Medikine, Inc., Menlo Park, California, United States of America.
Department of Biomedical Engineering, and Center for Quantitative Bioinformatics and Quantitative Biology, Colleges of Engineering and Medicine, University of Illinois Chicago, IL, United States of America.
PLoS One. 2023 Oct 24;18(10):e0286834. doi: 10.1371/journal.pone.0286834. eCollection 2023.
Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia, and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm) which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur. The properties we report here implicate MDK-703 as a candidate for clinical evaluation in oncology, anti-viral and other infectious disease, vaccine enhancement, and treatment of lymphopenia.
白细胞介素（IL）-7 广泛作用于 T 细胞群，经改良的版本已在多种治疗应用中进行了临床评估，包括癌症、淋巴细胞减少症和传染病；并且被发现具有相对良好的耐受性和生物活性。在这里，我们描述了新型的 IL-7R 激动剂，它们在结构上与 IL-7 无关，与 IL-7 不同的受体亚基结合，但紧密模拟 IL-7 的生物学特性。小分子大小、低结构复杂性和药理学活性肽 MDK1472 的天然氨基酸组成允许其易于整合到蛋白质结构中，例如 IgG2-Fc 融合 MDK-703。该分子具有比天然 IL-7 或其衍生物更适合治疗应用的特性。我们比较了这些化合物与 IL-7 在免疫细胞选择性、诱导 IL-7R 信号转导、受体介导的内化、增殖以及体外在人源和非人灵长类（NHP）外周血细胞中产生免疫细胞表型方面的特性；并发现它们在生物学活性上与 IL-7 相似。在食蟹猴中，MDK-703 的半衰期为 46 小时，可产生类似于 IL-7 治疗的持续 T 细胞扩增。在人免疫系统的 huCD34+-移植 NSG 小鼠模型中，MDK-703 诱导的免疫细胞表型与由 IL-7 衍生的化合物产生的表型非常相似；包括记忆 T 细胞的显著扩增，特别是记忆 T 细胞（Tscm）的群体，这可能对 IL-7 治疗报告的抗肿瘤活性很重要。据报道，IL-7 和改良变体的临床给药会诱导抗药物抗体（ADA），包括 IL-7 中和抗体。这里报道的新型肽激动剂在预测免疫原性方面得分非常低，并且由于该肽与 IL-7 缺乏序列相似性，因此不会发生内源性细胞因子的问题免疫中和。我们报告的这些特性表明 MDK-703 是在肿瘤学、抗病毒和其他传染病、疫苗增强以及淋巴细胞减少症治疗中进行临床评估的候选药物。
