Abstract
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.
Highlights
The use of checkpoint inhibitor monoclonal antibodies (MAbs) has transformed the use of immunotherapy as a major modality in the treatment of several forms of cancer [1,2,3,4,5]
In contrast to the antibody-dependent cellmediated cytotoxicity (ADCC) induced by M7824, M7824mut, a molecule encompassing a mutant anti-PD-L1 that does not bind to PD-L1, did not enhance tumor cell lysis (Figure 1B, hatched bar)
To demonstrate that the enhanced lysis by natural killer (NK) cells observed with the addition of M7824 involves the ADCC mechanism, anti-CD16 MAb was shown to reduce the lysis of three different human tumor cell lines (Figure 1F)
Summary
The use of checkpoint inhibitor monoclonal antibodies (MAbs) has transformed the use of immunotherapy as a major modality in the treatment of several forms of cancer [1,2,3,4,5]. Most of the anti-PD-1/PD-L1 MAbs are either of the IgG4 isotype, www.impactjournals.com/oncotarget or of the IgG1 isotype and engineered to inhibit any potential antibody-dependent cell-mediated cytotoxicity (ADCC) in an effort to eliminate any potential toxicities due to the PD-1 or PD-L1 expression on normal cells. One exception to this is the human IgG1 anti-PD-L1 avelumab (Bavencio®). Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and bladder cancer Adverse events, above those seen with other anti-PD-1/PD-L1 MAbs, have not been observed [8,9,10,11]. An extensive interrogation of 123 immune cell subsets in the periphery of patients receiving up to nine cycles of avelumab has shown [12] no statistically significant changes in any immune subset compared to baseline
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