Abstract 1554: Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies

T-cell recruiting bispecific antibody (T-BsAb) treatment is an emerging cancer immunotherapy notable for its highly-specific tumor killing activity in humans. However, the success of T-BsAbs in the clinic has been limited due to cytokine-release related toxicities. In order for this technology to reach its potential, the next generation of T-BsAbs must avoid this unintended toxicity by uncoupling cytokine-release from tumor-cell killing. To this end, we used a sequence-based discovery method on CD3-immunized OmniFlic rats, which express human fixed light-chain antibodies, to identify several novel anti-CD3 antibodies. These antibodies bind to multiple CD3 epitopes, each with varying affinities and degrees of T-cell activation. Furthermore, when placed in the context of a T-BsAb, these novel anti-CD3 antibodies achieve similar levels of T-cell mediated tumor-specific lysis, but with a thousand-fold range in potency. Among these antibodies, we identified one lead with particularly favorable properties, in that it stimulates very low levels of cytokine production without sacrificing its potent antigen-specific tumor lysis in vitro, in mouse xenograft assays, as well as ex vivo patient sample studies. This unique behavior gives our novel anti-CD3 antibody the potential to widen the therapeutic window when treating patients and ultimately usher in the next generation of T-BsAbs. Citation Format: Kyle Lorentsen, Preethi Sankaran, Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C. Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal Pratap, Udaya S. Rangaswamy, Harshad S. Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred. Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1554.