PO.CL05.11 · 临床研究
ALX006：一款具有同类最佳潜力的PD-1/VEGF双特异性抗体，在临床前模型中展现出卓越的抗肿瘤活性和良好的PK特征
ALX006, a PD-1/VEGF bispecific antibody with best-in-class potential demonstrates superior antitumor activity and favorable PK in preclinical models
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摘要 Abstract
中文摘要
背景：PD-1与VEGF在肿瘤微环境中常常共表达。PD-1阻断可逆转肿瘤诱导的免疫抑制，而VEGF抑制则可使肿瘤血管正常化并调节免疫细胞浸润。来自双特异性抗体（如依沃西单抗Ivonescimab）的临床数据，尤其是在晚期非小细胞肺癌中的数据，支持抗PD-1与抗VEGF疗法在增强疗效和降低全身毒性方面具有协同潜力。在此，我们开发了一款新型PD-1/VEGF双特异性抗体ALX006，并对其进行了全面的临床前表征。
方法：采用表面等离子共振（SPR）技术定量测定ALX006与PD-1和VEGF的结合亲和力。使用荧光素酶报告基因实验评估PD-1/PD-L1通路阻断。通过混合淋巴细胞反应实验评估T细胞再激活。在PBMC人源化小鼠的A375细胞来源异种移植（CDX）模型和人PD-1/PD-L1/VEGF转基因小鼠的MC38同基因模型中检测抗肿瘤活性。对生物物理缺陷和可开发性进行了分析。在Sprague-Dawley大鼠和食蟹猴中评估了药代动力学（PK）。
结果：ALX006是一款2+2对称型IgG1（Fc无效）双特异性抗体，能以高亲和力结合两个靶点。在VEGF存在的情况下，ALX006显著增强了PD-1细胞结合以及PD-1/PD-L1信号阻断。ALX006还在混合淋巴细胞反应中以剂量依赖的方式增加了IL-2和IFN-gamma的分泌。此外，ALX006有效抑制了VEGF诱导的内皮细胞增殖。重要的是，在A375 CDX模型中观察到与依沃西单抗（Ivonescimab）及另外两款临床阶段双特异性抗体相比更优的抗肿瘤疗效。在转基因小鼠的MC38同基因肿瘤模型中也观察到一致的活性。ALX006表现出良好的生物物理特性和整体可开发性，且与依沃西单抗相比具有更佳的PK特征。
结论：ALX006是一款具有同类最佳潜力的PD-1/VEGF双特异性抗体，在临床前模型中展现出卓越的抗肿瘤活性和良好的PK特征，支持其作为免疫肿瘤学应用治疗候选药物的潜力。
查看英文原文 English abstract
Background: PD-1 and VEGF are frequently co-expressed in the tumor microenvironment. PD-1 blockade reverses tumor-induced immunosuppression, while VEGF inhibition normalizes tumor vasculature and modulates immune cell infiltration. Clinical data from bispecific antibodies, such as Ivonescimab, particularly in advanced non-small cell lung cancer, support the synergistic potential of anti-PD-1 and anti-VEGF therapies to enhance efficacy and reduce systemic toxicity. Here we developed a novel PD-1/VEGF bispecific antibody ALX006 with thoroughly preclinical characterization.
Methods: Binding affinities of ALX006 to PD-1 and VEGF were quantified by surface plasmon resonance (SPR). PD-1/PD-L1 pathway blockade was assessed using a luciferase reporter assay. T-cell reactivation was evaluated by mixed lymphocyte reaction assays. Antitumor activity was tested in A375 cell-derived xenograft (CDX) model in PBMC humanized mice and MC38 syngeneic model in human PD-1/PD-L1/VEGF transgenic mice. Biophysical liabilities and developability were profiled. Pharmacokinetics (PK) were evaluated in Sprague-Dawley rats and cynomolgus macaques.
Results: ALX006 is a 2+2 symmetric IgG1 (Fc-null) bispecific antibody that binds to both targets with high affinity. In the presence of VEGF, ALX006 significantly enhanced PD-1 cell binding and PD-1/PD-L1 signal blockade. ALX006 also increased IL-2 and IFN-gamma secretion in a dose-dependent manner in mixed lymphocyte reaction. In addition, ALX006 potently suppressed VEGF-induced endothelial cell proliferation. Importantly, superior antitumor efficacy was observed in the A375 CDX model compared with Ivonescimab and two other clinical-stage bispecifics. Consistent activity was also observed in the MC38 syngeneic tumor model in transgenic mice. ALX006 exhibited favorable biophysical properties and overall developability, with an improved PK profile compared with Ivonescimab.
Conclusions: ALX006, a PD-1/VEGF bispecific antibody with best-in-class potential, demonstrates superior antitumor activity and favorable PK in preclinical models, supporting its potential as a therapeutic candidate for immuno-oncology applications.
利益披露 Disclosure
Z. Pei, None..
Y. Zhu, None..
J. Xia, None..
Z. An, None..
B. Duplantis, None..
Y. Wang, None..
Y. Wang, None..
J. Ge, None..
X. Zhang, None..
L. Yang, None..
L. Du, None..
X. He, None..
Y. Li, None.