Humanization of a strategic CD3 epitope enables evaluation of clinical T-cell engagers in a fully immunocompetent in vivo model.

Autor: Zorn JA; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Wheeler ML; Immuno Oncology Discovery, Bristol Myers Squibb, Redwood City, 94063, USA., Barnes RM; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA. ralston.barnes@bms.com., Kaberna J; Immuno Oncology Discovery, Bristol Myers Squibb, Redwood City, 94063, USA., Morishige W; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Harris M; Immuno Oncology Discovery, Bristol Myers Squibb, Redwood City, 94063, USA., Huang RY; Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Lawrenceville, 08543, USA., Lohre J; In Vivo Pharmacology, Bristol Myers Squibb, Redwood City, 94063, USA., Chang YC; Translational Research, Bristol Myers Squibb, Redwood City, 94063, USA., Chau B; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Powers K; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Schindler I; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Neradugomma N; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Thomas W; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Liao X; Translational Research, Bristol Myers Squibb, Redwood City, 94063, USA., Zhou Y; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., West SM; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Wang F; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Kotapati S; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Chen G; Analytical Development & Attribute Sciences, Biologics Development, Bristol Myers Squibb, New Brunswick, 08903, USA., Yamazoe S; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Kosenko A; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Dollinger G; Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, 94063, USA., Sproul T; In Vivo Pharmacology, Bristol Myers Squibb, Redwood City, 94063, USA., Rajpal A; Genentech, South San Francisco, 94080, USA., Strop P; Biologics Discovery, Tallac Therapeutics, Burlingame, 94010, USA.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Mar 03; Vol. 12 (1), pp. 3530. Date of Electronic Publication: 2022 Mar 03.
DOI: 10.1038/s41598-022-06953-7
Abstrakt: T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft tumor models in human T-cell reconstituted immunodeficient mice, which have a number of limitations. To explore the efficacy of human TCEs in fully immunocompetent hosts, we developed a knock-in mouse model (hCD3E-epi) in which a 5-residue N-terminal fragment of murine CD3-epsilon was replaced with an 11-residue stretch from the human sequence that encodes for a common epitope recognized by anti-human CD3E antibodies in the clinic. T cells from hCD3E-epi mice underwent normal thymic development and could be efficiently activated upon crosslinking of the T-cell receptor with anti-human CD3E antibodies in vitro. Furthermore, a TCE targeting human CD3E and murine CD20 induced robust T-cell redirected killing of murine CD20-positive B cells in ex vivo hCD3E-epi splenocyte cultures, and also depleted nearly 100% of peripheral B cells for up to 7 days following in vivo administration. These results highlight the utility of this novel mouse model for exploring the efficacy of human TCEs in vivo, and suggest a useful tool for evaluating TCEs in combination with immuno-oncology/non-immuno-oncology agents against heme and solid tumor targets in hosts with a fully intact immune system.
(© 2022. The Author(s).)
Databáze: MEDLINE
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