Galiximab Sensitizes Malignant Human B Cell Lines to Apoptosis by Chemotherapeutic Drugs.

Abstract

Galiximab is a primatized anti-CD80 antibody that is being investigated as a treatment for non-Hodgkin's lymphoma. Results to date from clinical trials indicate that galiximab is well-tolerated and suggest clinical activity both as monotherapy and in combination with rituximab (anti-CD20). CD80 (B7.1), expressed not only by malignant B cells but also by normal B cells, monocytes/macrophages, dendritic cells as well as T cells, plays an important role in the complex and dynamic regulation of adaptive immunity by interacting with either co-stimulatory (e.g. CD28) or co-inhibitory (e.g. CTLA-4, PD-L1) receptors expressed by T lymphocytes. Inhibition of anti-lymphoma immunity that exists within the tumor microenvironment may reflect selection of inhibitory immune regulation mediated through CD80. Galiximab may thus function by directly targeting malignant and possibly non-malignant CD80-expressing cells for antibody-dependent cytotoxicity, or by blocking CD80 interactions involved in suppressing anti-tumor immunity. In preclinical xenograft models, which do not assess the effect of galiximab on non-malignant cells given a lack of cross-reactivity with murine CD80, treatment with galiximab exhibited enhanced tumor growth inhibition when used in combination with either rituximab or with the chemotherapeutic drugs fludarabine and doxorubicin (Hariharan et al., abstract 3040, ASCO, 2007). However, the mechanisms by which galiximab enhances the cytotoxic effects of chemotherapy remain unclear. Rituximab has been shown by us to chemosensitize tumor cells by inhibiting intracellular survival pathways. Thus, we hypothesized that treatment of B lymphoma cells with galiximab facilitates the cytotoxic activity of chemotherapeutic drugs by modifying intracellular anti-apoptotic signaling pathways, resulting in the alteration of pro and anti-apoptotic gene products. The above hypothesis was examined using Raji (Burkitt lymphoma) and IM-9 (multiple myeloma) cell lines as models. Treatment with galiximab resulted in significant inhibition of cell growth and proliferation and modest apoptosis with high concentration. Both Raji and IM-9 are resistant to chemotherapeutic drugs; however, pretreatment with galiximab significantly sensitized the tumor cells to apoptosis induced by CDDP. The synergy achieved was found with subtoxic concentrations of CDDP (5–10 ug/mL) and galiximab. Analysis of the survival pathways and gene products regulating apoptosis following treatment with galiximab, CDDP, and combination will be presented. The present findings demonstrate that galiximab can synergistically enhance cytotoxicity mediated by chemotherapeutic drugs. These findings suggest that in vivo galiximab may have a chemosensitizing effect on resistant B cell malignancies, in addition to its direct cytotoxic effect via ADCC and CDC. The clinincal relevance of these findings will be discussed.