PO.CL07.05 · 临床研究
DB-1326是一种新型双载荷TA-MUC1靶向抗体药物偶联物，在临床前肿瘤模型中显示出强效的抗肿瘤疗效
DB-1326, a novel dual-payload TA-MUC1-directed antibody-drug conjugate, shows potent antitumor efficacy in pre-clinical tumor model
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：肿瘤相关黏蛋白-1（TA-MUC1）是MUC1蛋白的一种糖型，其糖基化异常，且由癌细胞高度特异性表达。TA-MUC1在多种人类上皮性癌症中高表达，使其成为癌症治疗的有吸引力靶点。多种靶向TA-MUC1的抗体药物偶联物（ADC）正处于临床和临床前阶段开发中，如DS-3939a、CAT-09-833。然而，其应用因疗效不足而仍受限，凸显了提高单载荷ADC疗效这一未满足的临床需求。本研究呈现了一种新型双载荷TA-MUC1靶向ADC DB-1326的临床前评估，它由一种特异性识别TA-MUC1的全人源IgG1抗体经偶联一种拓扑异构酶I抑制剂和一种新型艾克替耐辛（ecteinascidin）衍生物组成。DB-1326的双重机制使其在MUC1表达水平不同的多种肿瘤类型中产生强效的抗肿瘤效应。
方法：通过ELISA评估DB-1326与TA-MUC1的结合活性。通过FACS分析评估肿瘤细胞与正常细胞之间的肿瘤选择性。通过Incucyte检测DB-1326对肿瘤细胞的内化。采用CTG法评估DB-1326对多种靶点阳性细胞系的癌细胞杀伤作用。建立了细胞系来源异种移植（CDX）模型和患者来源异种移植（PDX）模型以评估DB-1326单药的体内疗效。
结果：DB-1326的裸抗体表现出对TA-MUC1的强结合能力，但不结合未糖基化的MUC1肽，且肿瘤选择性显著高于传统MUC1抗体。内化试验表明，未偶联的DB-1326在表达TA-MUC1的肿瘤细胞中被内吞。DB-1326在体外对多种肿瘤细胞系表现出强烈的细胞毒性。DB-1326表现出剂量依赖的肿瘤生长抑制，并在CDX和PDX模型中于不同靶点表达水平下展现出较单载荷ADC更优的抗肿瘤活性。
结论：DB-1326是一种带有TA-MUC1抗体的新型双载荷ADC。它在临床前研究中表现出高肿瘤细胞选择性和更优的抗肿瘤效应。这些发现支持DB-1326作为肿瘤治疗有前景的先进候选药物的潜力。
查看英文原文 English abstract
Introduction: Tumor-associated mucin-1 (TA-MUC1) is a glycoform of the MUC1 protein that is aberrantly glycosylated and is highly specific expressed by cancer cells. TA-MUC1 is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapies. Several antibody-drug conjugates (ADCs) targeting TA-MUC1 are in development in clinical and preclinical stage, such as DS-3939a, CAT-09-833. However, their application remains limited by inadequate efficacy, highlighting the unmet clinical need for improving the efficacy of single payload ADCs. This study presents the preclinical evaluation of a novel dual-payload TA-MUC1-targeting ADC, DB-1326, composed of a fully human IgG1 antibody specific recognize TA-MUC1 which is conjugated to a topoisomerase I inhibitor and a novel ecteinascidin derivative. The dual mechanism of DB-1326 results in potent anti-tumor effect across different tumor types with a range of MUC1 expression levels.
Methods: Binding activity of DB-1326 to TA-MUC1 was evaluated by ELISA. The tumor selectivity between tumor cell and normal cell was evaluated via FACS analysis. The internalization of DB-1326 to tumor cell was tested by Incucyte. CTG assay was used to evaluate the cancer cell killing of DB-1326 on multiple target positive cell lines. Both cell line-derived xenograft (CDX) models and patient-derived xenograft (PDX) models were established to evaluate the in vivo efficacy of DB-1326 monotherapy.
Results: The naked antibody of DB-1326 showed strong binding ability to TA-MUC1 but not MUC1 peptide without glycosylation and significant higher tumor selectivity than traditional MUC1 antibody. Internalization assays demonstrated that unconjugated DB-1326 was endocytosed in tumor cells expressing TA-MUC1. DB-1326 exhibited strong cytotoxicity in vitro against several tumor cell lines. DB-1326 exhibited dose-dependent tumor growth inhibition and demonstrated superior anti-tumor activity compared to the single payload ADC in both CDX and PDX models across a range of target expression.
Conclusions: DB-1326 is a novel dual-payload ADC with a TA-MUC1 antibody. It displayed high tumor cell selectivity and superior anti-tumor effects in preclinical studies. These findings support the potential of DB-1326 as a promising advanced therapeutic candidate for tumors.
利益披露 Disclosure
L. Yi, None..
H. Hua, None.