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 Citations (Scopus)

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

Fingerprint

Voltage-Gated Potassium Channels
Ion Channels
Monoclonal Antibodies
Tetrahymena thermophila
New World Camelids
Antibodies
Drug Discovery
Autoimmune Diseases
Inhibitory Concentration 50
Chickens
Immunization
Proteins
T-Lymphocytes
Therapeutics

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., ... 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

A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3. / Bednenko, Janna; Harriman, Rian; Mariën, Lore; Nguyen, Hai M.; Agrawal, Alka; Papoyan, Ashot; Bisharyan, Yelena; Cardarelli, Joanna; Cassidy-Hanley, Donna; Clark, Ted; Pedersen, Darlene; Abdiche, Yasmina; Harriman, William; van der Woning, Bas; de Haard, Hans; Collarini, Ellen; Wulff, Heike; Colussi, Paul.

In: mAbs, 29.03.2018, p. 1-15.

Research output: Contribution to journalArticle

Bednenko, J, Harriman, R, Mariën, L, Nguyen, HM, 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 2018, 'A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3', mAbs, pp. 1-15. https://doi.org/10.1080/19420862.2018.1445451
Bednenko, Janna ; Harriman, Rian ; Mariën, Lore ; Nguyen, Hai M. ; Agrawal, Alka ; Papoyan, Ashot ; Bisharyan, Yelena ; Cardarelli, Joanna ; Cassidy-Hanley, Donna ; Clark, Ted ; Pedersen, Darlene ; Abdiche, Yasmina ; Harriman, William ; van der Woning, Bas ; de Haard, Hans ; Collarini, Ellen ; Wulff, Heike ; Colussi, Paul. / A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3. In: mAbs. 2018 ; pp. 1-15.
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