PO.CL05.12 · 临床研究
QLS2309，一种靶向 CD70 的三功能 NKp46/CD16a-NK 细胞衔接器，通过缓解对治疗性抗体依赖性细胞毒性的耐受来增强对急性髓系白血病的疗效
QLS2309, a trifunctional NKp46/CD16a-NK cell engager targeting CD70 enhances efficacy against acute myeloid leukemia via mitigating the refraction to therapeutic antibody-dependent cytotoxicity
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摘要 Abstract
中文摘要
急性髓系白血病（AML）是成人中最常见的急性白血病，其特征是骨髓（BM）和外周血中髓系前体细胞的克隆性扩增。尽管治疗有所进展，AML 仍存在未满足的医疗需求，高达 50% 的患者在初始化疗后复发，老年患者预后不良。CD70 是肿瘤坏死因子家族的成员，在超过 80% 的 AML 原始细胞中表达，并对白血病干细胞（LSC）表现出高特异性，而正常造血干细胞（HSC）和免疫细胞表达极少或不表达。这使 CD70 成为极具吸引力的 AML 治疗靶点。然而，约三分之一的 AML 患者表达高亲和力 Fc 受体 CD64，这可能损害治疗性单克隆抗体经 Fc 介导的 ADCC 所产生的肿瘤杀伤疗效。为应对这一挑战，我们生成了一种三功能自然杀伤细胞衔接器（NKCE）QLS2309，它通过结合 CD70 靶向 AML 原始细胞，并通过结合 NK 细胞上的 NKp46/CD16a 来衔接 NK 细胞。QLS2309 是一种人 IgG1 双特异性抗体，具有抗 NKp46 纳米抗体（VHH）和抗 CD70 抗原结合片段（Fab）。与抗 CD70 单克隆抗体不同，无论 CD64 表达如何，QLS2309 均保留了对原代 AML 原始细胞的强效抗肿瘤活性。此外，它仅在 AML 细胞存在时选择性诱导 NK 细胞激活和细胞因子分泌。体内研究显示 QLS2309 具有剂量依赖性的肿瘤生长抑制，与 cusatuzumab（一种 ADCC 增强型单克隆抗体）相比疗效更优。在非人灵长类动物（NHP）中的单次给药药代动力学显示线性暴露，而多次给药毒代动力学显示无明显蓄积。在食蟹猴中的 GLP 毒性研究（QW×4）证实了良好的安全性，QLS2309 在高达 100 mg/kg 时耐受性良好，细胞因子释放极少。总之，QLS2309 兼具卓越疗效、良好的药代动力学和强劲的安全性特征，优于 cusatuzumab。这些数据支持 QLS2309 作为一种有前景的 AML 新型疗法。一项针对 CD70+ 复发/难治性血液系统恶性肿瘤的 1 期剂量递增研究目前正在进行中（NCT07173595）。
查看英文原文 English abstract
Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is characterized by clonal expansion of myeloid precursors in the bone marrow (BM) and peripheral blood. Despite advancements in treatment, unmet medical needs persist in AML, with up to 50% of patients relapsing after initial chemotherapy and older patients facing a poor prognosis. CD70, a member of the tumor necrosis factor family, is expressed in over 80% of AML blasts and exhibits high specificity for leukemia stem cells (LSCs), while normal hematopoietic stem cells (HSCs) and immune cells show minimal or no expression. This makes CD70 an attractive therapeutic target for AML. However, approximately one-third of AML patients express the high-affinity Fc receptor CD64, which may impair the tumor-killing efficacy caused by Fc-mediated ADCC of therapeutical monoclonal antibodies. To address this challenge, we generated a trifunctional natural killer cell engager (NKCE), QLS2309, which targets AML blasts via binding to CD70 and engages NK cells via binding to NKp46/CD16a on NK cells. QLS2309 is a human IgG1 bispecific antibody featuring an anti-NKp46 nanobody (VHH) and an anti-CD70 antigen-binding fragment (Fab). Unlike anti-CD70 monoclonal antibodies, QLS2309 retained potent antitumor activity against primary AML blasts regardless of CD64 expression. Additionally, it selectively induced NK cell activation and cytokine secretion only in the presence of AML cells. In vivo studies demonstrated dose-dependent tumor growth inhibition with QLS2309, showing superior efficacy compared to cusatuzumab (an ADCC-enhanced monoclonal antibody). Single-dose pharmacokinetics in non-human primates (NHPs) revealed linear exposure, while multiple-dose toxicokinetics showed no significant accumulation. A GLP toxicity study in cynomolgus monkeys (QW × 4) confirmed favorable safety, with QLS2309 well-tolerated up to 100 mg/kg and minimal cytokine release. In conclusion, QLS2309 combines excellent efficacy, favorable pharmacokinetics, and a strong safety profile, outperforming cusatuzumab. These data support QLS2309 as a promising novel therapy for AML. A Phase 1 dose-escalation study in CD70+ relapsed/refractory hematologic malignancies is currently ongoing (NCT07173595).
利益披露 Disclosure
L. Yang, None..
R. Li, None..
X. Wu, None..
S. Zhao, None..
H. Ying, None..
W. Tao, None.