - genetics ; Melanoma, Experimental - pathology ; Membrane Glycoproteins - analysis ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - immunology ; Mice ; Mice, Nude ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; Oligopeptides - therapeutic use ; Pharmacology. Drug treatments ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Treatment Outcome ; Tumors of the skin and soft tissue. Premalignant lesions ; Xenograft Model Antitumor Assays - methods
É parte de: Clinical cancer research, 2006-02, Vol.12 (4), p.1373-1382
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: Philadelphia, PA: American Association for Cancer Research
Idioma: Inglês

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

Philadelphia, PA: American Association for Cancer Research

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