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Analyses of functions of an anti-PD-L1/TGF?R2 bispecific fusion protein (M7824).

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 TGF? receptor 2 (TGF?R2) molecules serving as a TGF? 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. TGF? is a known immunosuppressive entity. Studies reported here show TGF?1 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.

SUBMITTER: Jochems C

PROVIDER: S-EPMC5650414 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Jochems Caroline C Tritsch Sarah R SR Pellom Samuel Troy ST Su Zhen Z Soon-Shiong Patrick P Wong Hing C HC Gulley James L JL Schlom Jeffrey J

Oncotarget 20170908 43

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 th ...[more]

PMID: 29088859

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Project description:BACKGROUND:Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and urothelial carcinoma. M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGF?) receptor 2, which functions as a TGF? "trap." Advanced urothelial tumors have been shown to express TGF?, which possesses immunosuppressive properties that promote cancer progression and metastasis. The rationale for a combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and immune cell infiltrate and simultaneously reduce or eliminate TGF? from the tumor microenvironment. In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines. METHODS:Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1 (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL, antigen-specific cytotoxic T lymphocytes and natural killer cells. RESULTS:M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-L1. However, compared to anti-PD-L1, M7824 increases (A) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B) TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8+ T-cell-mediated lysis of tumor cells. CONCLUSIONS:These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune-mediated lysis. Compared to anti-PD-L1 or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. These findings show the relevance of the dual blockade of PD-L1 and TGF? in urothelial carcinoma cell lines and thus support the rationale for future clinical studies of M7824 in patients with urothelial cancer.

Project description:Abstract BACKGROUND TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. METHODS In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. RESULTS Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. CONCLUSIONS M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.

Project description:BackgroundSecond-generation programmed cell death-protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, such as bintrafusp alfa (M7824), SHR-1701, and YM101, have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor (TGF-β/TGF-βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors.MethodsMultivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor-infiltrating immune cells.ResultsFor lung cancer patients treated with anti-PD-1/PD-L1 antibodies, poor lymphocyte recovery was associated with a shorter progression-free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8+ T cells in the peripheral blood. Levels of CD8+ T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-L1/TGF-βR fusion protein (SHR-1701). Consistently, SHR-1701 but not anti-PD-1 antibodies, markedly enhanced IFN-γ production and Ki-67 expression in peripheral CD8+ T cells from patients with impaired lymphocyte recovery.ConclusionsLung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.

Dataset Information

Analyses of functions of an anti-PD-L1/TGF?R2 bispecific fusion protein (M7824).

Publications

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

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