A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies
Dimitris Skokos, Janelle Waite, Lauric Haber, Alison Crawford, Aynur Hermann, Erica Ullman, Rabih Slim, Stephen Godin, Dharani K. Ajithdoss, Xuan Ye, Bei Wang, Qi Wu, Ilyssa Ramos, Arpita Pawashe, Lauren Canova, Kristin Vazzana, Priyanka Ram, Evan Herlihy, Hassan Ahmed, Erin Oswald, Jacquelynn Golubov, Patrick Poon, Lauren S. Havel, Danica Chiu, Miguel Lazo, Kathleen Provoncha, Kevin Yu, Julie Kim, Jacqueline J. Warsaw, Nicole Stokes Oristian, Chia-Jen Siao, Drew Dudgeon, Tammy Huang, Terra Potocky, Joel Martin, Douglas MacDonald, A. Oyejide, Ashique Rafique, William Poueymirou, Jessica R. Kirshner, Eric Smith, William C. Olson, John Lin, Gavin Thurston, Matthew A. Sleeman, Andrew Murphy, George D. Yancopoulos
Abstract
T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.