Preclinical development of a novel CCR8/CTLA-4 bispecific antibody for cancer treatment by disrupting CTLA-4 signaling on CD8 T cells and specifically depleting tumor-resident Tregs.

IF 4.6 2区 医学 Q2 IMMUNOLOGY
Cuicui Guo, Xiaodong Dai, Yulei Du, Xiumei Xiong, Xun Gui
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Abstract

Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody's capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials.

Abstract Image

新型 CCR8/CTLA-4 双特异性抗体的临床前开发,通过破坏 CD8 T 细胞上的 CTLA-4 信号传导和特异性消耗肿瘤驻留的 Tregs 来治疗癌症。
抗CTLA-4抗体因不良反应频发和疗效有限而面临挑战,这促使人们探索下一代CTLA-4疗法,以平衡调节性T细胞(Tregs)消耗和CD8 T细胞激活。CCR8主要在肿瘤浸润性Tregs上被发现,由于CCR8抗体介导的Tregs耗竭具有抗肿瘤作用,CCR8已成为人们关注的靶点。单细胞 RNA 测序分析表明,CCR8 阳性的 Tregs 构成了一个小的亚群,同时表达 CCR8 和 CTLA-4。因此,我们提出了一种靶向CCR8和CTLA-4的新型双特异性抗体,它有可能在增强T细胞活化的同时选择性地消耗肿瘤内的Tregs。候选分子 2MW4691 采用四价对称形式开发,与 CCR8 的结合亲和力很强,而与 CTLA-4 的结合力相对较弱。这种选择性结合能力使 2MW4691 能够以更高的特异性靶向并清除肿瘤浸润性集落细胞。体外实验验证了该抗体对高水平 CTLA-4 表达的 Tregs 的抗体依赖性细胞毒性(ADCC)能力,但对细胞表面 CTLA-4 水平相对较低的 CD8 T 细胞的抗体依赖性细胞毒性(ADCC)能力却没有验证。此外,2MW4691还能抑制CTLA-4通路,增强T细胞活化。使用 hCCR8 或 hCTLA-4 人源化小鼠模型和 hCCR8/hCTLA-4 双基因敲入小鼠模型进一步证实了 2MW4691 的体内疗效。在猴体内,2MW4691的耐受性良好,表现出预期的药代动力学特征,并且对外周T细胞群的影响极小。充满希望的临床前研究结果支持在临床试验中进一步评估 2MW4691 作为基于 Treg 的下一代疗法。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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