Abstract 625: Preclinical characterization of an auristatin-based anti-CD19 drug conjugate, SGN-19A

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL CD19 has multiple attributes that make it an attractive target for an antibody-drug conjugate (ADC). CD19 is uniformly expressed on the cell surface of almost all malignancies of B cell origin, including non-Hodgkin lymphoma (NHL), B cell precursor acute lymphoblastic leukemia (B-ALL), and chronic lymphocytic leukemia (CLL). In addition, CD19 has very limited normal tissue expression, restricted only to B lymphocytes and their precursors, and it internalizes rapidly, which are favorable characteristic for targeted drug delivery. SGN-19A is an ADC comprised of a humanized anti-CD19 mAb and the potent cytotoxic drug-linker maleimidocaproyl monomethyl auristatin F (mcMMAF). Here we demonstrate internalization and trafficking, in vivo antitumor activity, and in vivo on-target pharmacodynamic effect of B cell depletion following SGN-19A treatment. Internalization and trafficking of SGN-19A through the endosomal-lysosomal pathway resulted in potent in vitro cytotoxic activity against CD19+ cell lines derived from B-ALL, follicular lymphoma, diffused large B cell lymphoma, Burkitt's lymphoma, and plasma cell leukemia. In mouse xenografts modeling different B-lineage malignancies, SGN-19A demonstrated antitumor activity including tumor regression and prolonged survival at doses well below its maximum tolerated dose. We also show that the in vivo antitumor activity is directly related to the duration of the pharmacokinetic half-life among a panel of ADCs targeting CD19. Since SGN-19A cross-reacts with its ortholog expressed in non-human primates, we examined its pharmacodynamic effect on B cell depletion in cynomolgus monkeys. Depletion of peripheral B cells was observed following SGN-19A and correlated with results from terminal immunohistochemical (IHC) analysis demonstrating the depletion of Ki67+ germinal center B cells. Furthermore, using an antibody against mcMMAF we confirmed delivery of the cytotoxic agent to the B cell areas in peripheral lymphoid tissues. Taken together, these results support the further evaluation of SGN-19A as a therapy for B-lineage derived malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 625. doi:10.1158/1538-7445.AM2011-625