Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies

Curr Opin Investig Drugs. 2009 Jun;10(6):579-87.

Abstract

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • CD40 Antigens / antagonists & inhibitors*
  • CD40 Antigens / immunology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Drug Evaluation, Preclinical
  • Hematologic Neoplasms / drug therapy*
  • Humans
  • Lymphoma, B-Cell / therapy
  • Macaca fascicularis
  • Mice
  • Multiple Myeloma / therapy
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • CD40 Antigens
  • dacetuzumab