肿瘤细胞治疗研究
英文原题：Identification of a Fully Human Antibody VH Domain Targeting Anaplastic Lymphoma Kinase (ALK) with Applications in ALK-Positive Solid Tumor Immunotherapy.
间变性淋巴瘤激酶（ALK，CD247）是基于抗体治疗的潜在靶点。
间变性淋巴瘤激酶（ALK，CD247）是基于抗体治疗的潜在靶点。然而，尚无靶向ALK的抗体类药物进入临床试验，因此需要开发具有独特治疗优势的新型抗体。与全长抗体相比，单域抗体（sdAb）具有治疗优势，包括更深的肿瘤穿透性、成本效益高的生产以及从正常组织中快速清除。在本研究中，我们从内部噬菌体库中鉴定出一个人免疫球蛋白重链可变域（VH域）（VH20）。VH20表现出良好的可开发性和高特异性，对约6000种人膜蛋白无脱靶结合。VH20以0.4 nM的EC 50和6.54 nM的KD有效结合ALK的富含甘氨酸区域。基于VH20的双特异性T细胞衔接器（TCE）和CAR-T 细胞（CAR T）均以ALK依赖的方式对表达ALK的肿瘤细胞表现出强效的细胞溶解活性。VH20 CAR T在与ALK阳性细胞孵育后特异性分泌促炎细胞因子，包括IL-2、TNFα和IFNγ。据我们所知，这是首个报道的针对ALK的人单域抗体。我们的体外表征数据表明，VH20可能是一个有前景的靶向ALK的sdAb，在表达ALK的肿瘤中具有潜在应用，包括神经母细胞瘤（NBL）和非小细胞肺癌。
The anaplastic lymphoma kinase (ALK, CD247) is a potential target for antibody-based therapy. However, no antibody-based therapeutics targeting ALK have entered clinical trials, necessitating the development of novel antibodies with unique therapeutic merits. Single-domain antibodies (sdAb) bear therapeutic advantages compared to the full-length antibody including deeper tumor penetration, cost-effective production and fast washout from normal tissues. In this study, we identified a human immunoglobulin heavy chain variable domain (VH domain) (VH20) from an in-house phage library. VH20 exhibits good developability and high specificity with no off-target binding to ~6000 human membrane proteins. VH20 efficiently bound to the glycine-rich region of ALK with an EC 50 of 0.4 nM and a KD of 6.54 nM. Both VH20-based bispecific T cell engager (TCE) and chimeric antigen receptor T cells (CAR Ts) exhibited potent cytolytic activity to ALK-expressing tumor cells in an ALK-dependent manner. VH20 CAR Ts specifically secreted proinflammatory cytokines including IL-2, TNFα and IFNγ after incubation with ALK-positive cells. To our knowledge, this is the first reported human single-domain antibody against ALK. Our in vitro characterization data indicate that VH20 could be a promising ALK-targeting sdAb with potential applications in ALK-expressing tumors, including neuroblastoma (NBL) and non-small cell lung cancer.
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