PO.IM01.15 · 免疫学
AZD6750：一种 CD8α 引导的 IL-2 免疫细胞因子，与 rilvegostomig（一种 PD-1/TIGIT 双特异性抗体）有效联用以增强内源性免疫
AZD6750, a CD8alpha-guided IL-2 immunocytokine effectively combines with rilvegostomig, a PD-1/TIGIT bispecific antibody, to enhance endogenous immunity
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摘要 Abstract
中文摘要
背景：AZD6750 是一种 CD8α 引导的 IL-2 免疫细胞因子，经改造以通过减少与 aldesleukin 相关的毒性来提高 IL-2 的治疗指数，同时保留近期临床 IL-2 突变体策略所损害的疗效。这应能产生一种更安全、更有效的 IL-2，有潜力惠及更多患者，并允许在协同联合中利用 IL-2。抗 PD-1 与 IL-2 疗法的联合目前正在临床中探索，初步的临床和非临床证据均表明该联合可产生改善的应答。因此，一种潜在有效的疗法是 AZD6750 加 rilvegostomig（一种单价、Fc 减弱的、针对 PD-1 和 TIGIT 受体的双特异性 IgG1 抗体）的联合，以增强 IO 活性。
方法：在体外，评估经 AZD6750、rilvegostomig 或两者联合治疗后抗原特异性肿瘤细胞的溶解。在离体，用 AZD6750、rilvegostomig 或两者联合治疗非小细胞肺癌（NSCLC）患者来源的肿瘤样本，并通过 IFN-γ 分泌评估活性。在体内，将表达抗原的肿瘤皮下植入 NSG 小鼠，移植含有富集抗原特异性 CD8+ T 细胞的扩增人 PBMC，并用 AZD6750、rilvegostomig、两者联合或同型对照治疗，监测肿瘤生长。
结果：在体外，与 AZD6750 单药相比，AZD6750 联合 rilvegostomig 改善了抗原特异性肿瘤细胞溶解（EC50 p<0.01）。此外，用 rilvegostomig 加 AZD6750 离体治疗原发性 NSCLC 肿瘤，与 AZD6750（2 倍）或 rilvegostomig（6 倍）单药相比，驱动了 IFN-γ 分泌的增加，突显了该联合增强肿瘤浸润淋巴细胞功能性应答的潜力。在体内，在抗原特异性人源化小鼠肿瘤模型中，与同型 IgG（所有研究）、rilvegostomig（所有研究）或 AZD6750（3 项研究中的 2 项）相比，AZD6750 加 rilvegostomig 导致肿瘤生长率有统计学显著的降低。
结论：这些临床前数据表明，AZD6750 与 rilvegostomig 联合可增强抗肿瘤免疫应答，导致更强的肿瘤细胞杀伤。一项在特定晚期或转移性实体瘤中研究 AZD6750 的 1 期研究目前正在进行中（NCT07115043）。
查看英文原文 English abstract
Background: AZD6750 is a CD8alpha-guided IL-2 immunocytokine engineered to enhance the therapeutic index of IL‑2 by reducing aldesleukin‑associated toxicities, while preserving the efficacy that has been compromised with recent clinical IL‑2 mutein strategies. This should result in a safer, more effective IL-2 with the potential to benefit larger numbers of patients and allow for the utilization of IL-2 in synergistic combinations. Combinations of anti-PD-1 with IL-2 therapies are currently being explored in the clinic with both preliminary clinical and nonclinical evidence that this combination can generate improved responses. As such, a potentially effective therapy is the combination of AZD6750 plus rilvegostomig, a monovalent, Fc-reduced, bispecific IgG1 antibody against PD-1 and TIGIT receptors, to enhance IO activity.
Methods: In vitro , antigen-specific tumor cell cytolysis was evaluated after treatment with AZD6750, rilvegostomig, or a combination of both therapies. Ex vivo , non-small cell lung cancer (NSCLC) patient-derived tumor samples were treated with AZD6750, rilvegostomig, or a combination of both therapies, and the activity evaluated by IFN-gamma secretion. In vivo , NSG mice were implanted subcutaneously with antigen-expressing tumors, engrafted with expanded human PBMCs containing enriched antigen-specific CD8 + T cells, and treated with AZD6750, rilvegostomig, a combination of both therapies, or an isotype control and tumor growth was monitored.
Results: In vitro , AZD6750 in combination with rilvegostomig improved antigen-specific cytolysis of tumor cells compared with AZD6750 monotherapy (EC 50 p<0.01). In addition, ex vivo treatment of primary NSCLC tumors with rilvegostomig plus AZD6750 drove an increase in IFN-gamma secretion compared with either AZD6750 (2-fold) or rilvegostomig (6-fold) monotherapies, highlighting the potential of this combination to augment functional responses in tumor infiltrating lymphocytes. In vivo , AZD6750 plus rilvegostomig resulted in a statistically significant reduction in tumor growth rate when compared to an isotype IgG (all studies), rilvegostomig (all studies), or AZD6750 (in 2 out of 3 studies) in an antigen-specific humanized mouse tumor model.
Conclusions: These preclinical data demonstrate that AZD6750 combined with rilvegostomig can enhance anti-tumor immune responses, leading to greater tumor cell killing. The Phase 1 study investigating AZD6750 in select advanced or metastatic solid tumors is currently ongoing (NCT07115043).
利益披露 Disclosure
M. J. Elder,
AstraZeneca Employment, Stock, Patent.
A. H. Riley,
AstraZeneca Employment, Stock, Patent.
S. Tan,
AstraZeneca Employment, Stock, Patent.
J. Mastio,
AstraZeneca Employment, Stock, Patent.
B. Frederico,
AstraZeneca Employment, Stock, Patent.
F. Garcon,
AstraZeneca Employment, Stock, Patent.
H. Khalique,
AstraZeneca Employment, Stock.
G. Bowyer,
AstraZeneca Employment, Stock, Patent.
P. Chariou,
AstraZeneca Employment, Stock.
N. M. Durham,
AstraZeneca Employment, Stock.
M. Broggi,
AstraZeneca Employment, Stock.
E. Hsiue,
AstraZeneca Employment, Stock.
S. Rodney,
AstraZeneca Employment, Stock.
J. B. Fitzgerald,
AstraZeneca Employment, Stock.
N. Luheshi,
AstraZeneca Employment, Stock.
M. Cobbold,
AstraZeneca Employment, Stock.
S. Cemerski,
AstraZeneca Employment, Stock, Patent.
S. J. Dovedi,
AstraZeneca Employment, Stock, Patent.