Novel therapy for arthrofibrosis

关节纤维化的新疗法

基本信息

批准号：
10759562
负责人：
ANDRZEJ FERTALA
金额：
$ 27.58万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-26 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759562
关键词：
Adverse effects Affect Affinity Animal Model Animals Antibodies Antibody Therapy Architecture Binding Biological Assay Blocking Antibodies C-terminal Cells Cicatrix Clinical Collagen Collagen Fibril Color Continuous Passive Motion Data Deposition Development Drug Kinetics Dryness Ensure Extracellular Space Fibrosis Human In Vitro Incidence Individual Injury Joints Laboratories Lead Letters Link Microfibrils Modeling Operative Surgical Procedures Organ Oryctolagus cuniculus Patients Peptides Phase Physical therapy Polymers Resistance Site Splint Device Tertiary Protein Structure Therapeutic Time Tissues Toxic effect Work anterior cruciate ligament reconstruction assay development crosslink effective therapy healing improved in vitro Assay in vivo in vivo evaluation inhibiting antibody joint mobilization joint stiffness knee replacement arthroplasty lead candidate monomer novel therapeutics pre-clinical preclinical study prevent residence response to injury therapeutic target therapeutically effective

项目摘要

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.

关节纤维化的新疗法抽象的关节纤维化 (AF) 是关节手术的常见结果，富含胶原蛋白的纤维化疤痕的形成。对于 AF 来说是绝对必要的，并提出了一种有效的治疗方法。细胞外空间由细胞产生的单个胶原蛋白分子（单体）聚集而成 I 型胶原蛋白分子组装成原纤维的过程取决于它们之间的结合相互作用。一个胶原蛋白分子的最末端，即端肽，以及一个胶原蛋白分子的端肽结合区（TBR）用抗 α2(I)Ct 阻断 I 型胶原蛋白 α2(I)Ct 的 C 末端端肽。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并减少不必要的疤痕，而纤维结合的胶原蛋白 I 分子是稳定的。在体内，不属于原纤维的游离胶原分子（例如，由于 ACA 阻断）不稳定并因此发生降解，抑制胶原纤维形成的程度是 ACA 浓度。因此，减少了过量的富含胶原蛋白的沉积物，并仅阻止了所有产生的一小部分。 I 型胶原蛋白分子仍然可以形成胶原纤维并实现有效的愈合。创伤后关节僵硬的兔子模型显示 ACA 没有不良影响对于潜在的临床应用，我们使 ACA 人性化。在这个第一阶段项目中，我们将通过连接胶原蛋白结合肽来改善输送和组织停留 (CBP) 到我们领先的人源化 ACA。CBP 结构域将抗体靶向正在进行的胶原纤维位点。受影响区域合成 α2(I)Ct 的胶原蛋白逐渐释放将促进长期的形成。治疗，使 ACA 能够抑制正在进行的纤维化。我们将在体外表征该结构，以确保所需的结合和可开发性，并开始在 AF 模型中进行体内评估，第二阶段工作将进一步进行。在其他 AF 动物模型中评估 ACA-CBP 并开始支持 IND 的临床前研究。