Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies.
Dacetuzumab, a humanized mAb targeting the CD40 antigen, is in development by Seattle Genetics Inc and licensee Genentech Inc for the potential treatment of hematological malignancies. The CD40 antigen is a highly expressed cell surface transmembrane protein that is present in normal B-cells. Experiments using blocking antibodies for the CD40 ligand demonstrated that CD40 signaling may play a role in the development and maintenance of B-cell hematological malignancies and some solid tumors. In vitro, dacetuzumab exhibited antitumor activity against several B-cell lymphoma and multiple myeloma (MM) cell lines, and induced direct apoptosis as well as the engagement of effective antibody-dependent cell-mediated cytotoxicity. In vivo, dacetuzumab demonstrated enhanced antitumor efficacy in combination with other mAbs and chemotherapeutic agents; many of these combinations are now being tested clinically. Early clinical trials have evaluated the pharmacokinetics, safety and efficacy of dacetuzumab monotherapy in patients with relapsed/refractory B-cell lymphomas or MM. Targeting CD40 with dacetuzumab resulted in modest antitumor activity in B-cell lymphomas and, to a lesser extent, in MM. In particular, patients with diffuse large B-cell lymphoma responded well to dacetuzumab; the drug is being pursued for this indication in phase II trials.
Khubchandani
Sapna
S
Roswell Park Cancer Institute, Department of Medicine and Immunology, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Czuczman
Myron S
MS
Hernandez-Ilizaliturri
Francisco J
FJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D009101:Multiple Myeloma / Q000628:therapy; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C543331:dacetuzumab