Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant
Abstract
There is considerable interest in developing immunosuppressants that can specifically target effector memory T cells which are key to the pathogenesis of many inflammatory disorders. The potassium channel Kv1.3 has been found to play an important role in TEM activation, but not in naive and central memory T cells. It has proven challenging to generate small molecules or antibodies that potently and selectively block Kv1.3 function. We generated antibody fusions by grafting potent Kv1.3 blocking peptides into complementary-determining regions (CDRs) of humanized antibodies, and among those, identified a candidate with high in vitro potency, excellent physiochemical and pharmacologic properties, and in vivo efficacy in a rat model. These novel toxin-antibody fusions have therapeutic potential for a variety of TEM-mediated inflammatory diseases.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- October 2016
- DOI:
- 10.1073/pnas.1612803113
- Bibcode:
- 2016PNAS..11311501W