Antibody-dual drug conjugates for eradicating triple-negative breast cancer with heterogeneity

抗体双药结合物用于根除异质性三阴性乳腺癌

基本信息

批准号：
10731809
负责人：
Kyoji Tsuchikama
金额：
$ 48.21万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731809
关键词：
Acceleration Adjuvant Chemotherapy Adverse effects Affinity Alkylating Agents Antibodies Antibody-drug conjugates Antigens Antimitotic Agents Binding Biodistribution Biological Assay Breast Cancer Cell Cell Cycle Cell Cycle Arrest Cell membrane Cells Chemicals Chemistry Citrulline Clinical Colorectal Neoplasms DNA Data Dependence Diagnosis Diffusion Disease Dose Drug Kinetics Drug resistance Drug toxicity Duocarmycin ERBB2 gene Ensure Enzymes FDA approved Failure Foundations Gene Expression Glutamic Acid Glycine Goals Grant Hematology Hepatotoxicity Heterogeneity Kinetics Liver Lung Neoplasms Malignant Neoplasms Microtubules Modality Molecular Target Morphology Mus Neoadjuvant Therapy Neutropenia Normal Cell Organ Outcome Patient-derived xenograft models of breast cancer Patients Pattern Peptide Hydrolases Peptides Pharmaceutical Preparations Platinum Population Process Proteins Proteomics Recurrence Refractory Relapse Research Resistance SN-38 Safety Series Serum Site Solid Surface Antigens Technology Testing Therapeutic Therapeutic Index Tissues Toxic effect Treatment Efficacy Treatment Protocols Valine Work cancer cell cell killing chemical property design drug candidate effective therapy improved in vitro testing in vivo inhibitor intravenous injection liver injury malignant breast neoplasm mass spectrometric imaging medication safety mouse model novel novel drug class novel therapeutics overexpression pancreatic neoplasm stemness success targeted treatment triple-negative invasive breast carcinoma trophoblast tumor

项目摘要

ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive and refractory subtype of breast cancer for which limited clinical options are currently available. Although initially responsive to platinum-based neoadjuvant chemotherapy, patients with metastatic TNBC rarely survive 5 years after diagnosis. Most TNBC tumors consist of heterogeneous cell populations with different gene expression profiles. This heterogeneity contributes to drug resistance, early relapse, and therapeutic failure. Although extensive research efforts have made a few clinical options available, developing therapeutics that can effectively eradicate a broad range of TNBC cell populations remains a challenge. Antibody-based drugs such as antibody-drug conjugates (ADCs) are the most promising targeted therapeutic modality for treating TNBC. Trophoblast cell-surface antigen 2 (TROP2) is a protein overexpressed in more than 80% of TNBC, representing a promising molecular target. Recently, Sacituzumab Govitecan (Trodelvy), a TROP2-targeted antibody-drug conjugate (ADC), was granted accelerated approval for the third or later line of treatment of metastatic TNBC. However, TNBC often relapses after continuous treatment; the intratumor heterogeneous expression of TROP2 and drug resistance induced by its payload SN-38 likely contribute to poor clinical outcomes. In addition, patients treated with Trodelvy often suffer from adverse effects, including neutropenia. Thus, enhancing the efficacy, expanding the target scope, and ensuring the safety of this drug class remain critical clinical needs to develop safe and effective therapies for patients with heterogeneous TNBC. We have developed novel ADC technologies, including: 1) peptide linkers for maximizing ADC therapeutic index, and 2) bifunctional chemical spacers and a site-specific conjugation for generating homogeneous ADCs containing two distinct payloads (termed dual-drug ADCs). Specifically, our dual-drug ADCs containing two different antimitotic agents showed greatly improved safety and efficacy in mouse models of HER2-low refractory breast cancer compared with the FDA-approved ADCs Kadcyla and Enhertu. Based on this success and our preliminary data, we hypothesize that optimally designed anti-TROP2 dual-drug ADCs effectively eradicate a broad range of solid and metastatic TNBC tumors. In Aim 1, we will investigate how our novel linkers are processed in cancer and normal cells by cell-based assays, proteomic analysis, and in vivo biodistribution analysis. In Aim 2, we will synthesize novel DNA-alkylator payloads and potentiators with varying chemical properties. We will then prepare a series of anti-TROP2 dual- drug ADCs varying in the combination and the number of drugs conjugated to the antibody. In Aim 3, we evaluate the dual-drug ADCs for toxicity efficacy in TNBC mouse models. Successful completion of this project will lay the foundations for this novel drug class with the potential to overcome heterogeneity and resistance of TNBC, which may eventually revolutionize current therapeutic strategies for this devastating disease.

抽象的三阴性乳腺癌（TNBC）是乳腺癌的侵略性和难治性亚型目前可提供有限的临床选择。虽然最初对基于铂的新辅助敏感化学疗法，转移性TNBC患者诊断后5年很少生存。大多数TNBC肿瘤由具有不同基因表达谱的异质细胞群组成。这种异质性有助于耐药性，早期复发和治疗衰竭。尽管广泛的研究工作已经提供了一些临床选择，开发了可以有效地消除广泛范围的治疗剂 TNBC细胞种群仍然是一个挑战。基于抗体的药物，例如抗体 - 药物结合物（ADC）是治疗TNBC的最有希望的靶向治疗方式。滋养细胞细胞表面抗原2 （Trop2）是一种在超过80％的TNBC中过表达的蛋白质，代表了有前途的分子靶标。最近，被授予了trop2靶向抗体 - 药物结合物（ADC）的sacituzumab govitecan（Trodelvy）。加速批准转移性TNBC的第三或更高版本。但是，TNBC经常复发连续治疗后； trop2和耐药性诱导的肿瘤内异质表达通过其有效载荷SN-38可能导致临床结果不佳。此外，经常接受毒死的患者患有不良反应，包括中性粒细胞减少症。因此，增强功效，扩大目标范围，并确保该药物的安全仍然是开发安全有效疗法的关键临床需求用于异质TNBC的患者。我们开发了新颖的ADC技术，包括：1）肽最大化ADC治疗指数的接头和2）双功能化学垫片和特定于位点的特定地点共轭用于生成均匀的ADC，其中包含两个不同的有效载荷（称为双毒ADC）。具体而言，我们的双毒ADC包含两种不同的抗魔法剂，显示出大大提高的安全性与FDA批准的ADC相比 kadcyla和enhertu。基于这个成功和我们的初步数据，我们假设最佳设计抗Trop2双药ADC有效地消除了广泛的固体和转移性TNBC肿瘤。目标 1，我们将通过基于细胞的测定法调查如何在癌症和正常细胞中处理新颖的接头，蛋白质组学分析和体内生物分布分析。在AIM 2中，我们将合成新型的DNA-烷基机构具有不同化学特性的有效载荷和电位器。然后，我们将准备一系列抗Trop2 dual- 药物ADC的组合和与抗体结合的药物数量有所不同。在AIM 3中，我们评估TNBC小鼠模型中的毒性功效的双药ADC。成功完成该项目将为这个新型药物类奠定基础，以克服异质性和抵抗力的潜力 TNBC，最终可能会彻底改变这种毁灭性疾病的当前治疗策略。