TARGETING TREG CELLS BY TNFR2 ANTIBODY INDUCES TUMOR REGRESSION IN VIVO

Q2 Medicine Antibody Therapeutics Pub Date : 2023-07-01 DOI:10.1093/abt/tbad014.015
Zuoan Yi, C. He, Yueh-Mei Hso, M. Strainic, Yong Yin, W. Zhai
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Abstract

Abstract Background Tumor necrosis factor receptor 2 (TNFR2) is considered an appealing target due to its low-level expression on immune cells, but it could be upregulated on regulatory T cells (Tregs) in the tumor microenvironment which plays key roles in Treg proliferation and function. It has been demonstrated that Tregs with high TNFR2 expression were the most suppressive subsets among all Treg populations in the tumor. While early studies showed that TNFR2 co-stimulates naïve T cells, it has been revealed later that TNFR2 also limits CD8+ T-cell-mediated viral clearance and anti-tumor immunity by inducing rapid contraction of CD8+ T cells. Consistent with these findings, several publications reported that anti-TNFR2 antibody treatment exhibited robust antitumor efficacy. In short, TNFR2 signaling is critical in regulating immune response in different diseases. In the current study, the anti-human TNFR2 antibody SBT-1901 was developed and the anti-tumor activity was evaluated. Materials and methods SBT-1901 was generated through hybridoma and humanization technologies. The binding affinity and specificity were tested by ELISA, FACS, and OCTET. The function of SBT-1901 was tested in TNFR2-Fas overexpressing Ramos cells and in Treg proliferation assay. The in vivo anti-tumor activity and pharmacokinetics of SBT-1901 were evaluated in the human TNFR2 transgenic mouse model (Biocytogen) bearing MC38 tumor. Results SBT-1901 binds to the extracellular domain of human and cynomolgus TNFR2 with the affinity of single digit-nanomolar. It competes with TNFα for binding to TNFR2 receptor and inhibits TNFα-induced TNFR2-Fas overexpressing RAMOS cell death. SBT-1901 also blocks TNFα induced Treg proliferation in human PBMC. In addition, SBT-1901 significantly inhibits MC38 tumor growth in a dose-dependent manner as a monotherapy and enhances anti-tumor efficacy of mPD-1 antibody in a combination study in human TNFR2 transgenic mouse model. SBT-1901 is currently under preclinical development. Conclusions Our studies show that SBT-1901 exhibits a very potent anti-tumor efficacy in vivo as a single agent or the combination. Therefore, it is highly valuable to further develop SBT-1901 for human cancer treatment.
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体内用tnfr2抗体靶向treg细胞诱导肿瘤消退
摘要背景肿瘤坏死因子受体2(TNFR2)由于其在免疫细胞上的低水平表达而被认为是一个有吸引力的靶点,但它可能在肿瘤微环境中的调节性T细胞(Treg)上上调,这在Treg的增殖和功能中起着关键作用。已经证明具有高TNFR2表达的Treg是肿瘤中所有Treg群体中最具抑制性的亚群。虽然早期研究表明TNFR2共同刺激幼稚的T细胞,但后来发现,TNFR2还通过诱导CD8+T细胞的快速收缩来限制CD8+T介导的病毒清除和抗肿瘤免疫。与这些发现一致,一些出版物报道了抗TNFR2抗体治疗显示出强大的抗肿瘤功效。简而言之,TNFR2信号传导在调节不同疾病的免疫反应中至关重要。本研究开发了抗人TNFR2抗体SBT-1901,并对其抗肿瘤活性进行了评价。材料与方法通过杂交瘤和人源化技术制备SBT-1901。通过ELISA、FACS和OCET测试结合亲和力和特异性。SBT-1901的功能在TNFR2-Fas过表达的Ramos细胞和Treg增殖测定中进行了测试。在携带MC38肿瘤的人TNFR2转基因小鼠模型(生物细胞原)中评估SBT-1901的体内抗肿瘤活性和药代动力学。结果SBT-1901与人和食蟹猴TNFR2细胞外结构域结合,亲和力为个位数纳摩尔。它与TNFα竞争与TNFR2受体的结合,并抑制TNFα诱导的TNFR2 Fas过表达RAMOS细胞死亡。SBT-1901还阻断TNFα诱导的人PBMC中Treg的增殖。此外,在人TNFR2转基因小鼠模型的联合研究中,SBT-1901作为单一疗法以剂量依赖性方式显著抑制MC38肿瘤生长,并增强mPD-1抗体的抗肿瘤功效。SBT-1901目前正在进行临床前开发。结论SBT-1901作为单一药物或联合药物在体内具有很强的抗肿瘤作用。因此,进一步开发用于人类癌症治疗的SBT-1901具有很高的价值。
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来源期刊
Antibody Therapeutics
Antibody Therapeutics Medicine-Immunology and Allergy
CiteScore
8.70
自引率
0.00%
发文量
30
审稿时长
8 weeks
期刊最新文献
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