Figure 2.

Monoclonal antibody mechanisms of action and interactions with immune cells that can influence checkpoint inhibition: isotype switching, Fc domain optimization and BiTEs. (A) Isotype switching and Fc optimization of mAbs to increase binding to activatory Fc receptors on effector cells, such as monocytes, macrophages and NK cells, to enhance T-reg depletion by ADCC, and in the presence of GM-CSF, to enhance ADCC of tumor cells. (B) Development of bispecific T cell engaging antibody structures (BiTE) that can either simultaneously engage tumor-associated antigen (TAA, e.g., CEA or CD19) and T cell specific molecules (e.g., CD3 or CD47) to promote cytolysis of tumor cells (B,i) or simultaneously inhibit two T cell checkpoint molecules; such as CTLA-4 and PD-1, to circumvent mechanisms of resistance (B,ii).