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

Autor:	Trinklein ND; a Teneobio, Inc ., Menlo Park , CA , USA., Pham D; a Teneobio, Inc ., Menlo Park , CA , USA., Schellenberger U; a Teneobio, Inc ., Menlo Park , CA , USA., Buelow B; a Teneobio, Inc ., Menlo Park , CA , USA., Boudreau A; a Teneobio, Inc ., Menlo Park , CA , USA., Choudhry P; b Department of Laboratory Medicine , University of California , San Francisco , CA , USA., Clarke SC; a Teneobio, Inc ., Menlo Park , CA , USA., Dang K; a Teneobio, Inc ., Menlo Park , CA , USA., Harris KE; a Teneobio, Inc ., Menlo Park , CA , USA., Iyer S; a Teneobio, Inc ., Menlo Park , CA , USA., Jorgensen B; a Teneobio, Inc ., Menlo Park , CA , USA., Pratap PP; a Teneobio, Inc ., Menlo Park , CA , USA., Rangaswamy US; a Teneobio, Inc ., Menlo Park , CA , USA., Ugamraj HS; a Teneobio, Inc ., Menlo Park , CA , USA., Vafa O; a Teneobio, Inc ., Menlo Park , CA , USA., Wiita AP; b Department of Laboratory Medicine , University of California , San Francisco , CA , USA., van Schooten W; a Teneobio, Inc ., Menlo Park , CA , USA., Buelow R; a Teneobio, Inc ., Menlo Park , CA , USA., Force Aldred S; a Teneobio, Inc ., Menlo Park , CA , USA.
Jazyk:	angličtina
Zdroj:	MAbs [MAbs] 2019 May/Jun; Vol. 11 (4), pp. 639-652. Date of Electronic Publication: 2019 Feb 20.
DOI:	10.1080/19420862.2019.1574521
Abstrakt:	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.
Databáze:	MEDLINE
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