Abstract
Matriptase is a transmembrane serine protease, synthesized as an inactive single-chain zymogen on the endoplasmic reticulum and transported to the plasma membrane. Matriptase is activated in different epithelial and some B-cell malignancies and changes its conformation and activity is inhibited mainly by its endogenous inhibitor HAI-1. Activated matriptase plays a key role in tumor initiation as well as tumor progression, including invasiveness, and metastasis. To target the anti-mitotic toxin (monomethyl auristatin-E) to activated matriptase, a novel antibody to activated matriptase was conjugated with this toxin via a valine-citrulline-PABA linker. In a previous study, this antibody-toxin conjugate was found to be effective against triple negative breast cancer cell lines and xenografts, alone, or in combination with cisplatin (1). In this study, we examined the anti-tumor effect of the antibody toxin conjugate (ADC) against activated matriptase positive mantle cell lymphoma cell lines (JeKo-1, Maver, Mino, and Z138). This ADC was cytotoxic to these cell lines with IC50s between 5 and 14 μg/mL. The ADC also showed a dose dependent anti-tumor effect on the JeKo-1 xenograft in mice without toxicity.
Highlights
Mantle Cell Lymphoma (MCL), represents 6- percent of all lymphoma cases, and currently the survival time is 4–5 years, shorter compared to other hematologic malignancies [2,3,4]
In this study we show that a novel anti-matriptase antibody toxin (Monomethyl auristatin-E, monomethyl auristatin-E (MMAE)) conjugate potently inhibited growth of mantle cell lymphoma cell lines (JeKo-1, Maver, Mino and Z138) and caused significant growth inhibition of the JeKo-1 xenograft in vivo
Activated matriptase expression was evaluated in different MCL cell lines (JeKo-1, Mino, Maver, and Z138) by Western blotting using the M-69 antibody that recognizes activated matriptase alone or in complex with hepatocyte growth factor activator inhibitor (HAI)-1
Summary
Mantle Cell Lymphoma (MCL), represents 6- percent of all lymphoma cases, and currently the survival time is 4–5 years, shorter compared to other hematologic malignancies [2,3,4]. Matriptase, a glycoprotein (80–90 kDa), is a member of type II transmembrane serine proteases. It is synthesized as a latent single-chain structure and with many regulatory mechanisms and functions [7, 8], and is activated through an auto-activation step resulting in a disulfide-linked-twochain structure. Matriptase is rapidly inactivated by its endogenous inhibitor HAI-1. This activated matriptase-HAI-1 complex remains present in most epithelial carcinomas and some B-cell malignancies [9,10,11]. While matriptase is present in a latent form on epithelial cells and B-cells, activated matriptase expression is mainly restricted to the membranes of epithelial tumors, and some B-cell malignancies, in particular MCL [10,11,12]
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