Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells.

Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer.

A novel modality of BAFF-specific inhibitor AMG623 peptibody reduces B-cell number and improves outcomes in murine models of autoimmune disease.

OBJECTIVES: AMG623, also known as A-623, is an antagonist of B-cell activating factor (BAFF). The present study was to evaluate the effects of AMG623 on murine models of autoimmune diseases. METHODS: AMG623 was generated through phage library. Inhibitory activities of AMG623 against human and murine BAFF were measured by biacore binding and BAFF-mediated B-cell proliferation assay. Pharmacological effects of AMG623 were studied in BALB/c mice, collagen-induced arthritis model (CIA) and in the NZBxNZW F1 lupus model. RESULTS: AMG623 binds to both soluble and cell surface BAFF. AMG623 blocks both human murine BAFF binding to the receptors. Treatment of AMG623 resulted in B-cell number reduction, and improvement of arthritis and lupus development in mice. CONCLUSIONS: AMG623 is a novel modality of BAFF antagonist. AMG623 is a potential therapeutic agent for the treatment of SLE, rheumatoid arthritis, and other B-cell-mediated autoimmune diseases.

Pharmacodynamic effects of the murine p75-Fc fusion protein in mice.

Overproduction of inflammatory mediators, such as tumor necrosis factor (TNF), is key to the development and maintenance of inflammatory processes. Etanercept is a soluble TNF receptor fusion protein used in the treatment of various chronic inflammatory diseases, including rheumatoid arthritis and psoriasis. This study investigated the effects of murine p75-Fc, a soluble TNF receptor protein, on TNF-induced IL-6 production in mice. Six groups of mice received either murine p75-Fc (0.15, 0.50, 1.5, 5, and 15 mg/kg) or phosphate-buffered saline. Three days later, mice were injected intravenously with 10 microg of murine TNF and blood samples were taken after 3 hours. Serum IL-6 and TNF were measured by ELISA. Mice treated with 5 and 15 mg/kg murine p75-Fc demonstrated complete inhibition of TNF-induced IL-6 production. Murine p75-Fc (1.5 mg/kg) resulted in a partial but significant reduction of TNF-induced IL-6 production. No TNF was detected in 5 and 15 mg/kg murine p75-Fc-treated mice, except one in the 5 mg/kg dose group. In conclusion, murine p75-Fc completely inhibits TNF-induced IL-6 production in mice.