IL-2-armored peptide-major histocompatibility class I bispecific antibodies redirect antiviral effector memory CD8+ T cells to induce potent anti-cancer cytotoxic activity with limited cytokine release.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-08-28 DOI:10.1080/19420862.2024.2395499
John S Schardt, Even Walseng, Kim Le, Chunning Yang, Pooja Shah, Ying Fu, Kausar Alam, Cathryn R Kelton, Yu Gu, Fengying Huang, Jia Lin, Wenhai Liu, Andrew Dippel, Hanzhi Zhang, Kathy Mulgrew, Stacy Pryts, Vijaykumar Chennupati, Hung-Chang Chen, Jessica Denham, Xiaoru Chen, Pallab Pradhan, Yuling Wu, Colin Hardman, Chihao Zhao, Michael Kierny, Yang Song, Simon J Dovedi, Saso Cemerski, Yariv Mazor
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引用次数: 0

Abstract

T cell engagers (TCEs) are becoming an integral class of biological therapeutic owing to their highly potent ability to eradicate cancer cells. Nevertheless, the widespread utility of classical CD3-targeted TCEs has been limited by narrow therapeutic index (TI) linked to systemic CD4+ T cell activation and aberrant cytokine release. One attractive approach to circumvent the systemic activation of pan CD3+ T cells and reduce the risk of cytokine release syndrome is to redirect specific subsets of T cells. A promising strategy is the use of peptide-major histocompatibility class I bispecific antibodies (pMHC-IgGs), which have emerged as an intriguing modality of TCE, based on their ability to selectively redirect highly reactive viral-specific effector memory cytotoxic CD8+ T cells to eliminate cancer cells. However, the relatively low frequency of these effector memory cells in human peripheral blood mononuclear cells (PBMCs) may hamper their redirection as effector cells for clinical applications. To mitigate this potential limitation, we report here the generation of a pMHC-IgG derivative known as guided-pMHC-staging (GPS) carrying a covalent fusion of a monovalent interleukin-2 (IL-2) mutein (H16A, F42A). Using an anti-epidermal growth factor receptor (EGFR) arm as a proof-of-concept, tumor-associated antigen paired with a single-chain HLA-A *02:01/CMVpp65 pMHC fusion moiety, we demonstrate in vitro that the IL-2-armored GPS modality robustly expands CMVpp65-specific CD8+ effector memory T cells and induces potent cytotoxic activity against target cancer cells. Similar to GPS, IL-2-armored GPS molecules induce modulated T cell activation and reduced cytokine release profile compared to an analogous CD3-targeted TCE. In vivo we show that IL-2-armored GPS, but not the corresponding GPS, effectively expands grafted CMVpp65 CD8+ T cells from unstimulated human PBMCs in an NSG mouse model. Lastly, we demonstrate that the IL-2-armored GPS modality exhibits a favorable developability profile and monoclonal antibody-like pharmacokinetic properties in human neonatal Fc receptor transgenic mice. Overall, IL-2-armored GPS represents an attractive approach for treating cancer with the potential for inducing vaccine-like antiviral T cell expansion, immune cell redirection as a TCE, and significantly widened TI due to reduced cytokine release.

IL-2铠装肽-主要组织相容性I类双特异性抗体可重定向抗病毒效应记忆CD8+T细胞,从而在释放有限细胞因子的情况下诱导强大的抗癌细胞毒活性。
T 细胞吞噬剂(TCEs)具有高效的消灭癌细胞的能力,因此正在成为一类不可或缺的生物疗法。然而,经典的 CD3 靶向 TCEs 的广泛应用受到了治疗指数(TI)狭窄的限制,这与全身 CD4+ T 细胞活化和异常细胞因子释放有关。要避免泛 CD3+ T 细胞的全身性激活并降低细胞因子释放综合征的风险,一种有吸引力的方法是重定向特定的 T 细胞亚群。肽-主要组织相容性 I 类双特异性抗体(pMHC-IgGs)是一种很有前景的策略,这种抗体能够选择性地重新定向高活性病毒特异性效应记忆细胞毒性 CD8+ T 细胞以消灭癌细胞,因此已成为一种令人感兴趣的 TCE 模式。然而,这些效应记忆细胞在人类外周血单核细胞(PBMCs)中出现的频率相对较低,这可能会阻碍它们被重新定向为效应细胞用于临床应用。为了缓解这一潜在的局限性,我们在此报告了一种被称为引导-pMHC-分期(GPS)的 pMHC-IgG 衍生物的产生,这种衍生物携带单价白细胞介素-2(IL-2)静音素(H16A,F42A)的共价融合。我们使用抗表皮生长因子受体(EGFR)臂作为概念验证,将肿瘤相关抗原与单链 HLA-A *02:01/CMVpp65 pMHC 融合分子配对,在体外证明了 IL-2armored GPS 模式能强有力地扩增 CMVpp65 特异性 CD8+ 效应记忆 T 细胞,并诱导针对靶癌细胞的强大细胞毒活性。与 GPS 相似,与类似的 CD3 靶向 TCE 相比,IL-2-armored GPS 分子可诱导调节的 T 细胞活化并减少细胞因子的释放。在体内,我们发现在 NSG 小鼠模型中,IL-2-armored GPS(而非相应的 GPS)能有效扩增来自未刺激人 PBMCs 的 CMVpp65 CD8+ T 细胞。最后,我们证明了在人类新生 Fc 受体转基因小鼠体内,IL-2-armored GPS 模式具有良好的可发展性和类似单克隆抗体的药代动力学特性。总之,IL-2-armored GPS 是治疗癌症的一种有吸引力的方法,它有可能诱导类似疫苗的抗病毒 T 细胞扩增、作为 TCE 的免疫细胞重定向以及因细胞因子释放减少而显著扩大的 TI。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
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