An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer

Martina S Lutz; Kevin Wang; Gundram Jung; Helmut R Salih; Ilona Hagelstein

doi:10.3389/fimmu.2024.1343929

An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer

Front Immunol. 2024 Jan 22:15:1343929. doi: 10.3389/fimmu.2024.1343929. eCollection 2024.

Authors

Martina S Lutz^{1

2}, Kevin Wang¹, Gundram Jung^{2

3}, Helmut R Salih^{1

2}, Ilona Hagelstein^{1

2}

Affiliations

¹ Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany.
² Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.
³ Department of Immunology, Eberhard Karls Universität Tübingen, Tuebingen, Germany.

Abstract

Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ability to stimulate antibody-dependent cellular cytotoxicity (ADCC), which plays a crucial role in their therapeutic efficacy. As a result, significant effort has been focused on improving this critical function by engineering mAbs with Fc regions that have increased affinity for the Fc receptor CD16 expressed on natural killer (NK) cells, the major cell population that mediates ADCC in humans. Here we report on the preclinical characterization of a mAb directed to the target antigen B7-H3 (CD276) containing an Fc part with the amino acid substitutions S239D/I332E to increase affinity for CD16 (B7-H3-SDIE) for the treatment of pancreatic cancer. B7-H3 (CD276) is highly expressed in many tumor entities, whereas expression on healthy tissues is more limited. Our findings confirm high expression of B7-H3 on pancreatic cancer cells. Furthermore, our study shows that B7-H3-SDIE effectively activates NK cells against pancreatic cancer cells in an antigen-dependent manner, as demonstrated by the analysis of NK cell activation, degranulation and cytokine release. The activation of NK cells resulted in significant tumor cell lysis in both short-term and long-term cytotoxicity assays. In conclusion, B7-H3-SDIE constitutes a promising agent for the treatment of pancreatic cancer.

Keywords: B7-H3; NK cells; immunotherapy; pancreatic cancer; therapeutic antibody.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal
Antibody-Dependent Cell Cytotoxicity
B7 Antigens / metabolism
Humans
Immunotherapy* / methods
Killer Cells, Natural
Pancreatic Neoplasms* / metabolism

Substances

Antibodies, Monoclonal
CD276 protein, human
B7 Antigens

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This project was supported by the Deutsche Krebshilfe (70114180, 70113999), the Wilhelm Sander-Stiftung (2017.100.3), and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy -EXC 2180 -10084-1_1. We acknowledge support from the Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of University of Tübingen.