Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning
Lauric Haber, Kara Olson, Marcus P. Kelly, Alison Crawford, David J. DiLillo, Richard Tavaré, Erica Ullman, Shu Mao, Lauren Canova, Olga Sineshchekova, Jennifer Finney, Arpita Pawashe, Supriya Patel, Ryan T. McKay, Sahar Rizvi, Ermelinda Damko, Danica Chiu, Kristin Vazzana, Priyanka Ram, Katja Mohrs, Amanda D’Orvilliers, Jenny Xiao, Sosina Makonnen, Carlos Hickey, Cody Arnold, Jason T. Giurleo, Yaping Chen, Courtney Thwaites, Drew Dudgeon, Kevin Bray, Ashique Rafique, Tammy Huang, Frank J. Delfino, Aynur Hermann, Jessica R. Kirshner, Marc W. Retter, Robert Babb, Douglas MacDonald, Gang Chen, William C. Olson, Gavin Thurston, Samuel Davis, John Lin, Eric Smith
Abstract
T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.