Engineered antibody for reducing localized fibrotic scarring

描述（由申请方提供）：拟定研究的主要目标是设计过度瘢痕形成的抑制剂。这些抑制剂的具体目标是形成胶原纤维，构成纤维化沉积物的主要质量的结构。这种方法限制纤维化沉积物的病理性积累的原理已经在体外和体内进行了测试，并且已经证明了其高治疗潜力。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异性相互作用，因此我们专注于开发关键胶原/胶原相互作用的基于抗体的阻断剂。具体来说，我们将设计和测试原型小鼠衍生抗体的人类相关变体，这些变体在我们的初步研究中表现出限制原纤维形成的高潜力。对这种过度瘢痕形成的人类相关的基于抗体的阻断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。驱动当前提议的假设是，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。基于对许多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体将是活性的，并且适合于临床前和临床测试。此外，在未来，计划的抗体变体的基本设计将作为催化剂，通过互补决定区（CDR）移植开发其完全人源化的版本。提出了两个具体的目标来测试上述假设：（1）基因工程抗体为基础的过度疤痕抑制剂。(2)为了测试基因工程抑制过度疤痕的潜力。 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。这一概念是基于胶原纤维的过度沉积是所有纤维化瘢痕的共同特征的事实。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.