Human Antibody Domains and Fragments Targeting Neutrophil Elastase as Candidate Therapeutics for Cancer and Inflammation-Related Diseases

Neutrophil elastase (NE) is a serine protease released during neutrophil maturation. High levels of NE are related to lung tissue damage and poor prognosis in cancer; thus, NE is a potential target for therapeutic immunotherapy for multiple lung diseases and cancers. Here, we isolate and characterize two high-affinity, specific, and noncompetitive anti-NE antibodies Fab 1C10 and V-H 1D1.43 from two large phage-displayed human Fab and V-H libraries. After fusion with human IgG1 Fc, both of them (V-H-Fc 1D1.43 and IgG1 1C10) inhibit NE enzymatic activity with V-H-Fc 1D1.43 showing comparable inhibitory effects to that of the small molecule NE inhibitor SPCK and IgG1 1C10 exhibiting even higher (2.6-fold) activity than SPCK. Their epitopes, as mapped by peptide arrays combined with structural modeling, indicate different mechanisms for blocking NE activity. Both V-H-Fc and IgG1 antibodies block NE uptake by cancer cells and fibroblast differentiation. V-H-Fc 1D1.43 and IgG1 1C10 are promising for the antibody-based immunotherapy of cancer and inflammatory diseases.

Automated summary

The study identified two high-affinity, specific, and noncompetitive anti-NE antibodies from human libraries, which can effectively inhibit NE enzymatic activity and have potential for antibody-based immunotherapy for cancer and inflammatory diseases.