Enhancing Antitumor Activity of Immunotherapy using a Bifunctional Fusion Protein Simultaneously Targeting the Tumor Architecture and cMET

Introduction

The tumor microenvironment (TME) is a crucial contributor to cancer biology. Certain tumors are classified by a desmoplastic phenotype which is characterized by aberrant production of extracellular matrix (ECM) a constituent of the TME. Excessive amounts of ECM around and within the tumor tissue result in poorer perfusion and higher interstitial pressure hampering access and efficacy of the immune system and administered therapeutic drugs.

Targeting the extracellular matrix may therefore present a promising approach to significantly improve on existing treatment regimens for desmoplastic tumors. A primary focus presents in this context pancreatic ductal adenocarcinoma (PDAC) as the vast majority (85%) of tumor specimens is characterized by a desmoplastic phenotype.

Components of the extracellular matrix are expressed throughout the body and thus the concept of systemic application of drugs targeting the ECM may suffer from a narrow therapeutic window. Nonetheless, first signs of clinical efficacy have been reported for therapies combining removal of ECM components and chemotherapy.

Material & method

Our concept relies on combining preferential enzymatic activity at the tumor site and inhibition of tumor growth and invasion. For that purpose, we are using a bifunctional fusion protein simultaneously targeting the TME architecture and a widely expressed oncogene, cMET. This bifunctional fusion protein supposedly results in enrichment of active enzyme at the tumor site and will thereby increase treatment efficiency while retaining a favorable therapeutic window.

Results & discussion

In this study, we successfully designed, generated and biochemically characterized antibody-enzyme fusion constructs. In a series of in vitro experiments, we confirmed cellular binding as well as enzymatic activity. In addition, we evaluated tolerability as well as pharmacokinetic properties in non-tumor bearing mice. Expression of cMET in desmoplastic tumors xenografts was evaluated. Our results confirm in vivo tolerability and favorable pharmacokinetics properties in the selected dose range. We can demonstrate localization to the tumor and in vitro experiments support the anticipated mode of action and efficacy. In vivo pharmacodynamics studies with xenografts and syngeneic mouse models in combination with other treatment regimens are ongoing.

Conclusion

Pancreas cancer is projected to surpass breast, prostate, and colorectal cancers to become the second leading causes of cancer-related death by 2030 in USA. Until today, clinicians face lack of therapeutics options. Modulating the extracellular matrix of desmoplastic tumors could be a promising approach to improve recent cancer immunotherapy such as antibody therapy or CAR-T Cells therapy in solid tumor such as PDAC.