Effect of MOR202, a human CD38 antibody, in combination with lenalidomide and bortezomib, on bone lysis and tumor load in a physiologic model of myeloma.Sub-category: Multiple Myeloma Category: Lymphoma and Plasma Cell Disorders Meeting: 2011 ASCO Annual Meeting Abstract No: 8078 Citation: J Clin Oncol 29: 2011 (suppl; abstr 8078) Author(s): J. Endell, C. Samuelsson, R. Boxhammer, S. Strauss, S. Steidl; MorphoSys AG, Martinsried/Planegg, Germany Abstract Disclosures Abstract: Background: MOR202, a HuCAL-derived fully human anti-CD38 antibody mediates ADCC of multiple myeloma (MM) patient cells with high potency (EC50 ~200 pM) and represents a promising new therapy for MM patients. Bortezomib (BOR), a proteasome inhibitor, and lenalidomide (LEN), an immunomodulatory agent, two commonly used agents in MM therapy were evaluated for their ability to enhance the cytotoxicity of MOR202 in vitro and in vivo. Methods: Drug effects were assessed in vitro by FACS analysis using a panel of CD38+ MM cell lines. Different incubation schemes were used to separate effects of BOR or LEN on target or effector cells. A novel murine MM model of intra-tibially injected NCI-H929 MM cells was employed to study MOR202 effects in vivo using bone density and M protein plasma levels as endpoints. Synergy was determined according to Chou-Talalay (Pharmacol Rev. 2006 Sep;58(3):621-81). Results: MOR202-mediated cytotoxicity was enhanced in vitro by BOR and LEN. The enhancement by BOR was mediated through a direct cytotoxic effect on MM cells. In contrast, LEN synergistically enhanced MOR202 activity (CI<0.1) by several mechanisms identified to be direct cytotoxicity, activation of effector cells and increased CD38 expression levels on MM cells. In vivo, MOR202 reduced bone lysis dose-dependently by up to 55% at 12 mg/kg compared to vehicle control. Co-administration of a lower dose of 3 mg/kg MOR202 with either 0.6 mg/kg BOR or 50 mg/kg LEN, however, completely abolished bone lysis. Since BOR and LEN at these doses inhibited bone lysis by only 40% and 20%, respectively, these findings support a synergistic effect of combination therapy. The markedly reduced bone lysis in the combination therapy was accompanied by a reduction (>90%) of serum M protein levels, indicating a significant decrease of tumor load. Conclusions: The cytotoxic activity of MOR202 on MM cells was enhanced by BOR and LEN by different mechanisms. Inhibition of MM-mediated bone lysis and tumor load in vivo was enhanced by both compounds in a synergistic manner with MOR202. These results provide a mechanistic rationale for MOR202 drug combinations which warrant further evaluation in future clinical trials. http://abstract.asco.org/AbstView_102_80499.html Auf der Asco wird es einen Vortrag geben: Time: Monday June 6, 1:00 PM to 5:00 PM
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