Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant

Rongsheng E. Wang, Ying Wang, Yuhan Zhang, Chase Gabrelow, Yong Zhang, Victor Chi, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Sean Joseph, Kristen Johnson, Arnab K. Chatterjee, Timothy M. Wright, Vân T.B. Nguyen-Tran, John Teijaro, Argyrios N. Theofilopoulos, Peter G. Schultz, Feng Wang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel "stalk-knob" structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both β-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values). This fusion antibody also had significantly improved plasma half-life and serum stability in rodents compared with the parent Vm24 peptide. Finally, this fusion protein showed potent in vivo efficacy in the delayed type hypersensitivity in rats. These results illustrate the utility of antibody CDR fusions as a general and effective strategy to generate long-acting functional antibodies, and may lead to a selective immunosuppressive antibody for the treatment of autoimmune diseases.

Original languageEnglish
Pages (from-to)11501-11506
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number41
DOIs
StatePublished - Oct 11 2016
Externally publishedYes

Keywords

  • Antibody
  • Autoimmune
  • Immunosuppressive
  • Kv1.3
  • Protein engineering

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