PO.ET09.10 · 实验与分子治疗

CGT4255的临床前特征描述：一种不影响EGFR的泛突变HER2临床开发候选药物，具有潜在同类最佳的脑渗透性

Preclinical characterization of CGT4255, an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration

编号 5869 展板 7 时间 4/21 02:00–05:00 区域 Section 18 主讲 Emily Plummer

分会场 Tyrosine Kinase, Phosphatase, and Other Inhibitors

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Paul Larsen, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana, Richard K. Brizendine, Eric Brown, LouAnn Cable, Mark J. Chicarelli, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, Leyla Haygood, Ravi Jalluri, Vijay Kumar, Cori A. Malinky, Maralee McVean, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, John I. Trujillo, Logan E. Vine, Shannon Winski, Yeyun Zhou

Cogent Biosciences, Inc, Boulder, CO

摘要 Abstract

中文摘要

HER2改变（包括扩增、过表达、插入和点突变）是多种实体瘤类型中已确立的致癌驱动因素。HER2在15-20%的乳腺癌患者中出现扩增或过表达。相比之下，激活性突变约见于4%的病例，其中L755S突变通常与耐药相关。高达50%的HER2+转移性乳腺癌患者在病程中可能发生脑转移，凸显出对具有脑渗透性的HER2靶向疗法的迫切需求。在肺癌中，激活性HER2突变见于2-4%的晚期病例，并与脑转移发生率增加相关。对于肿瘤携带exon 20 YVMA插入的患者，该风险尤其高。由于大多数治疗选择的CNS渗透有限，治疗这类患者的脑转移仍是一项临床挑战。在此，我们描述了CGT4255的高级临床前特征分析。CGT4255是一种靶向突变型和野生型HER2的在研药物，不影响EGFR，并展现出潜在同类最佳的脑渗透性。CGT4255对常见点突变（如L755S）和exon 20 YVMA插入表现出强效活性。体外实验证实CGT4255在血脑屏障处不是P-gp或BCRP外排转运体的底物。在小鼠和猴中进行的CGT4255体内药代动力学研究显示CNS中药物水平高，预示着较高的人脑暴露。CGT4255在HER2过表达和HER2 YVMA颅内模型中表现出稳健的疗效。CGT4255与T-DXd联合展现出对ADC内化的增强作用，从而凸显了联合治疗的生物学依据。在HER2过表达、L755S、YVMA以及T-DXd耐药的皮下异种移植中，CGT4255表现出剂量依赖性的肿瘤生长抑制（TGI），并在低至30 mg/kg的剂量水平观察到肿瘤消退。

查看英文原文 English abstract

HER2 alterations including amplification, overexpression, insertions, and point mutations are established oncogenic drivers across various solid tumor types. HER2 is amplified or overexpressed in 15-20% of breast cancer patients. In contrast, activating mutations are found in approximately 4% of cases with the L755S mutation commonly associated with drug resistance. Up to 50% of patients with HER2+ metastatic breast cancer may develop brain metastasis over the course of the disease, highlighting a critical need for brain penetrant HER2-directed therapies. In lung cancer, activating HER2 mutations occur in 2-4% of advanced cases and are linked to increased incidence of brain metastasis. The risk is especially high in patients whose tumors harbor an exon 20 YVMA insertion. Treating brain metastasis in this group of patients remains a clinical challenge, as most therapeutic options have limited CNS penetration. Herein, we describe the advanced preclinical profiling of CGT4255, an investigational drug targeting mutant and wild type HER2, which spares EGFR and demonstrates potential best-in-class brain penetrance. CGT4255 shows potent activity against commonly occurring point mutations such as L755S and exon 20 YVMA insertions. In vitro assays confirmed that CGT4255 is not a substrate of the P-gp or BCRP efflux transporters at the blood-brain barrier. In vivo pharmacokinetic studies with CGT4255 in mice and monkeys showed high drug levels in the CNS, predicting high human brain exposure. CGT4255 demonstrated robust efficacy in HER2 overexpressed and HER2 YVMA intracranial models. The CGT4255 and T-DXd combination demonstrated enhancement of ADC internalization, thus highlighting a biological rationale for combination therapy. In HER2-overexpressed, L755S, YVMA, and T-DXd resistant subcutaneous xenografts, CGT4255 demonstrated dose dependent TGI with tumor regressions observed at dose levels as low as 30 mg/kg.

利益披露 Disclosure

P. Larsen, Cogent Biosciences, Inc. Employment, Stock, Stock Option. T. Bettendorf, Cogent Biosciences, Inc. Employment, Stock, Stock Option. A. Blandon, Cogent Biosciences, Inc. Employment, Stock, Stock Option. K. Bouhana, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. K. Brizendine, Cogent Biosciences, Inc. Employment, Stock, Stock Option. E. Brown, Cogent Biosciences, Inc. Employment, Stock, Stock Option. L. Cable, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. J. Chicarelli, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. Crow, Cogent Biosciences, Inc. Employment, Stock, Stock Option. B. Fell, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Fischer, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Fulton, Cogent Biosciences, Inc. Employment, Stock, Stock Option. A. Guarnieri, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Harrison, Cogent Biosciences, Inc. Employment, Stock, Stock Option. L. Haygood, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. Jalluri, Cogent Biosciences, Inc. Employment, Stock, Stock Option. V. Kumar, Cogent Biosciences, Inc. Employment, Stock, Stock Option. C. A. Malinky, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. McVean, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. Rieger, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Robinson, Cogent Biosciences, Inc. Employment, Stock, Stock Option. L. Stunkard, Cogent Biosciences, Inc. Employment, Stock, Stock Option. F. Sullivan, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. I. Trujillo, Cogent Biosciences, Inc. Employment, Stock, Stock Option. L. E. Vine, Cogent Biosciences, Inc. Employment, Stock, Stock Option. S. Winski, Cogent Biosciences, Inc. Employment, Stock, Stock Option. Y. Zhou, Cogent Biosciences, Inc. Employment, Stock, Stock Option.

← 返回 AACR 2026 检索