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.
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.
|Fertala, Jolanta; Kostas, James; Hou, Cheryl et al. (2014) Testing the anti-fibrotic potential of the single-chain Fv antibody against the ?2 C-terminal telopeptide of collagen I. Connect Tissue Res 55:115-22|
|Fertala, Jolanta; Steplewski, Andrzej; Kostas, James et al. (2013) Engineering and characterization of the chimeric antibody that targets the C-terminal telopeptide of the ?2 chain of human collagen I: a next step in the quest to reduce localized fibrosis. Connect Tissue Res 54:187-96|
|Barnes, Aileen M; Duncan, Geraldine; Weis, Maryann et al. (2013) Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. Hum Mutat 34:1279-88|
|Steplewski, Andrzej; Fertala, Andrzej (2012) Inhibition of collagen fibril formation. Fibrogenesis Tissue Repair 5 Suppl 1:S29|