Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity

Molecular Cancer

Research

Adrien Kissenpfennig¹  Julie A Gormley²  Breena Gray²  Diana Kuehn²  Jenny Lowry²  Angela McClurg²  Nigel Courtenay-Luck²  Declan Doherty²  Ka Lai Leung²  Richard J Buick²  Shane A Olwill²  Jacob Jaworski²  Thomas J Jaquin²  Teresa Byrne²  Christine McAnally²  Claire Ward²  Natalia Gruszka²  Philip Snoddy²  Isabelle Sermadiras²  Hang Fai Kwok²  James A Johnston³  Roberta E Burden⁴  Christopher J Scott⁵ 

[1] Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL, Northern Ireland;Fusion Antibodies Ltd., Springbank Ind. Est. Belfast, BT17 0QL, Northern Ireland;Fusion Antibodies Ltd., Springbank Ind. Est. Belfast, BT17 0QL, Northern Ireland;Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL, Northern Ireland;Fusion Antibodies Ltd., Springbank Ind. Est. Belfast, BT17 0QL, Northern Ireland;Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, BT9 7BL, Northern Ireland;Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, BT9 7BL, Northern Ireland;

关键词: Cathepsin S;    ADCC;    antibody;    protease;    microenvironment;   

DOI  :  10.1186/1476-4598-10-147

 received in 2011-08-16, accepted in 2011-12-14,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundProteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting.ResultsHere we report the cell surface characterization of cathepsin S and the development of a humanized antibody (Fsn0503h) with immune effector function and a stable in vivo half-life of 274 hours. Cathepsin S is expressed on the surface of tumor cells representative of colorectal and pancreatic cancer (23%-79% positive expression). Furthermore the binding of Fsn0503h to surface associated cathepsin S results in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model Fsn0503h elicits a 22% cytotoxic effect.ConclusionsThis data highlights the potential to target cell surface associated enzymes, such as cathepsin S, as therapeutic targets using antibodies capable of elicitingADCC in tumor cells.

【 授权许可】

CC BY   
© Kwok et al; licensee BioMed Central Ltd. 2011