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抑制过度瘢痕形成的药物。这些抑制剂的特定靶点是形成胶原纤维，这是构成纤维沉积的主要结构。这种方法限制纤维沉积病理性堆积的原理已经在体外和体内进行了测试，并证明了其高度的治疗潜力。由于抗体可以通过与相互作用部位的高亲和力结合来阻断特定的相互作用，我们专注于开发基于抗体的关键胶原/胶原相互作用的阻断剂。具体地说，我们将设计和测试一种原型鼠源性抗体的人类相关变体，这种抗体在最初的研究中显示出限制纤维形成的高潜力。对这种与人类相关的抗体为基础的过度瘢痕阻滞剂的需求是由我们将拟议的治疗方法应用于人类的长期计划推动的。目前提出的假设是，阻断胶原纤维形成的单抗的基因工程变体将具有与其原型对应物类似的抑制潜力。基于对一些临床有效的基于抗体的疗法的广泛类比，我们建议我们计划在这里开发的变种将是活跃的，适合临床前和临床试验。此外，在未来，计划中的抗体变体的基本设计将成为通过互补决定区域(CDR)嫁接开发其完全人源化版本的催化剂。提出了两个特定的目标来检验上述假设：(1)对过度瘢痕形成的基于抗体的抑制剂进行基因工程。(2)检测过度瘢痕形成的基因工程抑制剂的潜力。我们预计，我们拟议的关于预防过度疤痕的研究结果的总体影响将很大。这一概念是基于这样一个事实，即胶原纤维过度沉积是所有纤维性瘢痕的共同特征。因此，我们预测，我们建议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的纤维化瘢痕抑制剂的原型。

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.