Imaging the multifaceted response to a bispecific antibody therapy

双特异性抗体疗法的多方面反应成像

• 批准号: 10451574
• 负责人: Bernadette Marquez-Nostra
• 金额: $ 55.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451574
• 关键词: Affinity; Animal Model; Antibodies; Antibody Therapy; Antigens; Binding; Biological; Bispecific Antibodies; Breast Cancer cell line; Cancer cell line; Cell Line; Cell surface; Clinical Trials; Complement; Correlative Study; DNA Sequence Alteration; Data; Diagnostic Procedure; Drug Delivery Systems; Drug Exposure; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Future; Gene Amplification; Goals; Half-Life; Heterogeneity; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Individual; Label; Ligands; MET gene; Measures; Mesenchymal; Methods; Monitor; Mutation; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Patients; Positron-Emission Tomography; Pre-Clinical Model; Predictive Value; Radioactive; Resistance; Resistance development; Role; Specificity; Techniques; Testing; Therapeutic; Tissue Sample; Tracer; Transitional Epithelium; Translating; Xenograft Model; Xenograft procedure; base; cancer cell; companion diagnostics; design; imaging approach; imaging biomarker; in vivo; in vivo Model; innovation; mortality; mutant; mutational status; non-invasive imaging; novel; novel therapeutics; overexpression; preclinical study; predicting response; radioligand; radiotracer; receptor; receptor expression; resistance mechanism; response; response biomarker; standard of care; targeted treatment; tool; translational study; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; uptake

Project Summary Resistance to the standard of care treatments contributes to mortality in patients with metastatic triple negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC). In metastatic TNBC, the epidermal growth factor receptor (EGFR) and cytoplasmic mesenchymal-epithelial transition (cMET) receptor are both overexpressed in the basal-like subtype of TNBC. Metastatic NSCLC often harbors mutations in the epidermal growth factor receptor (EGFR), in which patients can develop resistance to EGFR tyrosine kinase inhibitors (TKI). MET gene amplification is also a resistance mechanism for EGFR TKIs. To overcome resistance to EGFR TKI, a bispecific antibody called JNJ-61186372 (BsAb) was developed that targets both EGFR and cMET receptors simultaneously, inhibiting receptor-ligand activation and degrading these receptors upon internalization of the bsAb. Currently, there are no effective methods to predict and monitor response to bsAb, making it difficult to select patients most likely to respond to this new therapy in a clinical trial setting and save those unlikely to respond from undue drug exposure. We aim to develop PET imaging biomarkers to look at the multifaceted response to bsAb therapy: bsAb delivery to the tumor (Aim 1) and changes in individual receptor status in vivo (Aim 2). Through correlative studies among PET imaging, response to bsAb therapy, and known genetic mutation status in EGFR, we will produce the right PET imaging toolkit to understand the mechanisms of action of bsAb in vivo. Our techniques can complement standard of care analysis of EGFR mutation status to select patients most likely to respond to bsAb therapy and monitor response to treatment. This future goal will require an IND, for which our studies will provide proof-of-feasibility in preclinical models. Ultimately, establishing our imaging techniques as companion diagnostic agents could have high impact in accelerating FDA-approval of bsAb for the treatment of patients with NSCLC or TNBC who have developed resistance to standard of care of treatments.

项目摘要 对护理标准治疗标准的抵抗力导致转移性三重阴性患者的死亡率 乳腺癌（TNBC）或非小细胞肺癌（NSCLC）。在转移性TNBC中，表皮生长因子 受体（EGFR）和细胞质间质上皮转变（CMET）受体均过表达 在TNBC的基础样子类型中。转移性NSCLC通常在表皮生长因子中具有突变 受体（EGFR），其中患者可以对EGFR酪氨酸激酶抑制剂（TKI）产生抗性。大都会基因 放大也是EGFR TKI的电阻机制。为了克服对EGFR TKI的抵抗力 开发了靶向EGFR和CMET受体的双特异性抗体称为JNJ-61186372（BSAB） 同时，抑制受体 - 配体激活并在内部化后降解这些受体 BSAB。当前，没有有效的方法来预测和监视对BSAB的反应，因此很难 选择最有可能在临床试验环境中对这种新疗法做出反应的患者，并保存不太可能的患者 不适当的药物暴露。我们旨在开发宠物成像生物标志物，以查看多方面的 对BSAB疗法的反应：BSAB递送到肿瘤（AIM 1）和体内单个受体状态的变化 （目标2）。通过PET成像之间的相关研究，对BSAB治疗的反应和已知遗传 EGFR中的突变状态，我们将生成正确的PET成像工具包，以了解作用机理 bsab in Vivo。我们的技术可以补充EGFR突变状态的护理标准分析以选择 患者最有可能对BSAB治疗反应并监测对治疗的反应。这个未来的目标将需要 我们的研究将在临床前模型中提供可行性证明。最终，建立我们的 成像技术作为伴侣诊断剂可能会在加速FDA批准方面产生很大的影响 BSAB用于治疗NSCLC或TNBC患者的BSAB 治疗。