Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy
Janelle Waite, Bei Wang, Lauric Haber, Aynur Hermann, Erica Ullman, Xuan Ye, Drew Dudgeon, Rabih Slim, Dharani K. Ajithdoss, Stephen Godin, Ilyssa Ramos, Qi Wu, Erin Oswald, Patrick Poon, Jacquelynn Golubov, Devon Grote, Jennifer Stella, Arpita Pawashe, Jennifer Finney, Evan Herlihy, Hassan Ahmed, Vishal Kamat, Amanda D’Orvilliers, Elizabeth Navarro, Jenny Xiao, Julie Kim, Shao Ning Yang, Jacqueline J. Warsaw, Clarissa Lett, Lauren Canova, Teresa Schulenburg, Randi Foster, Pamela Krueger, Elena Garnova, Ashique Rafique, Robert Babb, Gang Chen, Nicole Stokes Oristian, Chia-Jen Siao, Christopher Daly, Cagan Gurer, Joel Martin, Lynn E. Macdonald, Douglas MacDonald, William Poueymirou, Eric Smith, Israel Lowy, Gavin Thurston, William C. Olson, John Lin, Matthew A. Sleeman, George D. Yancopoulos, Andrew Murphy, Dimitris Skokos
Abstract
Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of "costimulatory bispecifics" that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti-PD-1 approach and endow responsiveness-as well as long-term immune memory-against tumors that otherwise do not respond to anti-PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and "off the shelf" combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.