Clarke S, et al. - Since therapies focused against prostate specific membrane antigen (PSMA), particularly chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs), effectively kill tumor cells but bring about cytokine release-related toxicities, researchers developed fully human CD3xPSMA bispecific antibodies that efficiently eradicate prostate tumor cells while curtailing cytokine release. They generated antibodies targeting CD3 and PSMA in transgenic rats that produce human antibodies (UniRat, OmniFlic). After assembling CD3xPSMA T-BsAbs, their ability to activate T cells and eliminate PSMA+ tumor cells in vitro was assessed. Tumor cell cytotoxicity induced by CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain was comparable to that induced by CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but attenuated cytokine production was with the former. These new CD3xPSMA bispecific antibodies mediated T-cell killing of PSMA+ tumor cells with minimal release of cytokines and could improve safety, effectiveness, and scope for combination therapy to treat castration resistant prostate cancer.