Research Papers:

Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824)

Caroline Jochems, Sarah R. Tritsch, Ping Wang _, Zhen Su, Patrick Soon-Shiong, Hing C. Wong, James L. Gulley and Jeffrey Schlom _

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Oncotarget. 2017; 8:75217-75231. https://doi.org/10.18632/oncotarget.20680

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Caroline Jochems1, Sarah R. Tritsch1, Samuel Troy Pellom1, Zhen Su2, Patrick Soon-Shiong3, Hing C. Wong4, James L. Gulley5 and Jeffrey Schlom1

1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2EMD Serono, Rockland, MA, USA

3NantWorks, Culver City, CA, USA

4Altor BioScience Corporation, Miramar, FL, USA

5Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Jeffrey Schlom, email: js141c@nih.gov

Keywords: anti-PD-L1/TGFβR2, M7824, checkpoint inhibitors, immunotherapy, anti-PD-L1

Received: June 27, 2017     Accepted: August 15, 2017     Published: September 08, 2017


M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein consisting of a fully human IgG1 anti-PD-L1 monoclonal antibody (with structural similarities to avelumab) linked to the extracellular domain of two TGFβ receptor 2 (TGFβR2) molecules serving as a TGFβ Trap. Avelumab has demonstrated clinical activity in a range of human cancers and has been approved by the Food and Drug Administration for the therapy of Merkel cell and bladder carcinomas. Preclinical studies have shown this anti-PD-L1 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). In the studies reported here, it is shown that M7824 is also capable of mediating ADCC of a wide range of human carcinoma cells in vitro, employing natural killer (NK) cells as effectors, albeit not as potent as anti-PD-L1 employing some tumor cells as targets. The addition of the IL-15 superagonist fusion protein complex ALT-803 enhanced the ADCC capacity of both anti-PD-L1 and M7824, and to levels that both agents now demonstrated similar levels of ADCC of tumor cells. TGFβ is a known immunosuppressive entity. Studies reported here show TGFβ1 induced reduction of several NK activation markers as well as reduction of endogenous NK lytic activity and NK-mediated ADCC of tumor cells. These phenomena could be reduced or mitigated, however, by M7824, but not by anti-PD-L1. M7824, but not anti-PD-L1, was also shown to reduce the immunosuppressive activity of regulatory T cells on human CD4+ T-cell proliferation. These studies thus demonstrate the dual functionalities of M7824 and provide the rationale for its further clinical development.

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