PT - JOURNAL ARTICLE AU - Tsung-Yi Lin AU - Jeong A Park AU - Alan Long AU - Hong-Fen Guo AU - Nai-Kong V Cheung TI - Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy AID - 10.1136/jitc-2021-003114 DP - 2021 Sep 01 TA - Journal for ImmunoTherapy of Cancer PG - e003114 VI - 9 IP - 9 4099 - http://jitc.bmj.com/content/9/9/e003114.short 4100 - http://jitc.bmj.com/content/9/9/e003114.full SO - J Immunother Cancer2021 Sep 01; 9 AB - Background The prognosis for metastatic Ewing sarcoma family of tumors (EFT) is still poor despite high-dose chemotherapy and radiation treatment. Immunotherapies hold promise, but cancer antigen-targeting immunotherapies have largely failed to induce effective T cell receptor-mediated antitumor response. However, T cell-engaging bispecific antibodies (T-BsAbs) have yet to be adequately explored.Methods Rehumanized STEAP1-IgG was used to build T-BsAb (named BC261) using the 2+2 IgG-[L]-scFv platform carrying the anti-CD3 huOKT3 scFv as the second specificity. Its binding epitope mapping, species cross-reactivity, tumor cell line staining, and in vitro cytotoxicity were investigated thoroughly. Its potency in driving tumor-infiltrating lymphocytes (TILs) was quantified using bioluminescence, correlated with in vivo antitumor response against cell line-derived or patient-derived xenografts (CDXs or PDXs) and compared with anti-STEAP1 T-BsAbs built on representative antibody platforms.Results BC261 binding epitope was mapped to its second extracellular domain of STEAP1 shared among canine and primate orthologs. BC261 induced potent cytotoxicity against panels of EFT, prostate cancer, and canine osteosarcoma cell lines despite their low antigen density. BC261 drove significantly more TILs into tumors (30-fold) and exerted superior antitumor effects compared with the other standard BsAb platforms. The antitumor efficacy of BC261 was consistent against EFT and prostate cancer CDXs and PDXs.Conclusions BC261 was highly efficient in driving T cell infiltration and tumor ablation. Either as stand-alone therapeutics or for ex vivo armed T cells, this novel anti-STEAP1 T-BsAb BC261 has therapeutic potential.All data relevant to the study are included in the article or uploaded as supplementary information. All data generated or analyzed during this study are included in this published article.