Improvement in affinity and thermostability of a fully human antibody against interleukin-17A by yeast-display technology and CDR grafting

Publication date: Available online 22 February 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Wei Sun, Zhaona Yang, Heng Lin, Ming Liu, Chenxi Zhao, Xueying Hou, Zhuowei Hu, Bing CuiAbstractMonoclonal antibodies (mAbs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-hIL-17A antibody. From a large naïve phage-displayed library, we isolated the anti-IL-17A mAb 7H9 that can neutralize the effects of recombinant human IL-17A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. In vitro affinity optimization was then used to generate 8D3 by using yeast-displayed random mutagenesis libraries. This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions (CDRs) of 8D3 were further grafted onto the stable framework of the huFv 4D5 to improve thermostability. The resulting hybrid antibody 9NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma c...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research