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Tumor necrosis factor-related apoptosis-inducing ligand can induce apoptosis in many tumor cell lines. This apoptotic effect is mediated by interaction of TRAIL and its receptors, which include Death Receptor 4 (DR4) and Death Receptor 5 (DR5). Some antibodies to DR4 or DR5 do not have anti-tumor ability without cross-linking but exhibit anti-tumor ability in the presence of a cross-linking reagent. Here, we suggest that the tetravalent anti-DR5 antibody can induce apoptosis of cancer cells independent of cross-linking reagent. The single-chain variable fragment of the anti-DR5 antibody, HSA (human serum albumin) – p53 gene, comprising residues 490–513 of HSA and the tetramerization domain of human p53 were assembled into the tetravalent antibody by an overlapping PCR. Results of size exclusion HPLC indicated that the purified protein exhibited a major peak (tetramer) and a minor peak (dimer). MTT assay demonstrated the tetravalent antibody without cross-linking could inhibit survival of Jurkat and EC9706 cells in a dose-dependent manner while the monovalent antibody could not inhibit survival of Jurkat and EC9706 cells. IC50 of Jurkat cell was 3.2 mg/L and IC50 of EC9706 cell was 3.9 mg/L. Furthermore, the Annexin V/PI assay and the Hoechst 33258 staining showed that the tetravalent antibody could efficiently induce apoptosis of Jurkat and EC9706 cells. Therefore, the tetravalent anti-DR5 antibody can act as a direct agonistic antibody, and initiate efficient apoptotic independent of cross-linking reagent. Thus, the tetravalent anti-DR5 antibody will be a new kind of candidate for potential cancer therapeutics.

Indoleamine-2,3-dioxygenase (IDO1) is well-recognized as an important target for immunotherapeutic intervention. Growing interests on this target have been demonstrated by the recent expansion of enthusiasms to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression for cancer treatment. Clinical validation of IDO1 inhibitors for treating various tumors including glioblastoma, melanoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic diseases are currently pursued by pharmaceutical companies and other sponsors. These IDO1 inhibitors include several pioneering clinical compounds such as INCB024360 (epacadostat), GDC-0919, indoximod, and BMS-986205, etc. At the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO), it was reported that patients with squamous cell carcinoma of head and neck were responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. In addition, epacadostat also demonstrated very promising efficacy in combination with PD-1 checkpoint inhibitors for treating various kind of solid tumors. Most recently, at the 32nd SITC annual meeting held in this month, very exciting and encouraging results were just reported by BMS from an early clinical trials for the combo studies of BMS-986205 with Opdivo. Previously we reported a moderately potent IDO1/TDO dual inhibitor DN131 for cancer immunotherapy (AACR2015 Abstract# 4877), herewith we wish to present a much more potent and selective IDO1 inhibitor DN-016 with superior drug-like properties. DN-016 is a novel heterocyclic compound that was discovered through structure-based drug design and medicinal chemistry approaches. In in vitro studies, DN-016 showed very high potency in inhibiting hela IDO1 cell with an IC50 of 0.71 nM. It exhibited good ADME properties and safe hERG parameter with IC50 over 30 μM. Compared to the reference compounds in clinical stages, DN-016 exhibited much superior permeability with excellent efflux ratio (A-B/B-A: 22 × 10-6 cm.s-1 / 24 × 10-6 cm.s-1). In in vivo rat PK studies, DN-016 showed very high oral bioavailability (100% F) when dosing at 10 mg/kg via po. Currently DN-016 is under preclinical evaluation as a single agent and together with a PD-1 inhibitor. In summary, as a new anticancer agent, DN-016 demonstrated a remarkable in vitro potency and selectivity with favorable pharmacokinetic properties. Detailed preclinical evaluation of DN-016 will be presented. Citation Format: Shoujun Chen, Fengtao Liu, Hongli Guo, Shuwen Ren, Yikun Zeng, Wei Yang, Ping Qing, Tao Chen, Feng Zhou, Guocheng Li, Mingliang Sun, Xiaogang Ye, Xingzhong Zhang, Panhu Zhu, Hui Xu, Pei Li, Donghai Li, Zang Jie, Huanping Li, Shuda Zhao, Jiangjing Tan, Heping Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Jianggang Du, Hongye Yang, Wenting Xue, Pei Wang, Lan Guo, Lu Wang, Qun Li, Yuxun Wang, Daxin Gao. Discovery of DN-016: A highly potent, selective and orally available IDO1 inhibitor for treating cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5555.

Drawing from extant retailing and supply chain research, this paper studies the dual channel supply chain decision-making of member channel, and obtains the optimal price strategy, maximum demand and maximum total revenue of the supply chain of network channel and retailing channel under the centralized decision-making and decentralized decision-making respectively. The contributions of this study identify that investing in big data within a certain threshold can improve the channel service level, reduce the channel price and improve the income of the supply chain. Supply chain members improve the channel service level and increase the corresponding channel price. The supply chain can get the most advantages when manufacturers and retailers make centralized decisions. This paper provides a starting point for new retailing academic and practical research in a domain that is deficient in empirical research, provides the theoretical framework to new retailing enterprises and decision-making model for their sustainable competitive advantage.