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）是一种侵袭性且难治性的乳腺癌亚型，目前可用的临床选择有限。尽管最初对铂类新辅助治疗有反应化疗后，转移性 TNBC 患者很少能在诊断后存活 5 年。大多数 TNBC 肿瘤由具有不同基因表达谱的异质细胞群组成。这种异质性导致耐药性、早期复发和治疗失败。尽管广泛的研究工作已经提供了一些可用的临床选择，开发了可以有效根除多种疾病的疗法 TNBC 细胞群仍然是一个挑战。基于抗体的药物，例如抗体药物偶联物 (ADC) 是治疗 TNBC 最有前景的靶向治疗方式。滋养层细胞表面抗原2 (TROP2) 是一种在超过 80% 的 TNBC 中过表达的蛋白质，代表了一个有前途的分子靶点。近日，TROP2靶向抗体药物偶联物（ADC）Sacituzumab Govitecan（Trodelvy）获得批准加速批准转移性 TNBC 的第三线或更高线治疗。然而，TNBC经常复发持续治疗后； TROP2的瘤内异质表达与耐药诱导 SN-38 的有效载荷可能会导致不良的临床结果。此外，接受 Trodelvy 治疗的患者经常遭受不良反应，包括中性粒细胞减少症。从而，增强功效，扩大目标范围，确保此类药物的安全性仍然是开发安全有效疗法的关键临床需求对于异质 TNBC 患者。我们开发了新颖的 ADC 技术，包括：1）肽用于最大化 ADC 治疗指数的接头，以及 2) 双功能化学间隔基和位点特异性用于生成包含两种不同有效负载的同质 ADC（称为双药 ADC）的缀合。具体来说，我们含有两种不同抗有丝分裂剂的双药 ADC 的安全性大大提高与 FDA 批准的 ADC 相比，在 HER2 低难治性乳腺癌小鼠模型中的疗效和疗效卡德西拉和恩赫图。基于这一成功和我们的初步数据，我们假设优化设计抗 TROP2 双药 ADC 可有效根除多种实体瘤和转移性 TNBC 肿瘤。瞄准 1，我们将通过基于细胞的测定研究我们的新型接头如何在癌症和正常细胞中加工，蛋白质组分析和体内生物分布分析。在目标2中，我们将合成新型DNA烷基化剂具有不同化学性质的有效负载和增效剂。然后我们将准备一系列抗TROP2双药物 ADC 的组合和与抗体缀合的药物数量不同。在目标 3 中，我们评估双药 ADC 在 TNBC 小鼠模型中的毒性功效。本项目顺利完成将为这一新药类别奠定基础，并有可能克服药物的异质性和耐药性 TNBC，最终可能会彻底改变目前针对这种毁灭性疾病的治疗策略。