Dissecting T cell function induced by CD3 redirection bi-specific antibodies
Olesya Chornoguz, Karen Leander, Catherine Leettola, Mark Chiu, Sandra Santulli-Marotto
Janssen Research & Development, Springhouse, PA, USA
CD3 T cell redirecting bi-specific antibodies have been successfully utilized for the treatment of hematologic malignancies (Blinatumomab) and ovarian cancer ascites (Catumaxomab), but the signaling pathways induced by the CD3-redirecting bispecific antibodies in T cells are not well studied. Furthermore, clinical efficacy of CD3 redirection antibodies in solid tumors has been low.
We are dissecting function and signaling of murine T cells activated by CD3xEpCAM bi-specific antibody and comparing it to antigen-specific T cell activation. By activating OT1 T cells using either cognate antigen, SIINFEKL, or a murine version of the CD3xEpCAM bi-specific antibody we find that T cell cytoxicity, cytokine secretion, expression of activation markers and proliferation induced by CD3xEpCAM was markedly lower than the antigen-mediated response. The bi-specific antibody did not induce IL-2 secretion in pre-activated OT1 whereas antigen induced high levels of IL-2. This suggests that signaling induced by T cell redirection antibodies is profoundly different as compared to that induced by antigen. We are currently initiating immune synapse and Nanostring gene expression studies to investigate T cell signaling pathways induced by CD3xEpCAM.
This is the first study that investigates T cell function and signaling induced by the CD3 redirection bi-specific antibody. Our results suggest that T cell activation (measured by % cytoxicity, amount of cytokines secreted and % T-cells that proliferated) induced by CD3xEpCAM is lower as compared to antigen-induced activation. Furthermore, distinct signaling pathways may be induced by CD3 redirection antibody as compared to conventional antigen-specific T cell activation. Understanding T cell function and signaling induced by CD3 redirection bi-specific antibodies will help to develop more efficacious CD3 redirection therapeutics for cancer treatment; particularly for solid tumors.