PO.ET01.03 · 实验与分子治疗
一种新型 CDH17 靶向放射性配体疗法可克服对微管抑制剂和拓扑异构酶 I 抑制剂 ADC 的耐药，并在胃肠道肿瘤中实现强效疗效
A novel CDH17-targeted radioligand therapy overcomes resistance to microtubule and topoisomerase I inhibitor ADCs and achieves potent efficacy in GI-tract tumors
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摘要 Abstract
中文摘要
CDH17（钙黏蛋白 17）是一种单次跨膜蛋白，在结肠、胃和胰腺的腺癌以及部分卵巢癌和肺癌中高度且广泛表达。在此，我们描述了一种 CDH17 靶向抗体药物偶联物和一种放射性配体偶联物的开发、它们在大量胃肠道 PDX 肿瘤中的体内疗效，以及在非人灵长类动物中的药代动力学和安全性特征。制备了一种针对 CDH17 的全人源单克隆抗体，并以 8 的 DAR 与 Deruxtecan 偶联（CO-ADC-010）。CO-ADC-010 表现出快速内化和强效的 CDH17 依赖性细胞毒性，同时具有良好的血浆稳定性、药代动力学和可制造性。在一项大规模体内疗效研究中，CO-ADC-010 在 80% 的受试 PDX 模型中实现了 >90% 的肿瘤生长抑制（TGI）。这一表现显著优于一种携带 MMAE、DAR 为 4 的对照 ADC，后者仅在 33% 的模型中显示出类似的 TGI，提示基于拓扑异构酶的载荷更适合用于 CDH17 靶向递送。在非人灵长类动物中，一项以 10、30 和 45 mg/kg 单次给药的 CO-ADC-010 探索性毒理学研究显示，在任何剂量下均未出现靶点相关毒性，所有临床和病理学发现均判定为轻度且可逆。尽管对 CO-ADC-010 有强烈的初始应答，但许多肿瘤在长期治疗中因获得性载荷耐药而复发，而 CDH17 表达并未改变。为克服对 ADC 治疗的原发和获得性耐药的局限，我们还使用同一抗体骨架开发了一种 CDH17 靶向放射性配体疗法（RLT）。我们证明，CDH17 靶向 RLT 在整个 PDX 组中显示出广泛而持久的应答，包括在对基于 Deruxtecan 的 ADC 耐药的模型中仍具完全活性，表明 RLT 在这些适应症中在克服耐药和实现持久应答方面具有优越性。这些数据共同支持将 CDH17 靶向 RLT 作为一种针对 CDH17 阳性胃肠道恶性肿瘤的有前景的治疗方法。
查看英文原文 English abstract
CDH17 (Cadherin 17) is a single-pass transmembrane protein that is highly and widely expressed in adenocarcinomas of the colon, stomach, and pancreas, as well as in subsets of ovarian and lung cancers. Here, we describe the development of a CDH17-targeted antibody-drug and a radioligand conjugate, their in vivo efficacy across a large panel of GI-tract PDX tumors, and the pharmacokinetic and safety profiles in non-human primates. A fully human monoclonal antibody against CDH17 was generated and conjugated to Deruxtecan at a DAR of 8 (CO-ADC-010). CO-ADC-010 demonstrated rapid internalization and potent CDH17-dependent cytotoxicity, along with favorable plasma stability, pharmacokinetics, and manufacturability. In a large-scale in vivo efficacy study, CO-ADC-010 achieved >90% tumor growth inhibition (TGI) in 80% of tested PDX models. This performance significantly surpassed a comparator ADC carrying MMAE at DAR 4, which showed a similar TGI in only 33% of models, suggesting better suitability of topoisomerase-based payloads for CDH17-directed delivery. In non-human primates, a single-dose exploratory toxicology study of CO-ADC-010 at 10, 30, and 45 mg/kg revealed no target-related toxicities at any dose, with all clinical and pathological findings deemed mild and reversible.Despite strong initial responses to CO-ADC-010, many tumors relapsed over prolonged treatment due to acquired resistance to the payload, while CDH17 expression was not altered. To overcome the limitations of the de novo and acquired resistance to the ADC treatments, we also developed a CDH17-targeted radioligand therapy (RLT) using the same antibody scaffold. We demonstrate that CDH17-targeted RLT shows broad and durable responses across the PDX panel, including full activity in models refractory to Deruxtecan-based ADCs, demonstrating the superiority of RLT in these indications in overcoming drug resistance and achieving durable responses. These data collectively support CDH17-targeted RLT as a promising therapeutic approach for CDH17-positive gastrointestinal malignancies.
利益披露 Disclosure
A. Mondal,
Corellia AI Employment.
G. Kaushik,
Corellia AI Employment.
D. Beckford,
Champions Oncology Employment.
M. Ritchie,
Corellia AI Employment.