XmAb Fc engineered anti-CD19 monoclonal antibodies with enhanced in vitro efficacy against multiple lymphoma cell lines

Abstract

3021 Background: CD19 is a pan-B cell surface receptor that is expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive immunotherapy target for cancers of lymphoid origin since it is also expressed on the vast majority of Non-Hodgkin Lymphoma (NHL) cells as well as some leukemias. Despite major improvements in response rates and progression free survival the majority of NHL patients will relapse under the current combination chemotherapy with anti-CD20. Thus salvage regimens with new non-cross resistant antibody therapies are warranted. Methods: We employ our XmAb antibody engineering technology to increase the affinity of IgG antibodies for Fc gamma receptors (FcγR), improve the effector function of antibodies, and significantly increases their antitumor potency; we also we humanize and affinity mature such antibodies. Results: The XmAb technology was applied to a humanized anti-CD19 antibody to engineer a variant with significantly enhanced (10- to 100-fold) antibody-dependent cell-mediated cytotoxicity (ADCC). The resulting XmAb CD19 variant was assayed for ADCC against multiple cell lines representative of follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), B-cell acute lymphoblastic leukemia (B-ALL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), chronic myelogenous leukemia (CML), and Burkitt’s lymphoma (BL). The ADCC activity of the XmAb CD19 was in striking contrast to a wild type IgG1 version of the antibody that mediates little ADCC. Moreover, ADCC potency and efficacy of the anti-CD19 Fc variant antibody were superior to that of rituximab: CLL - 10- and 1.5-fold higher, ALL - 10- and 100-fold higher, and HCL - 6- and 1.2-fold higher, respectively. Further, we observed no correlation between ADCC and antigen expression based on the measured cell surface density of CD19 for these cell lines. Conclusions: The increased affinity for FcγRs exhibited by the anti-CD19 Fc variant antibody overcomes much of the dependence of cytotoxicity on surface antigen density. Our data suggest that the anti-CD19 Fc variant antibody engineered for increased effector function could be a promising next-generation NHL immunotherapeutic. No significant financial relationships to disclose.