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BGB-A445,a novel non-ligand-blocking agonistic anti-OX40 antibody,exhibits superior immune activation and antitumor effects in preclinical models

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Frontiers of Medicine 2023年第6期17卷 1170-1185页

作者： Beibei Jiang Tong Zhang Minjuan Deng Wei Jin Yuan Hong Xiaotong Chen Xin Chen Jing Wang Hongjia Hou Yajuan Gao Wenfeng Gong Xing Wang Haiying Li Xiaosui Zhou Yingcai Feng Bo Zhang Bin Jiang Xueping Lu Lijie Zhang Yang Li Weiwei Song Hanzi Sun Zuobai Wang Xiaomin Song Zhirong Shen Xuesong Liu Kang Li Lai Wang Ye Liu Department of Biology BeiGene(Beijing)Co.Ltd.Beijing 102206China Department of Discovery Biomarkers BeiGene(Beijing)Co.Ltd.Beijing 102206China Department of Clinic Development BeiGene(Beijing)Co.Ltd.Beijing 102206China Department of Biologics BeiGene(Beijing)Co.Ltd.Beijing 102206China

t OX40 is a costimulatory receptor that is expressed primarily on activated CD4+,CD8+,and regulatory T cells.The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion,differentiation,and activation and also promotes dendritic cells to mature to enhance their cytokine production.Therefore,the use of agonistic anti-Ox40 antibodies for cancer immunotherapy has gained great interest.However,most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy.Here,we discovered that BGB-A445,a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation,induced optimal T cell activation without impairing dendritic cell function.In addition,BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity.In the MC38 syngeneic model established in humanized OX40 knock-in mice,BGB-A445 demonstrated robust and dose-dependent antitumor efficacy,whereas the ligand-competitive anti-Ox40 antibody showed antitumor efficacy characterized by a hook effect.Furthermore,BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody.Taken together,our findings show that BGB-A445,which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies,shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

关键词： BGB-A445 OX40 agonistic antibody OX40L noncompetitive

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Immunotherapy with agonistic Anti-CD137:Two Sides of a Coin

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Cellular & Molecular Immunology 2004年第1期1卷 31-36页

作者： YonglianSun JonathanH.Chen YangxinFu TheDepartmentofPathologyandCommitteeinImmunology.TheUniversityofChicago.Chicago.Illinois.USA DeptartmentofPathology.MC3083.5841S.Maryland.J541.TheUniversityofChicago.Chicago.IL60637.USA

CD137 (4-1BB),a member of the TNF receptor superfamily,is an inducible T cell costimulatory receptor primarily expressed on activated CD4^+ and CD8^+ T cells.agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses.Surprisingly,these agonists also showed therapeutic effects in several autoimmune diseases.These findings suggest that in different disease environments,CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes.Therefore,CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders.However,CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically.Cellular & Molecular Immunology.2004;1(1):31-36.

关键词： CD 137 agonistic antibody immunotherapy immune disorders

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