LAUSR

CD28 bispecific antibodies are well tolerated and enhance the antitumor efficacy of CD3 bispecifics as a potential off-the-shelf antibody therapy. Double trouble for tumors Bispecific antibodies, which have one arm that binds to a cancer cell antigen and one arm that binds to CD3 on T cells, can help T cells recognize and eliminate cancer cells. However, they are not always sufficient to activate the T cells. To provide a boost to their activity, Skokos et al. designed a second type of bispecific antibodies that bind tumor antigens on one side and a T cell costimulatory receptor on the other side. These costimulatory bispecific antibodies had little activity alone but were effective in combination with CD3-targeting bispecific antibodies in multiple mouse models while showing no toxicity in mice or primates. 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.