D1.365 - ZL-1503: A Bispecific Antibody Targeting Inflammatory and Pruritogenic Pathways with a Prolonged Serum Half-life and Sustained Activity in Non-human Primates

The "itch-scratch-inflammation" cycle drives atopic dermatitis (AD) development and persistence. Targeting IL-13 and IL-31 signaling disrupts this cycle and has been clinically validated. ZL-1503, a bispecific antibody with an extended serum half-life, effectively inhibits IL-13 and IL-31 signaling in vitro and in vivo in rodent studies.

ZL-1503 was evaluated in a pilot study with three non-human primates (NHP) to assess its long-term effects on IL-31-mediated scratching and IL-13-induced pSTAT6. Baseline scratching was established with IL-31 injection prior to ZL-1503 dosing.

An intravenous single dose of ZL-1503 completely inhibited IL-13-mediated pSTAT6 and IL-31-induced scratching for at least 76 days in all three animals. Two out of the three animals exhibited prolonged IL-13-mediated pSTAT6 inhibition for over 118 days, and one out of the 3 animals sustained IL-31-induced scratching inhibition for over 115 days. Pharmacokinetic (PK) analysis of serum samples collected during the study revealed that ZL-1503 exhibited slow clearance, ranging from 1.42 to 2.52 mL/day/kg. ZL-1503 serum exposures correlated very closely with the PD responses. Additionally, in vitro studies showed that binding to one target did not affect ZL-1503’s blocking effects on the other target. These findings demonstrate strong PK/PD relationships of ZL-1503 in blocking IL-13 and IL-31 in the NHP model.

ZL-1503 exhibited sustained inhibition of inflammatory and pruritogenic pathways in NHP, supporting its progression to IND-enabling studies as a potential treatment for moderate-to-severe AD, and other IL-13 and IL-31-driven diseases.