B77-24 Preclinical Characterization Of Ibi3038, An Anti-igf-1r And Anti-il6 Bispecific Antibody That Potently Inhibits Lung Fibrosis Development
Y Xiong, Z Zhang, Y Wu, J Gao, F Wang, J Feng, Z Wu, Y Song, G Yuan, S Wang, J Lu, J Hou, L Li, D Wu, Y Liu, Q ZhangAbstract
Rational
IBI3038 is an innovative first-in-class bispecific antibody currently at the Investigational New Drug (IND) stage, designed to address these challenges in fibrosis-related autoimmune diseases,especially for scleroderma related interstitial lung disease (SS-ILD). In a bivalent format, IBI3038 functions by potent co-blockade of IGF-1R and IL-6 (both cis- and trans- signaling). This molecule is rationally designed to inhibit the two-key process, chronic inflammation and fibroblasts stimulation, during fibrosis development.
Method
in vitro binding and blocking activity of IBI3038 was assessed using IL-6 or IL-6/IL-6R complex induced TF-1 and IGF-1 induced cell line proliferation assay. Human lung or dermal fibroblast function assays are used to evaluate the combine effect of dual blockade of IL-6 and IGF-1R. The synergy effect of dual blockade of IGF-1R and IL-6 are evaluated on bleomycin induced fibrosis model on mice using surrogates. Importantly, we evaluated the anti-fibrosis effect of IBI3038 on bleomycin induced lung fibrosis with IPSC induced lung organoids.
Results
IBI3038 binds human IGF-1R and IL-6 at nanomolar levels and effectively inhibits IL-6, IL-6/IL-6R complex or IGF-1 induced cell proliferation, with IC50 values around 1 nMs. The molecule also robustly suppresses HA production and proliferation on human lung or dermal fibroblast upon IGF-1 and IL-6/IL-6R stimulation. Additionally, IBI3038 significantly inhibits bleomycin induced atelectasis and collagen deposits on IPSC induced lung organoids. Importantly, in bleomycin-induced fibrosis mice model, dual blockades of IL-6 and IGF-1R significantly suppress lung fibrosis development and skin thickening, while no effect has been observed on either group of mono-blockade treatment.
Conclusion
an innovative and First-in-class IGF1RxIL-6 bispecific antibody is characterized for its potent and synergistic inhibition on inflammation and fibrosis development. This molecule dramatically suppresses atelectasis and collagen deposits than monoclonal blockade of IL-6. Therefore, IBI3038 can potentially bring new treatment and clinical benefits to lung fibrosis patients of scleroderma.
This abstract is funded by: none