Indirect mechanisms of action of a novel IgG1 monoclonal antibody, NEO-201, to enhance immune killing of tumor.

Abstract

17 Background: NEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 that demonstrates tumor sensitivity and specificity. Functional analysis revealed that NEO-201 is capable of engaging innate immune effector mechanism including ADCC and CDC to directly kill tumor cells expressing its target. Previous studies demonstrated safety/tolerability in non-human primates, and an on going clinical trial at the NCI is currently exploring its dosing and safety. We have explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 has the ability to enhance NK activity by blocking the binding of CEACAM5 on tumor cells to CEACAM1 on NK cells. In addition NEO-201 can target and eliminate regulatory T cells (Tregs). Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells (CEACAM1+/CD16−) as effectors, were conducted to assess the ability of NEO-201to enhance antitumor cytotoxicity of NK-92 cells by blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells. In addition, flow cytometry analsyis and CDC assays were performed to evaluate the ability of NEO-201 to target and eliminate human Tregs in vitro. Results: Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5+/NEO-201+ cells, suggesting that its activity is correlated with the level of CEACAM5+/NEO-201+ tumor cells. Furthermore, NEO-201 targets human Tregs and mediates killing of opsonized T-reg cells via CDC. Conclusions: Previously we have demonstrated the ability of NEO-201 as an IgG1 mab to destroy tumor cells expressing its target directly through both ADCC and CDC. This study suggests that in addition, NEO-201may also mediate immune killing through additional mechanisms including blocking the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity. In addition, we have shown that NEO-201 is also able to recognize and eliminate human Tregs. Ongoing studies are looking at leveraging this phenomenon by combining NEO-201 with checkpoint inhibitors.