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Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β

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Science Translational Medicine  17 Jan 2018:
Vol. 10, Issue 424, eaan5488
DOI: 10.1126/scitranslmed.aan5488

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Doubling up against cancer

Inhibitors of immune checkpoints are increasingly used for cancer immunotherapy because they decrease cancer-associated immunosuppression and improve patients’ own immune responses against the disease. However, this type of treatment is not always sufficient to ensure protective immunity. To reinforce the effects of immune checkpoint inhibition, Lan et al. designed a bifunctional protein called M7824, which simultaneously targets an immune checkpoint and a different immunosuppressive pathway. This bifunctional protein was more effective at restoring antitumor immunity than interventions targeting one pathway at a time, and it showed promising results in multiple mouse models, alone and in combination with other treatment modalities.

Abstract

Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor–β (TGF-β) receptor II, which functions as a “trap” for all three TGF-β isoforms. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti–PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824’s antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.

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