title: A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides.
abstract: The introduction of TNF inhibitors has revolutionized the treatment of some chronic inflammatory diseases, e.g., rheumatoid arthritis and Crohn's disease. However, immunogenicity is one of the important mechanisms behind treatment failure, and generally, switching to another TNF inhibitor will be the first choice for patients and doctors, which results in unmet need for novel anti-TNF agents. Small antibody molecules with less number of epitope may be valuable in less immunogenicity. In this study, with the help of computer-guided molecular design, single-chain variable fragment (scFv) TSA2 was designed using consensus frameworks of human antibody variable region as scaffold to display anti-TNF antagonistic peptides. TSA2 showed evidently improved bioactivity over TSA1 (anti-TNF scFv explored before) and almost similar activity as S-Remicade (the scFv form of Remicade, anti-TNF antibody approved by FDA), especially in inhibiting TNF-induced cytotoxicity and NF-κB activation. Human antibody consensus frameworks with less immunogenicity have been used in the designing of VH domain antibody, scFv TSA1 and TSA2. A serial of TNF-related works convinced us that the novel design strategy was feasible and could be used to design inhibitors targeting more other molecules than TNF-α. More importantly, these designed inhibitors derived from computer modeling may form a virtual antibody library whose size depends on the number of candidate antagonistic peptides. It will be molecular-targeted virtual antibody library because of the specific antagonistic peptides and the potential antibodies could be determined by virtual screening and then confirmed by biologic experiments.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road, Beijing, 100850, People's Republic of China.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Geng
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Weisong
authors.initials: W
authors.lastname: Qin
authors.forename: Ming
authors.initials: M
authors.lastname: Lv
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000628:therapy; D002460:Cell Line; D003424:Crohn Disease / Q000628:therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D000069285:Infliximab / Q000276:immunology; D007739:L Cells; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D016328:NF-kappa B; D057127:Single-Chain Antibodies; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab