Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity

Abstract

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.

Roles of cathepsins in pancreatic cancer

“…56 Among other cathepsins, cathepsin H and cathepsin S were found to be upregulated in pancreatic cancer cell line. 57,58 These were also upregulated in a mouse model of endocrine tumors. 37 Cathepsin H was also expressed in insulinoma cells.…”

Antibody research targeting Cathepsin S for cancer therapy

“…Furthermore the binding of the Cathepsin S antibody to sur-face associated Cathepsin S resulted in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model the Cathepsin S antibody elicited a 22% cytotoxic effect [8]. The demonstration of Cathepsin S targeted ADCC efficacy opens up the possibility of targeting other enzymes such as MMP's and ADAMs in a similar way.…”

“…The expression of Cathepsin S on the surface of pancreatic and colon carcinoma cells has also been revealed recently through how cell surface associated Cathepsin S can be targeted to mediate ADCC by a fully humanized Cathepsin S antibody. Cathepsin S was expressed on the surface of tumor cells representative of colorectal and pancreatic cancer with 23% -79% positive expression [8]. Furthermore the binding of the Cathepsin S antibody to sur-face associated Cathepsin S resulted in natural killer (NK) cell targeted tumor killing.…”

“…The evidence available to date indicates that the use of an antibody that can selectively antagonize Cathepsin S in the tumor milieu may help circumvent toxicity issues that are likely to arise with small molecule inhibitors. Further in vivo stability study on the humanized Cathepsin S inhibitory antibody showed that this antibody possesses a stable half-life of 274 hours, and has the ability to target cell surface associated Cathepsin S, as therapeutic targets which capable of eliciting ADCC in tumor cells [8]. Recent findings were also exemplified the targeting of Cathepsin S in tumors, such as colorectal carcinomas, using antibody-based therapeutic inhibitors to block/inhibit tumor invasion and angiogenesis [9,13].…”

Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival

“…cathepsin S, are maintaining its proteolytic activity at neutral pH [3,4]. In addition to intracellular protein turnover, cysteine cathepsins are responsible for numerous specific physiological and pathological functions.…”