Antagonistic Targeting of FcγRIIB Overcomes Antibody Therapy Resistance

Therapeutic monoclonal antibodies (mAb), such as the anti-CD20 mAb rituximab, have shown clinical efficacy in patients with B-cell cancers, but are rarely curative and are limited by intrinsic and acquired resistance. Recent studies indicate that resistance may be mediated through the inhibitory FcγRIIB receptor, which promotes rituximab internalization from the surface of B cells, and that high tumor FcγRIIB expression correlates with poor responses to rituximab in patients with lymphoma. Roghanian, Teige, and colleagues generated 14 highly specific mAbs against human FcγRIIB, which did not bind the activatory FcγRIIA, to assess their therapeutic potential in overcoming resistance. Two high-affinity antagonistic mAbs, 6G11 and 7C07, prevented FcγRIIB activation and blocked internalization of rituximab. In addition, 6G11 exhibited intrinsic antitumor activity and induced high levels of antibody-dependent cellular cytotoxicity without cross-reactivity to other tissues. No adverse effects of 6G11 treatment were seen in dose escalation and repeat dosing studies in transgenic mice expressing the human FcγRIIB in the absence of mouse FcγRII. Treatment with 6G11 induced depletion of FcγRIIB-expressing B cells and potentiated rituximab-mediated target B-cell depletion in vivo, confirming the dual mechanism of action of 6G11. Importantly, combination therapy with 6G11 and rituximab resulted in enhanced antitumor efficacy against primary human chronic lymphocytic leukemia (CLL) cells and CLL cells isolated from treatment-refractory patients. Furthermore, treatment with 6G11 in combination with two other monoclonal antibody therapies, the type II anti-CD20 mAb obinutuzumab and the anti-CD52 mAb alemtuzumab, significantly augmented B-cell depletion and improved antitumor responses. These results suggest that FcγRIIB blockade may overcome mAb drug resistance for many targeted antibodies and support further clinical development of antagonistic FcγRIIB mAbs.

Roghanian A, Teige I, Mårtensson L, Cox KL, Kovacek M, Ljungars A, et al. Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo. Cancer Cell 2015;27:473–88.