阅读说明：本技术 基于细胞因子的可生物活化药物及其使用方法 (Cytokine-based bioactivatable agents and methods of use thereof ) 是由 李跃升 芮凌云 徐静 于 2019-06-20 设计创作，主要内容包括：本公开内容提供了一种基于细胞因子的可生物活化的药物构建体(“VitoKine”)平台,该平台旨在降低基于全身性机制的毒性,并使蛋白和细胞因子诸如IL-15和IL-2在治疗癌症、自身免疫性疾病、炎性疾病、病毒感染、移植和各种其他紊乱中具有更广泛的治疗用途。本发明的新的VitoKine构建体包含：1)组织或疾病部位靶向部分D1结构域(“D1”)、2)可生物活化部分D2结构域(“D2”)和遮蔽部分D3结构域(“D3”)。重要的是,因为VitoKine构建体的“活性部分”将保持惰性,直到被病变组织中上调的蛋白酶在局部活化,这将限制活性部分与非病变细胞和组织的外周中或细胞表面上的受体或靶的结合,以防止途径的过度活化并减少不期望的“组织外”“中靶”毒性。此外,在蛋白酶活化之前,VitoKine活性部分的惰性将显著降低潜在的抗原沉默或靶沉默,并从而延长体内半衰期且导致改进的生物分布、生物可利用度和治疗功效。(The present disclosure provides a cytokine-based bioactivatable pharmaceutical construct ("vitokinee") platform that aims to reduce systemic mechanism-based toxicity and to make proteins and cytokines such as IL-15 and IL-2 more broadly therapeutically useful in the treatment of cancer, autoimmune diseases, inflammatory diseases, viral infections, transplantation, and various other disorders. The novel vittokinene construct of the invention comprises: 1) a tissue or disease site targeting moiety D1 domain ("D1"), 2) a bioactivatable moiety D2 domain ("D2") and a masking moiety D3 domain ("D3"). Importantly, because the "active portion" of the vitokinene construct will remain inert until locally activated by proteases upregulated in diseased tissue, this will limit the binding of the active portion to receptors or targets in the periphery or on the cell surface of non-diseased cells and tissues to prevent over-activation of the pathway and reduce undesirable "out of tissue" or "in-target" toxicity. Furthermore, the inertness of the vitokinene active moiety prior to protease activation will significantly reduce potential antigen or target silencing and thereby prolong in vivo half-life and lead to improved biodistribution, bioavailability and therapeutic efficacy.)