Brentuximab Vedotin (SGN-35)

Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed-Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration. Clin Cancer Res; 17(20); 6428-36. (C) 2011 AACR.