Engineered antibody for reducing localized fibrotic scarring

描述（由申请人提供）：拟议研究的主要目标是设计过度瘢痕形成的抑制剂。这些抑制剂的特定目标是胶原原纤维的形成，胶原原纤维是构成纤维化沉积物的主要结构。这种限制纤维化沉积物病理积累的方法的原理已经在体外和体内进行了测试，其高治疗潜力已被证明。由于抗体可以通过与相互作用位点的高亲和力结合来阻断特定的相互作用，因此我们专注于开发基于抗体的关键胶原/胶原相互作用阻断剂。具体来说，我们将设计和测试一种原型小鼠衍生抗体的人类相关变体，该抗体在我们的初步研究中显示出限制原纤维形成的高潜力。对这种基于人类相关抗体的过度疤痕阻滞剂的需求是由我们在人类中应用所提出的治疗方法的长期计划驱动的。推动当前提案的假设是，阻断胶原原纤维形成的单克隆抗体的基因工程变体将具有与其原型对应物相似的抑制潜力。基于与许多临床有效的基于抗体的治疗方法的广泛类比，我们建议我们计划在这里开发的变体将是活跃的，适合临床前和临床试验。此外，在未来，计划抗体变体的基本设计将作为催化剂，通过互补决定区（CDR）嫁接开发其完全人源化的版本。为了验证上述假设，提出了两个具体的目标：(1)基因工程的基于抗体的过度疤痕抑制剂。(2)测试基因工程抑制剂抑制过度瘢痕形成的潜力。我们预计，我们提出的研究结果对预防过度疤痕的总体影响将是很高的。这个概念是基于胶原纤维的过度沉积是所有纤维化疤痕的共同特征这一事实。因此，我们预测，我们提出在特定模型中开发的基于抗体的抑制剂也可以作为在广泛的结缔组织和器官中开发类似纤维化疤痕抑制剂的原型。

DESCRIPTION (provided by applicant): The main goal of the proposed study is to engineer inhibitors of excessive scarring. The specific target for these inhibitors is formation of collagen fibrils, structures that constitute the main mass of fibrotic deposits. The principle for such an approach to limit pathological accumulation of fibrotic deposits has already been tested in vitro and in vivo, and its high therapeutic potential has been demonstrated. Since antibodies can block specific interactions through high-affinity binding to interacting sites, we focus on developing antibody-based blockers of the critical collagen/collagen interaction. Specifically, we will engineer and test human-relevant variants of a prototypic mouse-derived antibody that in our initial studies demonstrated a high potential to limit fibril formation. The need for such human-relevant antibody-based blockers of excessive scarring is driven by our long-term plans to apply proposed therapeutic approach in humans. The hypothesis driving the current proposal is that gene-engineered variants of a monoclonal antibody that blocks collagen fibril formation will have similar inhibitory potential as that of their prototypic counterpart. Based on the broad analogy to a number of clinically effective antibody-based therapeutics, we propose that the variants that we plan to develop here will be active and suitable for preclinical and clinical tests. Moreover, in the future, the basic design of the planned antibody variants will serve as a catalyst to develop their fully humanized versions through complementarily determining regions (CDR) grafting. Two specific aims are proposed to test the above hypothesis: (1) To genetically engineer antibody-based inhibitors of excessive scarring. (2) To test potential of genetically engineered inhibitors of excessive scarring. We expect that the overall impact of the results of our proposed research on the prevention of excessive scarring will be high. This notion is based on the fact that excessive deposition of collagen fibrils is a common characteristic of all fibrotic scars. Thus, we predict that the antibody-based inhibitors we propose to develop here in a specific model could also serve as prototypes for the development of similar inhibitors of fibrotic scars in a wide range of connective tissues and organs. PUBLIC HEALTH RELEVANCE: Formation of fibrotic scars is a serious medical problem that affects all collagen-rich connective tissues. Because one of the hallmarks of fibrosis is excessive accumulation of collagen fibrils, the objective of the proposed study is to develop novel approaches to inhibit fibrosis by blocking the extracellular process of collagen fibril assembly. Since results of our study will deliver antibody-based inhibitors suitable for tests in humans, the relevance of our proposed research for public health is high.