A humanizedaAnti-CD40 monoclonal antibody (SGN-40) demonstrates antitumor activity in non-Hodgkin’s lymphoma: Initiation of a phase I clinical trial

Abstract

6572 Background: CD40, a member of the Tumor Necrosis Factor (TNF) receptor family, is expressed on the cell surface of normal B lymphocytes, their progenitors, and B cell malignancies, including both indolent and aggressive forms of non-Hodgkin’s lymphoma (NHL). Because this represents an attractive target for immunotherapy, a humanized monoclonal anti-CD40 antibody (SGN-40) has been developed and tested in preclinical models. Methods: SGN-40-dependent proliferation and cell killing were tested in vitro using normal B cells and malignant lymphoma cell lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) was assessed by adding peripheral blood mononuclear cells or purified NK cells to malignant cell lines in the presence of SGN-40. In vivo activity of SGN-40 was determined by xenograft models in SCID mice. Results: Although SGN-40 induces proliferation of normal B cells when crosslinked and exposed to exogenous IL-4, there was dose-dependent B cell depletion and no evidence of activation in non-human primates. Furthermore, malignant cell lines undergo significant antibody-induced cell death (AICD) via apoptosis and ADCC in vitro. SGN-40 is highly active in xenotransplant models, in which Ramos and IM9 cell lines are injected into SCID mice. Mice receiving control IgG died by day 35 whereas those receiving SGN-40 4 mg/kg x 5 doses survived until day 90. Furthermore, these effects are seen in the SCID-beige mice, which lack significant NK cell activity (i.e. ADCC). SGN-40 has in vivo activity in transplanted malignant cell lines that are markedly resistant to rituximab and shows synergy when used together with anti-CD20 therapy. Conclusions: Based on these encouraging data, as well as adequate safety data from non-human primates and an ongoing trial in multiple myeloma, we have initiated a phase I dose escalation trial of SGN-40 in NHL. Anti-CD40 mAb will be given for four consecutive weeks at 2–16 mg/kg/week. Pharmacokinetic data, development of human anti-human antibodies, toxicity, and clinical responses will be evaluated carefully in this heavily pre-treated population of patients. This study is currently open in four sites and patient accrual has begun. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Seattle Genetics Seattle Genetics Seattle Genetics