Engineering Antibody Reactivity for Efficient Derivatization to Generate NaV1.7 Inhibitory GpTx-1 Peptide–Antibody Conjugates

The voltage-gated sodium channelNaV1.7 is a genetically-validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain, however functional NaV1.7 targeting antibodiesare not known. In this report we describe NaV1.7 inhibitory peptide- antibodyconjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified NaV1.7 inhibitory peptide GpTx-1 from tarantulavenom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodiesbifunctionally couples FcRn-based antibodyrecycling attributes to the NaV1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti- 2,4-dinitrophenolmonoclonal antibodyusing polyethylene glycol linkers. The reactivity of thirteen potential cysteine conjugation sites in the antibodyscaff...