Novel therapy for arthrofibrosis

关节纤维化的新疗法 摘要 关节纤维化(AF)是关节手术的常见结果。富含胶原蛋白的纤维性瘢痕的形成 对于房颤来说是无条件必要的，并建议了一种有效的治疗方法。胶原蛋白纤维形成于 由细胞产生的单个I型胶原分子(单体)聚集而形成的细胞外空间 对伤害的反应。I型胶原分子组装成纤维依赖于 一个胶原分子的末端，即端肽，以及一个胶原分子的端肽结合区(TbR) 互动伙伴。用抗α2(I)Ct封闭I型胶原α2(I)链α2(I)C端的端肽 抗体(称为ACA，抗胶原抗体)抑制单体-单体相互作用，从而抑制 胶原纤维的形成和减少不必要的疤痕。而纤维结合的I型胶原分子是稳定的 在体内，不是纤维一部分的游离胶原分子(例如，由于被ACA堵塞)不稳定 因此会发生退化。抑制胶原纤维形成的程度与ACA浓度有关。 依附的。因此，减少了过量的富含胶原的沉积，只阻止了所有产生的一小部分 I型胶原分子仍然可以形成胶原纤维，并使有效的愈合。我们在体内的研究 创伤后关节僵硬的兔模型没有显示出ACA的不良影响。对于潜在的临床应用， 我们已经使ACA人性化了。 在这个第一阶段的项目中，我们将通过连接胶原结合肽来改善递送和组织滞留。 (CBP)到我们领先的人性化ACA。CBP结构域将针对正在进行的胶原纤维部位的抗体 队形。在合成α2(I)CT的受影响区域逐渐从胶原释放将促进长期 治疗，使ACA能够抑制持续的纤维化。我们将在体外对构建的结构进行表征，以确保 所需的结合力和可发展性，并开始在房颤模型中进行体内评估。第二阶段的工作将进一步 评估ACA-CBP在其他房颤动物模型中的作用，并开始IND-Enabling临床前研究。

Novel therapy for arthrofibrosis Abstract Arthrofibrosis (AF) is a common result of joint surgeries. The formation of collagen-rich fibrotic scars is unconditionally necessary for AF and suggests an effective therapeutic approach. Collagen fibrils are formed in the extracellular space by aggregation of individual collagen I molecules (monomers) produced by cells in response to injury. The assembly of collagen I molecules into fibrils depends on the binding interaction between the very ends, i.e., telopeptides, of one collagen molecule and the telopeptide binding region (TBR) of an interacting partner. Blocking the C-terminal telopeptide of the α2(I) chain of collagen I α2(I)Ct with an anti-α2(I)Ct antibody (referred to as ACA, Anti-Collagen Antibody) inhibits monomer-monomer interaction, thereby inhibiting collagen fibril formation and reducing unwanted scarring. While fibril-incorporated collagen I molecules are stable in vivo, free collagen molecules that are not part of the fibrils (e.g., due to blocking with the ACA) are not stable and therefore undergo degradation. The extent of the inhibition of collagen fibril formation is ACA-concentration dependent. Thus, reducing the excess of collagen-rich deposits and blocking only a fraction of all produced collagen I molecules still allows collagen fibrils to be formed and enables effective healing. Our in vivo studies in a rabbit model of posttraumatic joint stiffness showed no adverse effects of the ACA. For potential clinical use, we have humanized the ACA. During this Phase I project, we will improve delivery and tissue residence by linking a collagen-binding peptide (CBP) to our lead humanized ACA. The CBP domain will target the antibody to sites of ongoing collagen fibril formation. Gradual release from collagen in affected regions that synthesize α2(I)Ct will facilitate long-term treatment, enabling the ACA to inhibit ongoing fibrosis. We will characterize the construct in vitro to ensure the required binding and developability and begin in vivo evaluation in a model of AF. Phase 2 work will further evaluate ACA-CBP in additional animal models of AF and begin IND-enabling preclinical studies.