Abstract BSTP0204A is a T-cell dependent-bispecific (TCB) antibody targeting six-transmembrane epithelial antigen of the prostate 1 (STEAP1) that induces T-cell mediated killing of STEAP1 expressing cancer cells. STEAP1 is considered an attractive target for prostate cancer due to high expression in prostate and prostate cancer. Characterization of BSTP0204A showed potent T-cell-mediated killing in vitro and anti-tumor activity in mouse xenograft models against prostate cancer cell lines with both moderate and high STEAP1 expression. Analysis of STEAP1 protein expression in human and monkey tissues confirmed low STEAP1 expression outside of the prostate, suggesting a low potential for on target/off-tumor toxicity. However, administration of BSTP0204A in a repeat-dose toxicity study in cynomolgus monkeys revealed adverse vascular inflammation that was inconsistent with STEAP1 expression observed in normal tissues. Additional assessments of STEAP1 expression in the vascular lesions from the toxicity study in monkeys and in human inflammatory disease conditions showed increased STEAP1 expression associated with inflammation and/or injury in both species. Furthermore, upregulation of STEAP1 was observed in both human and monkey primary cells in the presence of inflammatory stimuli. These findings suggest that systemic inflammation induced by T-cell activation following BSTP0204A treatment may have resulted in increased STEAP1 expression, inducing additional inflammation and tissue damage. This work demonstrated the need to understand not only baseline target expression for T-cell engaging therapies, but also expression under conditions such as inflammation, injury, or disease.
Tonkin et al. (Fri,) studied this question.