Imaging the multifaceted response to a bispecific antibody therapy

项目摘要 对标准治疗的耐药性导致转移性三阴性患者的死亡率 乳腺癌（TNBC）或非小细胞肺癌（NSCLC）。在转移性TNBC中， EGFR受体和cMET受体均过表达 在TNBC的基底样亚型中。转移性非小细胞肺癌常伴有表皮生长因子突变 EGFR受体（EGFR），其中患者可对EGFR酪氨酸激酶抑制剂（TKI）产生耐药性。MET基因 扩增也是EGFR TKI的耐药机制。为了克服对EGFR TKI的耐药性， 开发了一种名为JNJ-61186372（BsAb）的双特异性抗体，其靶向EGFR和cMET受体 同时，抑制受体-配体活化并在受体-配体的内化后降解这些受体。 bsAb.目前，还没有有效的方法来预测和监测对bsAb的反应， 在临床试验中选择最有可能对这种新疗法产生反应的患者， 会对过度的药物暴露产生反应我们的目标是开发PET成像生物标志物， 对bsAb治疗的反应：bsAb递送至肿瘤（目标1）和体内个体受体状态的变化 (Aim 2）。通过PET成像、对bsAb治疗的反应和已知的遗传学之间的相关性研究， EGFR的突变状态，我们将生产正确的PET成像工具包，以了解作用机制 bsAb在体内。我们的技术可以补充EGFR突变状态的护理标准分析， 最有可能对bsAb治疗有反应的患者，并监测对治疗的反应。这一未来目标将要求 IND，我们的研究将提供临床前模型的可行性证明。最终，建立我们的 作为伴随诊断剂的成像技术可能对加速FDA批准产生重大影响 bsAb用于治疗对标准治疗产生耐药性的NSCLC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.