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A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.

ABSTRACT: The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line. BsAb inhibited hepatocyte growth factor (HGF)-mediated proliferation, migration, and antiapoptosis, and downregulated HGF-stimulated phosphorylation of c-MET, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2). BsAb can also rescue T cell activation. Furthermore, xenograft analysis revealed that BsAb markedly inhibits the growth of subcutaneously implanted tumors and chronic inflammation. On the basis of these results, we have identified a potential bispecific drug, which can effectively target c-MET and PD-1 for the treatment of human solid cancers.

SUBMITTER: Sun ZJ

PROVIDER: S-EPMC5438713 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.

Sun Zu-Jun ZJ Wu Yi Y Hou Wei-Hua WH Wang Yu-Xiong YX Yuan Qing-Yun QY Wang Hui-Jie HJ Yu Min M

Oncotarget 20170401 17

The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can ind ...[more]

PMID: 28404966

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Project description:Introduction:Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing. Materials and Methods:A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb's effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody. Results:BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab. Conclusion:c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.

Project description:BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.MethodsPatients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.ResultsTotally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic-pharmacodynamic model, the preliminary exposure-response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.ConclusionsKN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.Trial registration numbersNCT03733951 .

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A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.

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A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer.

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