Author: Chu, Xiaojie; Sun, Zehua; Baek, Du-San; Li, Wei; Mellors, John W.; Shapiro, Steven D.; Dimitrov, Dimiter S.
Title: Human Antibody Domains and Fragments Targeting Neutrophil Elastase as Candidate Therapeutics for Cancer and Inflammation-Related Diseases Cord-id: fuci6zbk Document date: 2021_10_15
ID: fuci6zbk
Snippet: 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
Document: 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.
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