PO.CTP01.01 · 进行中的临床试验

BDC-4182（一种靶向claudin18.2的新一代免疫刺激抗体偶联物[ISAC]）在晚期胃癌和胃食管癌患者中的1/2期研究

A Phase 1/2 study of BDC-4182, a claudin18.2-targeting next generation immune-stimulating antibody conjugate (ISAC), in patients with advanced gastric and gastroesophageal cancer

编号 CT094 展板 25 时间 4/20 09:00–12:00 区域 Section 51 主讲 Sophia Frentzas, MD

分会场 Phase I Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Sophia Frentzas¹, Michelle Morris², Megan Barnet³, Niall Tebbutt⁴, Mark Wong⁵, Michael Michael⁶, Hyung-Don Kim⁷, Keun-Wook Lee⁸, Sun Young Rha⁹, Sang Cheul Oh¹⁰, I-Chen Wu¹¹, Li-Yuan Bai¹², Wen-Chi Chou¹³, Ming-Huang Chen¹⁴, Yen-Yang Chen¹⁵, Chia-Chi Lin¹⁶, Anthony Rodrigues³, Jason Ptacek¹⁷, Michael N. Alonso¹⁷, Tariq Arshad¹⁷, Jakob Dupont¹⁷, Kristi Balacy¹⁷, Sung Hee Lim¹⁸

¹Monash Medical Centre, Clayton, Australia,²Sunshine Coast University Hospital, Birtinya, Australia,³St Vincent Hospital Sydney (The Kinghorn Cancer Centre), Darlinghurst, Australia,⁴Austin Health, Heidelberg, Australia,⁵Westmead Hospital, Westmead, Australia,⁶Peter MacCallum Cancer Centre, Melbourne, Australia,⁷Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of,⁸Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea, Republic of,⁹Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of,¹⁰Korea University Guro Hospital, Seoul, Korea, Republic of,¹¹Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan,¹²China Medical University Hospital, China Medical University, Taichung City, Taiwan,¹³Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan,¹⁴Taipei Veterans General Hospital, Taipei City, Taiwan,¹⁵Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan,¹⁶National Taiwan University Hospital, Taipei, Taiwan,¹⁷Bolt Biotherapeutics, Redwood City, CA,¹⁸Samsung Medical Center, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景：Claudin 18.2（CLDN18.2）是一种跨膜紧密连接蛋白，其表达局限于胃黏膜上皮，在此CLDN18.2防止细胞旁酸泄漏及相关胃炎。¹已在多种肿瘤类型中观察到CLDN18.2过表达，包括胃癌、食管癌和胰腺癌。²,³这些肿瘤中细胞极性丧失导致CLDN18.2定位于生物制剂和效应细胞更易接近的表面。这种表达模式使CLDN18.2成为免疫刺激抗体偶联物（ISAC）的一个引人注目的靶点，ISAC将肿瘤靶向抗体的特异性与免疫激活的效力和持久性相结合。 BDC-4182是一种新一代ISAC，由靶向CLDN18.2的抗体经不可裂解连接子共价连接一种新型toll样受体（TLR）7/8激动剂组成。在临床前模型中，ISAC的全身给药已被证明可广泛激活先天性和适应性免疫系统，导致肿瘤完全消退。一种BDC-4182替代物诱导了免疫记忆和表位扩展，其证据是再次攻击后对不再表达靶抗原（CLDN18.2）的肿瘤细胞的排斥。⁴,⁵ 方法：这是一项BDC-4182的首次人体1期剂量递增和2期扩展研究。将招募多达122名晚期胃癌和胃食管癌患者。为优化耐受性，BDC-4182采用患者内递增给药方案，即受试者在达到目标剂量前先接受较低的初始启动剂量。主要目标是确定BDC-4182作为单药的安全性和耐受性并确定推荐2期剂量（RP2D）。次要目标将评估BDC-4182的初步抗肿瘤活性、分析BDC-4182的PK特征并评估BDC-4182作为单药的免疫原性。还将进行探索性分析以探究血液和肿瘤组织中与BDC-4182暴露、疗效或安全性相关的潜在生物标志物，并确定肿瘤组织中CLDN18的表达。本研究在澳大利亚、韩国和台湾开展。参考文献： 1. Suzuki K, Sentani K, Tanaka H, et al. Cell Mol Gastroenterol Hepatol. 2019;8:119-142. 2. Hong JY, An JY, Lee J, et al. Transl Cancer Res. 2020;9:3367-3374. 3. Chen J, Xu Z, Hu C, et al. Front Oncol. 2023;13:1132319. 4. Fu C, Luo A, Liu J, et al. J Immunother Cancer. 2024;12(Suppl 2):Abstract 1052. 5. Kim HK, Monnier J, Fu C, et al. J Immunother Cancer. 2023;11(Suppl 1):Abstract 1147-D。

