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Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11501-11506. Epub 2016 Sep 23.

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

Author information

1
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; California Institute for Biomedical Research, La Jolla, CA 92037.
2
California Institute for Biomedical Research, La Jolla, CA 92037.
3
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
4
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
5
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu fwang@calibr.org.
6
California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu fwang@calibr.org.

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.

KEYWORDS:

Kv1.3; antibody; autoimmune; immunosuppressive; protein engineering

PMID:
27663736
PMCID:
PMC5068325
DOI:
10.1073/pnas.1612803113
[Indexed for MEDLINE]
Free PMC Article

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