Mishra Akhilesh, Sharma Ajay Kumar, Gupta Kuldeep, Banka Dhanush R, Johnson Burles A, Hoffman-Censits Jeannie, Huang Peng, McConkey David J, Nimmagadda Sridhar
The Russell H. Morgan Department of Radiology and Radiological Science.
The Johns Hopkins Greenberg Bladder Cancer Institute.
bioRxiv. 2024 Dec 25:2024.12.25.630315. doi: 10.1101/2024.12.25.630315.
The optimization of dosing strategies is critical for maximizing efficacy and minimizing toxicity in drug development, particularly for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study demonstrates the utility of Nectin-4-targeted positron emission tomography (PET) imaging using [Ga]AJ647 as a non-invasive tool for real-time assessment of target engagement in enfortumab vedotin (EV) therapy for urothelial carcinoma (UC). By leveraging the specificity of [Ga]AJ647 for Nectin-4, we quantified dynamic changes in target engagement across preclinical models and established its correlation with therapeutic outcomes. PET imaging revealed dose-dependent variations in Nectin-4 engagement, with suboptimal EV doses resulting in incomplete Nectin-4 engagement and reduced tumor growth. Importantly, target engagement measured by PET emerged as a more reliable predictor of therapeutic efficacy than dose or baseline Nectin-4 expression alone. Receiver operating characteristic (ROC) analysis identified a target engagement threshold that is determinant of response, providing a quantitative benchmark for dose optimization. Furthermore, PET imaging measures provide a promising framework to account for key challenges in ADC development, including tumor heterogeneity, declining drug-to-antibody ratios over time, and limitations of systemic pharmacokinetic measurements to account for tumor-drug interactions. These findings underscore the transformative potential of integrating PET pharmacodynamic measures as early biomarkers to refine dosing strategies, improve patient outcomes, and accelerate the clinical translation of next-generation targeted therapeutics.
在药物研发中，优化给药策略对于最大化疗效和最小化毒性至关重要，尤其是对于治疗窗较窄的药物，如抗体药物偶联物（ADC）。本研究证明了使用[镓]AJ647进行Nectin-4靶向正电子发射断层扫描（PET）成像作为一种非侵入性工具，可实时评估恩杂鲁胺（EV）治疗尿路上皮癌（UC）时的靶点结合情况。通过利用[镓]AJ647对Nectin-4的特异性，我们量化了临床前模型中靶点结合的动态变化，并确定了其与治疗结果的相关性。PET成像显示Nectin-4结合存在剂量依赖性变化，次优的EV剂量导致Nectin-4结合不完全和肿瘤生长减缓。重要的是，与单独的剂量或基线Nectin-4表达相比，PET测量的靶点结合成为治疗疗效更可靠的预测指标。受试者操作特征（ROC）分析确定了一个决定反应的靶点结合阈值，为剂量优化提供了定量基准。此外，PET成像测量为解决ADC研发中的关键挑战提供了一个有前景的框架，包括肿瘤异质性、药物与抗体比例随时间下降以及全身药代动力学测量在解释肿瘤-药物相互作用方面的局限性。这些发现强调了将PET药效学测量作为早期生物标志物整合以优化给药策略、改善患者预后并加速下一代靶向治疗药物临床转化的变革潜力。
