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A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides

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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.

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Abbreviations

mAb:

Monoclonal antibody

scFv:

Single-chain variable fragment

PT:

Peptide

CDRs:

Complementarity-determining regions

HCDR:

CDR of heavy chain

LCDR:

CDR of light chain

TNFR:

TNF-α receptor

rhTNF-α:

Recombinant human TNF-α

S-Remicade:

scFv form of Remicade

IL:

Interleukin

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Acknowledgments

S.G.& H.C. designed and performed experiments & data analysis, wrote the paper. W.Q. designed the PCR primers, offer suggestions for the experiments. M.L. assisted with experiments. J.F. performed computer modeling. B.S., Y.L. and J.F. contributed to conception, design and final approval of the paper. This work is supported by National 863 Fund (No. 2012AA02A302), National Sciences Fund (No. 31200701) and Hebei Sciences Fund (No. C2013206353) of China.

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    Authors and Affiliations

    1. Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road, Beijing, 100850, People’s Republic of China

      Shusheng Geng, Ming Lv, Yan Li, Jiannan Feng & Beifen Shen

    2. College of Basic Medical Sciences, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China

      Hong Chang

    3. Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, People’s Republic of China

      Hong Chang

    4. Antibody Preparation Research Center of Hebei Province University, Shijiazhuang, People’s Republic of China

      Hong Chang

    5. National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, People’s Republic of China

      Weisong Qin

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    1. Shusheng Geng
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    3. Weisong Qin
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    4. Ming Lv
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    Corresponding authors

    Correspondence to Jiannan Feng or Beifen Shen.

    Additional information

    Shusheng Geng and Hong Chang have contributed equally to this work.

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    Geng, S., Chang, H., Qin, W. et al. A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides. Immunol Res 62, 377–385 (2015). https://doi.org/10.1007/s12026-015-8667-8

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    • DOI: https://doi.org/10.1007/s12026-015-8667-8

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