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Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies

2019; Landes Bioscience; Volume: 11; Issue: 4 Linguagem: Inglês

10.1080/19420862.2019.1574521

1942-0870

Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal Pratap, Udaya S. Rangaswamy, Harshad Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred,

Biosimilars and Bioanalytical Methods

T-cell-recruiting bispecific antibodies (T-BsAbs) have shown potent tumor killing activity in humans, but cytokine release-related toxicities have affected their clinical utility. The use of novel anti-CD3 binding domains with more favorable properties could aid in the creation of T-BsAbs with improved therapeutic windows. Using a sequence-based discovery platform, we identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T-cells, but potency varies by a thousand-fold. Our lead CD3-targeting arm stimulates very low levels of cytokine release, but drives robust tumor antigen-specific killing in vitro and in a mouse xenograft model. This new CD3-targeting antibody underpins a next-generation T-BsAb platform in which potent cytotoxicity is uncoupled from high levels of cytokine release, which may lead to a wider therapeutic window in the clinic.