CTLA4-Ig–Based Bifunctional Costimulation Inhibitor Blocks CD28 and ICOS Signaling to Prevent T Cell Priming and Effector Function

نویسندگان

چکیده

Abstract CTLA4-Ig/abatacept dampens activation of naive T cells by blocking costimulation via CD28. It is an approved drug for rheumatoid arthritis but failed to deliver efficacy in a number other autoimmune diseases. One explanation that activated rely less on CD28 signaling and use alternate coreceptors effector function. ICOS critical T-dependent humoral immune responses, which drives pathophysiology IgG-mediated In this study, we asked whether play nonredundant roles maintenance responses mouse models. Using hapten–protein immunization model, show during ongoing germinal center response, combination treatment with CTLA4-Ig ligand (ICOSL) Ab completely dissolves whereas single agents only partial activity. Next, took two approaches engineer therapeutic molecule blocks both pathways. First, engineered enhance binding ICOSL while retaining affinity CD80/CD86. library approach, human was increased significantly from undetectable 15–42 nM; however, the still insufficient block ICOS. Second, designed bispecific inhibitor high-affinity CTLA4 extracellular domains fused anti-ICOSL termed bifunctional inhibitor. With achieved complete inhibition CD80 CD86 as well ICOSL. Such molecules may provide greater benefit inflammatory diseases compared alone.

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ژورنال

عنوان ژورنال: Journal of Immunology

سال: 2021

ISSN: ['1550-6606', '0022-1767']

DOI: https://doi.org/10.4049/jimmunol.2001100