Bispecific Targeting of CHI3L1 and PD-1/PD-L1 Axis as a Novel Therapeutic Strategy for Idiopathic Pulmonary Fibrosis
Abstract
The overall hypothesis of current project is that chitinase 3-like protein 1 (CHI3L1) plays a key role in the development of fibrosis-prone microenvironment consisting of profibrotic macrophages and PD-L1(+) invasive fibroblasts. To test this hypothesis, we established aims that characterize the specific role and effect of CHI3L1 in the macrophages and fibroblast differentiation and determine the therapeutic efficacy of anti-CHI3L1 (FRG) and anti-PD-1 antibodies alone and bi-specific targeting. Using animal model of bleomycin-stimulated pulmonary fibrosis, we have identified that transgenic expression of CHI3L1 increased the number of profibrotic macrophages and PD-L1(+) invasive fibroblasts in the lung. In in vitro assays using bone marrow and human monocyte-derived macrophages revealed that CHI3L1 is required and sufficient to optimal profibrotic macrophage differentiation and invasive fibroblasts development. Importantly, application of bi-specific anti-CHI3L1-PD-1 antibodies showed most prominent anti-fibrotic effects on bleomycin-stimulated lung fibrosis along with decreased number of profibrotic macrophages and invasive fibroblasts than the mice treated with anti-CHI3L1 or anti-PD-1 antibodies alone. Current findings strongly support our original hypothesis that bispecific targeting of CHI3L1 and PD-1/PD-L1 axis effectively inhibits lung fibrosis via regulation of profibrotic macrophage activation and invasive fibroblasts development in the lung, at least in part.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2023
- Accession Number
- AD1196265
Entities
People
- Chun Lee
Organizations
- Brown University