Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

2区 · 医学

ArticleOA

作者: Tang, Jianxing ; Tang, Renhong ; Li, Xinxin ; Lu, Zhihong ; Huang, Yue ; Yang, Wenqing ; Yu, Xiaohong ; Gao, Xingyuan ; Zhang, Haoyu ; Wang, Qian ; Xue, Liting ; Li, Feng

AbstractBackgroundSignaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage.MethodsIn this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification.ResultsBD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells.ConclusionsThese data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

2020-09-01·Expert Opinion on Drug Metabolism & Toxicology2区 · 医学

Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management

2区 · 医学

Review

作者: Ping, Li ; Yan, Hao ; Luo, Peihua ; Yang, Xiaochun ; Jiang, Liyu ; Xu, Zhifei ; He, Qiaojun

INTRODUCTIONVascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity.AREAS COVEREDHere, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery.EXPERT OPINIONCardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.

2015-02-09·Current Drug Targets4区 · 医学

Inhibition of the VEGF/VEGFR Pathway Improves Survival in Advanced Kidney Cancer: A Systematic Review and Meta-Analysis

4区 · 医学

Review

作者: Sternberg, Cora N. ; Verzoni, Elena ; Porta, Camillo ; Iacovelli, Roberto ; Escudier, Bernard ; de Braud, Filippo ; Procopio, Giuseppe

Despite the improvement in progression-free survival and response rates, none of the five anti- VEGF/VEGFR agents used for treatment of metastatic renal cell carcinoma (mRCC) reported a significant increase in patients' survival. This analysis aims to investigate their effect on overall survival (OS), performing a meta-analysis of the available studies. MEDLINE/PubMed and the Cochrane Library were searched for randomised phase III trials that compared anti-VEGF/VEGFR agents with controls as upfront treatment for mRCC. The search was restricted to phase III trials, and data extraction was conducted according to the PRISMA statement. Five randomised phase III trials were included for a total of 3,469 patients; among these, 1,801 received anti-VEGF/VEGFR agents and 1,668 were treated with a placebo or interferon-α. In the overall population, the reduction in the risk of death was 13% (HR: 0.87; 95%CI, 0.80 - 0.95; p=0.002). When patients were divided based on use of VEGFR agents or an anti-VEGF monoclonal antibody, the reduction in the risk of death was 13% and 12%, respectively. If only treatmentnaïve patients are considered, we can confirm a significant reduction of 12% (HR=0.88; 95%CI, 0.79 - 0.97; p=0.010) in the risk of death. Our analysis reports a positive improvement of OS with the inhibition of the VEGF/VEGFR pathway in mRCC.

100 项与 anti-VEGF/PDGF antibody (Jiangsu hengrui) 相关的药物交易

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