Imaging the multifaceted response to a bispecific antibody therapy

项目摘要 对标准护理治疗的抵抗导致转移性三阴性患者的死亡 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)和胞浆间充质-上皮转化(CMET)受体均过表达 在TNBC的碱基样亚型中。转移性非小细胞肺癌通常含有表皮生长因子突变 受体(EGFR)，患者可在其中对EGFR酪氨酸激酶抑制剂(TKI)产生耐药性。MET基因 扩增也是EGFR TKIs的一种耐药机制。为了克服对EGFR TKI的耐药性，a 研制了针对表皮生长因子受体和甲硫氨酸受体的双特异性抗体JNJ-61186372(BsAb) 同时，抑制受体配体的激活，并在受体内化时降解这些受体 BsAb.目前，还没有有效的方法来预测和监测对bsAb的应答，这使得很难 在临床试验环境中选择最有可能对这种新疗法有反应的患者，并挽救那些不太可能对此有反应的患者 应对不当的药物暴露。我们的目标是开发PET成像生物标记物来观察多方面的 对bsAb治疗的反应：bsAb向肿瘤的传递(目标1)和体内个体受体状态的变化 (目标2)。通过PET成像、对bsAb治疗的反应和已知基因之间的相关性研究 在EGFR中的突变状态，我们将生产合适的PET成像工具包来了解其作用机制 体内的bsAb。我们的技术可以补充标准的关怀分析的EGFR突变状态来选择 最有可能对bsAb治疗有反应并监测治疗反应的患者。这一未来目标将需要 IND，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 成像技术作为辅助诊断试剂可能对加快FDA的批准产生很大影响 BsAb用于治疗对标准护理产生抵抗力的非小细胞肺癌或TNBC患者 治疗。

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.