PO.CL07.05 · 临床研究
DB-1329：一种靶向CDCP1的新型抗体药物偶联物在多种实体瘤中展现出强效的临床前抗肿瘤活性
DB-1329: A novel antibody-drug conjugate targeting CDCP1 demonstrates potent preclinical anti-tumor activity across multiple solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：抗体药物偶联物（ADC）旨在根除癌细胞的同时最大限度减少对健康组织的损伤。可行的肿瘤相关抗原（TAA）靶点的识别与优先排序对ADC开发至关重要。为此，我们采用了一种整合的多组学方法，系统性地发现并优先筛选适合ADC开发的细胞表面靶点。
方法：我们建立了一个用于识别和优先排序肿瘤相关抗原（TAA）靶点的整合框架。在靶点识别和验证之后，开发ADC并评估其抗肿瘤疗效和毒理学。
结果：我们的AI驱动的多组学平台识别出CUB结构域包含蛋白1（CDCP1），这是一种在许多实体瘤（尤其是肺癌、胰腺癌、卵巢癌和结直肠癌）的大部分癌细胞中显著上调、而在正常组织中表达有限的细胞表面蛋白。鉴于其在促进转移和治疗耐药中的作用，CDCP1是一个有吸引力的治疗靶点。我们开发了一种新型抗体药物偶联物DB-1329，它由一种高亲和力和高特异性的全人源抗CDCP1单克隆抗体经蛋白酶可切割连接子偶联一种强效的喜树碱类TOP1抑制剂载荷组成。DB-1329在与CDCP1结合后表现出快速高效的内化，并在CDCP1阳性癌细胞系中展现出强效且特异的细胞毒性。在体内，DB-1329在多种肺癌、胰腺癌和结肠癌的患者来源（PDX）和细胞系来源异种移植（CDX）模型中诱导了深度而持久的肿瘤消退，展现出较基准ADC治疗动物更优的抗肿瘤疗效。DB-1329还表现出良好的药代动力学特征，在毒理学研究中耐受性良好，并展现出可控的安全性特征。
结论：这些令人信服的临床前结果确立了CDCP1-ADC DB-1329作为一种有前景的治疗候选药物，对多种CDCP1阳性实体恶性肿瘤具有强效且靶向的抗肿瘤疗效。我们的研究结果有力地支持CDCP1-ADC的持续开发和临床转化。
查看英文原文 English abstract
Background: Antibody-drug conjugates (ADCs) are designed to eradicate cancer cells while minimizing damage to healthy tissues. The identification and prioritization of viable tumor-associated antigen (TAA) targets are crucial for ADC development. To address this, we employed an integrative multi-omics approach to systematically discover and prioritize cell surface targets suitable for ADC development.
Methods: We established an integrative framework for the identification and prioritization of tumor-associated antigen (TAA) targets. Following target identification and validation, ADCs were developed and evaluated for anti-tumor efficacy and toxicology.
Results: Our AI-driven multi-omics-based platform identified CUB Domain-Containing Protein 1 (CDCP1), as a cell surface protein that is significantly upregulated in a large proportion of cancer cells across many solid tumors (notably lung, pancreatic, ovarian, and colorectal cancers) with limited expression in normal tissues. Given its role in promoting metastasis and therapy resistance, CDCP1 represents an attractive therapeutic target. We developed a novel antibody-drug conjugate, DB-1329, which consists of a fully human anti-CDCP1 monoclonal antibody with high affinity and specificity, conjugated via a protease-cleavable linker to a potent camptothecin-based TOP1 inhibitor payload. DB-1329 exhibited rapid and efficient internalization upon binding to CDCP1 and demonstrated potent and specific cytotoxicity in CDCP1-positive cancer cell lines. In vivo, DB-1329 induced profound and durable tumor regression across multiple patient-derived (PDX) and cell line-derived xenograft (CDX) models of lung, pancreatic, and colon cancers, demonstrating superior antitumor efficacy compared to benchmark ADC-treated animals. DB-1329 also displayed a favorable pharmacokinetic profile, was well-tolerated in toxicology studies, and exhibited a manageable safety profile.
Conclusion: These compelling preclinical results establish CDCP1-ADC DB-1329 as a promising therapeutic candidate, with potent and targeted anti-tumor efficacy against multiple CDCP1-positive solid malignancies. Our findings strongly support the continued development and clinical translation of CDCP1-ADC.
利益披露 Disclosure
H. Yang, None..
H. Hua, None.