PO.CL07.05 · 临床研究
DB-1421是一种经优化的EGFR/MUC1双特异性ADC，在临床前研究中表现出更佳的肿瘤选择性以及令人期待的疗效和安全性
DB-1421, an optimized EGFR/MUC1 bispecific ADC, exhibits improved tumor selectivity, promising efficacy and safety in preclinical studies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：表皮生长因子受体（EGFR）是抗肿瘤治疗中已知且经过验证的靶点。然而，由于EGFR在正常组织中广泛表达，临床上抗EGFR治疗表现出明显的安全性问题，此类不良反应限制了这些产品的疗效。黏蛋白1（MUC1）在包括食管鳞状细胞癌（ESCC）、非小细胞肺癌（NSCLC）、乳腺癌（BC）、结直肠癌（CRC）等多种肿瘤类型中与EGFR高度共表达。同时靶向EGFR和MUC1是一种有前景的治疗策略，可增强肿瘤选择性靶向并避免抗EGFR疗法所观察到的非预期毒性。DB-1421是一种双特异性ADC，由一种全人源EGFR/MUC1双特异性抗体经可切割连接子偶联一种新型DNA拓扑异构酶I抑制剂组成。DB-1421的裸抗体由一个亲和力降低的EGFR结合臂和一个肿瘤相关MUC1（TA-MUC1）特异性结合臂构建。基于这一优化形式，DB-1421在临床前模型中表现出高肿瘤细胞选择性和高耐受性。
方法：通过FACS分析评估DB-1421在肿瘤细胞与正常细胞之间的肿瘤选择性。通过Incucyte检测DB-1421对肿瘤细胞的内化。采用CTG法评估DB-1421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-1421单药的体内疗效。通过体内猴研究评估DB-1421的安全性和PK。
结果：DB-1421的裸抗体表现出显著高于EGFR抗体的肿瘤选择性。内化试验表明，未偶联的DB-1421在共表达EGFR和TA-MUC1的肿瘤细胞中被内吞。DB-1421在体外对多种靶点表达水平不同的肿瘤细胞系表现出强烈的细胞毒性。DB-1421在CDX和PDX模型中以剂量依赖方式抑制体内肿瘤生长。此外，在猴中重复给药最高至80 mg/kg时具有良好的耐受性。
结论：DB-1421是一种EGFR/MUC1双特异性ADC，具有共同轻链双特异性抗体和一种DNA拓扑异构酶I抑制剂。通过对EGFR和MUC1结合臂的合理设计和工程改造，DB-1421表现出更佳的肿瘤选择性、疗效和非常好的安全性。其令人期待的疗效和安全性特征支持DB-1421进一步的临床开发。
查看英文原文 English abstract
Introduction: Epidermal growth factor receptor (EGFR) is a well-known and validated target for anti-tumor therapies. However, anti-EGFR therapy in clinical showed obvious safety concerns because of broad EGFR expression in normal tissue, and such adverse effects limit the efficacy of these products. Mucin 1 (MUC1) is highly co-expressed with EGFR in multiple tumor types including esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC) and others. Dual targeting of both EGFR and MUC1 is a promising therapeutic strategy to enhance tumor-selective targeting and avoid undesired toxicity observed with anti-EGFR therapeutics. DB-1421 is a bispecific ADC comprised of a fully human EGFR/MUC1 bispecific antibody conjugated to a novel DNA topoisomerase I inhibitor via a cleavable linker. The naked antibody of DB-1421 is constructed by an affinity reduced EGFR binding arm and a tumor-associated MUC1 (TA-MUC1) specific binding arm. Based to this optimized format, DB-1421 showed both high tumor cell selectivity and high tolerable in preclinical models.
Methods: The tumor selectivity of DB-1421 between tumor cell and normal cell was evaluated via FACS analysis. The internalization of DB-1421 to tumor cell was tested by Incucyte. CTG assay was used to evaluate the cancer cell killing of DB-1421 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-1421 monotherapy. The safety and PK of DB-1421 were evaluated by in vivo monkey studies.
Results: The naked antibody of DB-1421 showed significant higher tumor selectivity than EGFR antibody. Internalization assays demonstrated that unconjugated DB-1421 was endocytosed in tumor cells co-expressing EGFR and TA-MUC1. DB-1421 exhibited strong cytotoxicity in vitro against several tumor cell lines across a range of target expression. DB-1421 inhibited tumor growth in vivo in CDX and PDX models by dose dependent manner. Additionally, it was well tolerated with repeat dose administration up to 80 mg/kg in monkeys.
Conclusions: DB-1421 is an EGFR/MUC1 bispecific ADC with a common light chain bispecific antibody and a DNA topoisomerase I inhibitor. Through rational design and engineer of EGFR and MUC1 binding arm, DB-1421 showed improved tumor selectivity, efficacy and very good safety. The promising efficacy and safety profile warrants further clinical development of DB-1421.
利益披露 Disclosure
H. Hua, None.