A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3

Janna Bednenko, Rian Harriman, Lore Mariën, Hai M. Nguyen, Alka Agrawal, Ashot Papoyan, Yelena Bisharyan, Joanna Cardarelli, Donna Cassidy-Hanley, Ted Clark, Darlene Pedersen, Yasmina Abdiche, William Harriman, Bas van der Woning, Hans de Haard, Ellen Collarini, Heike Wulff, Paul Colussi

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein. Using this approach, we targeted human Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for the treatment of a variety of T-cell mediated autoimmune diseases. Recombinant Kv1.3 was used to generate and recover 69 full-length anti-Kv1.3 mAbs from immunized chickens and llamas, of which 10 were able to inhibit Kv1.3 current. Select antibodies were shown to be potent (IC50<10 nM) and specific for Kv1.3 over related Kv1 family members, hERG and hNav1.5.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalmAbs
DOIs
StateAccepted/In press - Mar 29 2018

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Keywords

  • antibody
  • Kv1.3
  • Tetrahymena
  • voltage-gated ion channel

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Bednenko, J., Harriman, R., Mariën, L., Nguyen, H. M., Agrawal, A., Papoyan, A., Bisharyan, Y., Cardarelli, J., Cassidy-Hanley, D., Clark, T., Pedersen, D., Abdiche, Y., Harriman, W., van der Woning, B., de Haard, H., Collarini, E., Wulff, H., & Colussi, P. (Accepted/In press). A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3. mAbs, 1-15. https://doi.org/10.1080/19420862.2018.1445451