The Oncologist, Vol. 12, No. 7, 873-883, July 2007; doi:10.1634/theoncologist.12-7-873
© 2007 AlphaMed Press
Melanoma and Cutaneous Malignancies |
Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte–Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer
Antoni Ribasa,c,
Douglas C. Hansond,
Dennis A. Noee,
Robert Millhamf,
Deborah J. Guyotg,
Steven H. Bernsteinh,
Paul C. Canniffd,
Amarnath Sharmae,
Jesus Gomez-Navarrof
aDepartment of Medicine, Division of Hematology/Oncology,
bDepartment of Surgery, Division of Surgical Oncology, and
cJonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California, USA;
Departments of dImmunology,
eClinical PK/PD,
gDrug Safety R&D, and
fClinical Oncology, Pfizer Global Research & Development, Groton-New London, Connecticut, USA;
hUniversity of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Key Words. CTLA-4 • Melanoma • T cell • Antitumor
Correspondence: Jesus Gomez-Navarro, M.D., Pfizer Global Research & Development, Groton-New London, Connecticut 06340, USA. Telephone: 860-732-2079; Fax: 860-732-7127; e-mail: jesus.gomez-navarro{at}pfizer.com
Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte–associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG2 isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma.
Disclosure of potential conflicts of interest is found at the end of this article.
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