Ptacin Jerod L, Ma Lina, Caffaro Carolina E, Acuff Nicole V, Germar Kristine, Severy Peter, Qu Yanyan, Vela Jose-Luis, Cai Xinming, San Jose Kristine M, Aerni Hans R, Chen David B, Esche Ean, Ismaili Taylor K, Herman Rob, Pavlova Yelena, Pena Michael J, Nguyen Jasmine, Koriazova Lilia K, Shawver Laura K, Joseph Ingrid B, Mooney Jill, Peakman Mark, Milla Marcos E
Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA.
Sanofi, 350 Water St., Cambridge, MA, 02141, USA.
Commun Med (Lond). 2024 Mar 26;4(1):58. doi: 10.1038/s43856-024-00485-z.
Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index.
A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor βγ (IL-2Rβγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rβγ complex.
Phenotypic screening in mouse identifies SAR444336 (SAR'336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR'336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR'336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation.
SAR'336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.
由于药理学和药代动力学（PK）特性欠佳，天然细胞因子不太适合全身给药治疗。重组人白细胞介素-2（rhIL-2）在治疗自身免疫性（AI）疾病方面显示出前景，但全身半衰期短，且免疫反应相反，导致治疗指数不理想。
使用半合成微生物技术平台设计一种位点特异性聚乙二醇化形式的rhIL-2，其具有增强的PK特性、诱导免疫抑制性调节性CD4 + T细胞（Tregs）的特异性，以及减少对非靶向效应T细胞和NK细胞的刺激。构建了一个rhIL-2分子文库，在IL-2与其同源受体βγ（IL-2Rβγ）信号复合物结合的界面附近安装了单一位点特异性、生物正交化学兼容的非标准氨基酸。生物正交位点特异性聚乙二醇化和功能筛选确定了在IL-2Rβγ复合物处效力减弱但仍保留与IL-αR链结合的变体。
在小鼠中的表型筛选确定了在H16位点聚乙二醇化的rhIL-2即SAR444336（SAR'336；原名THOR-八零九）作为潜在的开发候选物，它能特异性地扩增外周CD4 + Tregs，并上调与其抑制功能相关的标志物，包括FoxP3、ICOS和Helios，但对CD8 + T细胞或NK细胞的扩增作用极小。在非人类灵长类动物中，给予SAR'336也能诱导Tregs的剂量依赖性扩增和抑制性标志物上调，而CD8 + T细胞或NK细胞无明显扩增。在迟发型超敏反应小鼠模型中，给予SAR'336可减轻炎症，有效抑制CD4 +和CD8 + T细胞增殖。
SAR'336是一种特异性Treg激活剂，支持其进一步开发用于治疗AI疾病。
