Discovery of a new class of integrin antibodies for fibrosis

Area of Science:

• Integrin biology and targeted therapeutics
• Pulmonary fibrosis research
• Drug discovery and development

Background:

• Lung fibrosis, or lung scarring, is a severe condition with limited treatment options and a poor prognosis.
• Alpha-v (αv) integrins play a critical role in fibrotic processes.
• Previous research identified MK-0429 as a potent pan-inhibitor of αv integrins.

Purpose of the Study:

• To evaluate the efficacy of MK-0429 in a bleomycin-induced lung injury model of fibrosis.
• To discover and characterize novel integrin inhibitors, specifically monoclonal antibodies, for treating fibrotic lung diseases.
• To assess the potential of these novel inhibitors in modulating fibrotic pathways.

Main Methods:

• Utilized a bleomycin-induced lung injury model to assess fibrosis progression.
• Employed Adimab's yeast display platform for the discovery of monoclonal antibodies targeting integrins.
• Conducted in vitro assays to measure integrin-mediated cell adhesion, latent TGFβ activation, and αSMA expression in patient-derived fibroblasts.

Main Results:

• MK-0429 significantly inhibited fibrosis progression in the preclinical lung injury model.
• Identified potent neutralizing integrin antibodies, including Ab-31, with cross-reactivity and efficacy comparable to MK-0429.
• Both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation; Ab-31 also inhibited TGFβ-induced αSMA expression in IPF fibroblasts.

Conclusions:

• MK-0429 demonstrates therapeutic potential for inhibiting lung fibrosis progression.
• Novel integrin-targeting monoclonal antibodies, such as Ab-31, represent promising new candidates for treating fibrotic lung diseases.
• These findings support the development of advanced integrin therapeutics for unmet needs in fibrotic lung conditions.