Inhibition of B-NHL Tumor Xenografts Following Treatment with Galiximab (Anti-CD80 mAb) and Potentiation When Combined with Chemotherapy

Abstract 4873

The non-Hodgkin's lymphomas (NHLs) are a group of lymphoproliferative malignancies with divergent clinical courses. Although the NHLs have historically been treated with radiation therapy and/or chemotherapy, the standard of care has evolved to incorporate the use of rituximab, a mAb that is directed against the CD20 antigen expressed on the surface of transformed B-lymphocytes. However, there are subsets of patients who do not initially respond or become refractory to further treatments. Hence, there is a need for new therapeutic strategies for these patients. CD80 is constitutively expressed on the surface of many B-cell lymphomas. When cell-surface CD80 is cross-linked with anti-CD80 antibodies, cell proliferation is inhibited, proapoptotic molecules are upregulated and antibody-dependent cell cytotoxicity (ADCC) is induced. These findings provide the rationale for using an anti-CD80 mAb to treat lymphoma. Galiximab is a primatized monoclonal antibody that targets CD80 expressed on malignant B cells and is being studied in the clinic as a potential treatment for follicular NHL. Galiximab is a primatized anti-CD80 mAb that has been tested as monotherapy in phase I/II clinical trials involving patients with relapsed/refractory follicular lymphoma (FL), producing an overall response rate of 11% and tumor reductions in 46% of patients. In a recent phase I/II clinical trial involving patients with relapsed or refractory FL, combined therapy with galiximab and rituximab yielded an overall response rate of 66% and a median progression-free survival of 12.1 months at the recommended phase II dose of galiximab (500 mg/m²). We have recently reported that galiximab signals B-NHL cells in vitro and inhibits cell growth and sensitizes resistance tumor cells to apoptosis by chemotherapeutic drugs. The present finding was designed to validate the in vitro findings in in vivo in mice. Thus, we examined in vivo the anti-tumor activity of galiximab used alone and in combination with chemotherapeutic agents in SCID mice bearing human lymphoma xenografts. The in vivo anti-tumor effects of galiximab used alone and in combination with fludarabine or doxorubicin were determined in solid and disseminated human B-lymphoma tumors grown in SCID mice. Galiximab monotherapy in vivo demonstrated significant anti-tumor activity in a Raji lymphoma solid tumor model and in an SKW disseminated lymphoma tumor model. There was significant inhibition in tumor growth and prolongation of survival in both models. In vitro, galiximab sensitized Raji cells to apoptosis by both fludarabine and doxorubicin. Tumor growth inhibition was significantly enhanced when the mice were treated with the combination of galiximab and fludarabine. These findings support the potential clinical application of galiximab in combination with chemotherapeutic drugs for the treatment of CD80-expressing hematologic malignancies.