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The supernatant was concentrated with Ultra-4 Centrifugal Filters-3K MWCO (MerckMillipore, MA, USA). efficacy than other structural antibodies, greatly enhancing the survival of c-Met-positive tumor-bearing mice compared to single or combined c-Met and PD-1 blockade therapy. Furthermore, diabody-mp, which had a higher c-Met binding affinity, showed better anti-tumoral activity than diabody-pm, which had a lower c-Met binding affinity. In conclusion, bispecific anti-PD-1/c-Met diabody-mp, with high c-Met-associated affinity, inhibited tumor growth by activating T cells, suggesting its therapeutic potential for c-Met-positive solid tumors. KEYWORDS:PD-1, c-Met, bispecific antibodies, diabodies, immunotherapy, solid tumor == Introduction == Immunotherapy is usually a promising treatment that provides new hope for patients with advanced tumor that are not treatable with conventional treatment. Activated T cells induce immune tolerance by upregulating the expression of programmed cell death protein 1 (PD-1), a negative immune checkpoint receptor.1,2Tumor PHA-848125 (Milciclib) cells overexpress programmed cell death ligand 1 (PD-L1), a ligand of PD-1, to facilitate immune evasion.3Although blocking the PD-1/PD-L1 pathway could partially restore exhaustible T cells in preclinical models4and PD-1-based monotherapies have shown remarkable clinical efficacy in some patients with multiple cancers, including melanoma, non-small cell lung cancer, and colorectal cancer, most patients experience poorly sustained clinical benefit and relapse.5The objective response rate for nivolumab is 20% in patients with advanced hepatocellular carcinoma (HCC);6therefore, there is an urgent need to develop strategies that can improve the response rate of PD-1 inhibitors. PD-1 inhibition combined with radiotherapy, chemotherapy, or targeted therapy could achieve enhanced anti-tumor effect; however, the strategy is usually associated with increased risk of side effects. The c-Met tyrosine kinase receptor encoded by the MET proto-oncogene, also known as the hepatocyte growth factor (HGF) receptor, is usually activated in multiple malignancies through MET amplification, mutation, receptor overexpression, and/or a ligand-dependent mechanism.7Dimerization and activation of c-Met receptor after binding with HGF would promote the proliferation, migration, and invasion of tumor cells.79A previous preclinical study reported that abnormal activation of the c-Met signaling pathway is associated with poor clinical outcomes, and hence, c-Met-targeted therapy could be credible for cancer treatment.10Although several c-Met tyrosine kinase inhibitors (TKIs) have been used clinically with positive therapeutic effects,11,12HGF produced in the tumor microenvironment results in innate and acquired resistance to TKIs.13An alternative approach to the blocking of the HGF/c-Met pathway is the development of therapeutic antibodies; however, it is difficult to produce effective antibodies against both HGF-dependent and HGF-independent c-Met signaling. Moreover, bivalent anti-c-Met antibodies may promote receptor dimerization and activation,14and monovalent antibodies may lack potency.15 The combinations of immune checkpoint inhibitors and molecular targeted agents have shown great promise in recent years. Previous studies have reported that c-Met signaling plays immunosuppressive roles, such PHA-848125 (Milciclib) as the impairment of dendritic cell functions and the induction of T cell tolerance, which participate in immune regulation in tumors.16The mutation of MET as a driver gene in tumors could cause markedly decreased clinical efficacy of PD-1 inhibition therapy. Data from several clinical trials showed that the deficiency of PD-L1 in tumors might limit the efficacy of anti-PD-1 monoclonal antibodies.17However, most patients with MET exon 14-altered lung cancers expressing PD-L1 still have a low overall response rate to PD-1 inhibitors and a short median progression-free survival after treatment.18In addition, it has been Rabbit polyclonal to Zyxin proposed that c-Met inhibitors promote tumor immune escape in HCC by stabilizing PD-L1.19Therefore, dual blocking of c-Met and PD-1 as a feasible strategy could release or improve the efficacy of anti-PD-1/PD-L1 monoclonal antibodies (mAbs) for tumor immunotherapy. Several global clinical trials investigating PHA-848125 (Milciclib) the combination of PD-1/PD-L1 and c-Met inhibitors are in progress.20In 2020, the US FDA accepted priority review applications for nivolumab in combination with cabozantinib in advanced renal cell carcinoma.21 Mounting evidence suggests that T cells could play a powerful role in the inhibition of tumor growth in solid tumor patients.22Bispecific antibodies (bsAbs) with the specificity of two antibodies could simultaneously target two different antigens or epitopes, and hence, they could overcome MHC restriction to recruit T cells for the elimination of tumor cells.3,23In 2009, the anti-EpCAM/CD3 catumaxomab, a trifunctional bsAb for the treatment of cancerous ascites, was the first bsAb to receive market approval.24In 2014, blinatumomab was approved by the FDA for the treatment of patients with Philadelphia chromosome-negative precursor B cell acute lymphocytic leukemia.25At present, popular tumor immunotherapies, such as bsAbs and CAR-T, have been approved for the treatment of hematological malignancies, but most of these therapies do not have the desired effect on solid tumors. The design of monoclonal antibodies (mAbs) focuses on target selection,.