Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28. Fc-fusion proteins containing these engineered ICOSL domains significantly attenuate T cell activation in vitro and in vivo and can inhibit development of inflammatory diseases in mouse models. We also present evidence that engineered ICOSL domains can be formatted to selectively provide costimulatory signals to augment T cell responses. Our scientific platform thus provides a system for developing therapeutic protein candidates with selective biological impact for treatments of a wide array of human disorders including cancer and autoimmune/inflammatory diseases.

中文翻译：

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通过变种IgSF域的定向进化产生的新型免疫调节蛋白。

免疫球蛋白超家族成员（IgSF）蛋白在调节免疫应答方面发挥重要作用，其表面表达在所有免疫细胞亚群上，使IgSF成为有吸引力的蛋白质家族，可靶向治疗人类疾病。我们已经开发了一种定向进化平台，该平台能够工程化IgSF域，以增加对同源配体的亲和力和/或引入与非同源配体的结合。使用该科学平台，已经获得了与ICOS的增强结合以及与非同源受体CD28的其他高亲和力结合的ICOSL域。包含这些工程化ICOSL域的Fc融合蛋白可在体外和体内显着减弱T细胞活化，并可抑制小鼠模型中炎症性疾病的发展。我们还提供证据表明，可以将工程化的ICOSL域格式化，以选择性地提供共刺激信号来增强T细胞反应。因此，我们的科学平台提供了一种开发具有选择性生物学影响的治疗性蛋白质候选物的系统，可用于治疗多种人类疾病，包括癌症和自身免疫/炎性疾病。