Late Breaking Abstract - Preclinical study of anti-interleukin-4 alpha single domain antibody with therapeutic potential in asthma by oral inhalation

Traditional monoclonal antibody drugs that targeting IL4/IL 13 pathway had been widely developed. However, dupilumab was the only one that had been approved for asthma by FDA. There were several aspects that would contribute to this episode, for example, system administration caused on-target-off-tissue engagement, predicated ADA production by enduring drug exposure etc. A single domain antibody with a much smaller MW designed to be administrated by inhalation may bypass some of the unfavorable conditions. LQ036 is the first-in-class and very promising preclinical stage single domain antibody with a MW 15kD designed to be given by inhalation that could simultaneously block IL4 and IL13 TH2 signaling in the lung. Given to a high affinity of less than 1 picomolar against human IL4RA, LQ036 is much better than most of approved and clinically developing IL4RA antagonists. LQ036 could also potentially inhibit IL4 or IL13 induced TF-1 cell proliferation with the IC50 of 0.1680 ug/ml and 0.1179 ug/ml respectively. And in HEK-Blue™ IL4/IL-13 cells, LQ036 demonstrated a strong inhibition of STAT6 signaling detected by QUANTI-Blue™, with an IC50 of 0.0107 ug/ml for IL4 and IC50 of 0.02 ug/ml for IL13. The effect of LQ036 on IL4Ra signaling in human whole blood (WB) was determined. FACS results showed that IL036 could robustly inhibit the intracellular pSTAT6 status in CD3 cells. Moreover, LQ036 can tolerate 90℃ treatment for 1 hour and showed great stability. LQ036 has been successfully expressed in yeast strains with 3 g/L titer. All these data suggest that LQ036 is a potent IL4Ra blocker which can administrated by oral inhalation.