查看英文原文 English abstract

Background: Claudin 18.2 (CLDN18.2) is a transmembrane tight junction protein with expression restricted to the gastric mucosal epithelia where CLDN18.2 protects against paracellular acid leakage and associated gastritis. 1 CLDN18.2 overexpression has been observed in several tumor types, including gastric, esophageal, and pancreatic cancer. 2,3 Loss of cell polarity in these tumors results in CLDN18.2 localization to surfaces that are more readily accessible to biologics and effector cells. This expression pattern makes CLDN18.2 a compelling target for immune-stimulating antibody conjugates (ISACs) that combine the specificity of tumor-targeting antibodies with the potency and durability of immune activation. BDC-4182 is a next-generation ISAC consisting of a CLDN18.2-targeting antibody covalently attached to a novel toll-like receptor (TLR)7/8 agonist via a non-cleavable linker. In preclinical models, systemic delivery of ISACs has been shown to broadly activate the innate and adaptive immune system, leading to complete tumor regression. A BDC-4182 surrogate induced immunologic memory and epitope spreading as evidenced by rejection of tumor cells that no longer express the target antigen (CLDN18.2) following re-challenge. 4,5 Methods: This is a first-in-human Phase 1 dose escalation and Phase 2 expansion study of BDC-4182. Up to 122 patients with advanced gastric and gastroesophageal cancer will be enrolled. To optimize tolerability, BDC-4182 is administered via an intra-patient step-up dosing regimen wherein subjects receive lower initial priming doses prior to the target dose. Primary objectives are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-4182 as a single agent. Secondary objectives will evaluate the preliminary anti-tumor activity of BDC-4182, analyze PK characteristics of BDC-4182, and evaluate the immunogenicity of BDC-4182 as a single agent. Exploratory analyses will also be conducted to explore potential biomarkers in blood and tumor tissue associated with exposure, efficacy, or safety of BDC-4182, and to define CLDN18 expression in tumor tissue. This study is being conducted in Australia, South Korea, and Taiwan. References: 1. Suzuki K, Sentani K, Tanaka H, et al. Cell Mol Gastroenterol Hepatol. 2019;8:119-142. 2. Hong JY, An JY, Lee J, et al. Transl Cancer Res. 2020;9:3367-3374. 3. Chen J, Xu Z, Hu C, et al. Front Oncol. 2023;13:1132319.4. Fu C, Luo A, Liu J, et al. J Immunother Cancer. 2024;12(Suppl 2):Abstract 1052. 5. Kim HK, Monnier J, Fu C, et al. J Immunother Cancer. 2023;11(Suppl 1):Abstract 1147-D.

利益披露 Disclosure

S. Frentzas, None.. M. Morris, None.. M. Barnet, None.. N. Tebbutt, None.. M. Wong, None.. M. Michael, None.. H. Kim, None. K. Lee, Bolt Biotherapeutics ). ALX Oncology ). Amgen ). Arcus ). Astellas Independent Contractor, ), Other, Honoraria / speaker fees. AstraZeneca ). BeOne ). Daiichi Sankyo Independent Contractor, ), Other, Honoraria / speaker fees. Exelixis ). AbbVie Independent Contractor. GSK ). Sanofi/Aventis ), Other, Honoraria / speaker fees. Immuneoncia Independent Contractor, ). Jazz ). Leap ). Medicenna ). MedPacto ). Merck KGaA Honoraria / speaker fees. Pfizer ). Roche ). S. Rha, None.. S. Oh, None.. I. Wu, None.. L. Bai, None.. W. Chou, None.. M. Chen, None.. Y. Chen, None.. C. Lin, None.. A. Rodrigues, None. J. Ptacek, Bolt Biotherapeutics Employment, Stock Option. M. N. Alonso, Bolt Biotherapeutics Employment, Stock Option. T. Arshad, Bolt Biotherapeutics Employment, Stock Option. J. Dupont, Bolt Biotherapeutics g., Board of Directors, non-salaried role). K. Balacy, Bolt Biotherapeutics Employment, Stock Option. S. Lim, None.

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