A Novel Antigen Design Strategy to Isolate Single‐Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models
Marzia Martina, Umberto Banderali, Álvaro Yogi, Mehdi Arbabi Ghahroudi, Hong Liu, Traian Sulea, Yves Durocher, Greg Hussack, Henk van Faassen, Balu Chakravarty, Qing Yan Liu, Umar Iqbal, Binbing Ling, Étienne Lessard, Joey Sheff, Anna Robotham, Debbie Callaghan, María Moreno, Tanya Comas, Dao Ly, Danica Stanimirovic
Abstract
Abstract Genetic studies have identified the voltage‐gated sodium channel 1.7 ( Na v 1.7 ) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single‐domain antibodies ( V H Hs ) are developed against the human Na v 1.7 ( hNa v 1.7 ) using a novel antigen presentation strategy. A 70 amino‐acid peptide from the hNa v 1.7 protein is identified as a target antigen. A recombinant version of this peptide is grafted into the complementarity determining region 3 ( CDR3 ) loop of an inert V H H in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one V H H able to i) bind hNa v 1.7, ii) slow the deactivation of hNa v 1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This V H H exhibits the potential to be developed as a therapeutic capable of suppressing pain. This novel antigen presentation strategy can be applied to develop biologics against other difficult targets such as ion channels, transporters and GPCRs.