Targeting CD19 with SAR3419, an anti-CD19-Maytansinoid Conjugate for the Treatment of B Cell Malignancies

CD19 is a 95 kDa type 1 transmembrane glycoprotein whose expression is highly restricted to cells of B-lineage. CD19 expression is maintained in B-lineage cells that have undergone malignant transformation. Several approaches to exploit anti-CD19 monoclonal antibodies to treat B cell malignancies are being evaluated, including “naked” antibodies, bispecific antibodies, and immunoconjugates. SAR3419 is an ADC that is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached to a highly potent cytotoxic agent, the maytansinoid DM4, a tubulin agent, through reaction with a disulfide-containing linker. SAR3419 displays potent in vitro cytotoxicity towards CD19-positive lymphoma cell lines and shows good efficacy in several different in vivo models of lymphoma, including Burkitt’s lymphoma and diffuse large B cell lymphoma implanted into SCID mice. Initial clinical evaluation of SAR3419 was done in two phase I dose escalation studies exploring alternative schedules of administration, every 3 weeks and weekly, in patients with refractory/relapsed B cell non-Hodgkin’s lymphoma expressing CD19. Preliminary clinical activity is encouraging for its future development, with objective responses seen in both indolent and aggressive lymphomas in both phase I studies. There was a low incidence of clinically significant hematological toxicity, and the reversible ocular toxicity that defined the DLT on the 3-week schedule appeared to be manageable on weekly dosing regimens. The potential of SAR3419 is now being evaluated in a multi-trial phase II program which started in the second half of 2011.