Jin Ying, Chen Peng, Zhou Huajun, Mu Guangmao, Wu Simin, Zha Zhengxia, Ma Bin, Han Chao, Chiu Mark L
Research & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, China.
Global Center for Data Science and Bioinformatics, Crown Bioscience Inc., Suzhou, Jiangsu, China.
Front Immunol. 2025 Feb 10;16:1505868. doi: 10.3389/fimmu.2025.1505868. eCollection 2025.
TAVO412, a multi-specific antibody targeting epidermal growth factor receptor (EGFR), mesenchymal epithelial transition factor (c-Met), and vascular endothelial growth factor A (VEGF-A), is undergoing clinical development for the treatment of solid tumors. TAVO412 has multiple mechanisms of action for tumor growth inhibition that include shutting down the EGFR, c-Met, and VEGF signaling pathways, having enhanced Fc effector functions, addressing drug resistance that can be mediated by the crosstalk amongst these three targets, as well as inhibiting angiogenesis. TAVO412 demonstrated strong tumor growth inhibition in 23 cell-line derived xenograft (CDX) models representing diverse cancer types, as well as in 9 patient-derived xenograft (PDX) lung tumor models.
Using preclinical CDX data, we established transcriptomic biomarkers based on gene expression profiles that were correlated with anti-tumor response or distinguished between responders and non-responders. Together with specific driver mutation that associated with efficacy and the targets of TAVO412, a set of 21-gene biomarker was identified to predict the efficacy. A biomarker predictor was formulated based on the Linear Prediction Score (LPS) to estimate the probability of patients or tumor model response to TAVO412 treatment.
This efficacy predictor for TAVO412 demonstrated 78% accuracy in the CDX training models. The biomarker model was further validated in the PDX data set and resulted in comparable accuracy.
In implementing precision medicine by leveraging preclinical model data, a predictive transcriptomic biomarker empowered by next-generation sequencing was identified that could optimize the selection of patients that may benefit most from TAVO412 treatment.
TAVO412是一种靶向表皮生长因子受体（EGFR）、间充质上皮转化因子（c-Met）和血管内皮生长因子A（VEGF-A）的多特异性抗体，正在进行治疗实体瘤的临床开发。TAVO412具有多种抑制肿瘤生长的作用机制，包括阻断EGFR、c-Met和VEGF信号通路、增强Fc效应子功能、解决由这三个靶点之间的串扰介导的耐药性以及抑制血管生成。TAVO412在代表多种癌症类型的23个细胞系衍生异种移植（CDX）模型以及9个患者衍生异种移植（PDX）肺肿瘤模型中均表现出强大的肿瘤生长抑制作用。
利用临床前CDX数据，我们基于与抗肿瘤反应相关或区分反应者和非反应者的基因表达谱建立了转录组学生物标志物。结合与疗效相关的特定驱动突变以及TAVO412的靶点，确定了一组21基因生物标志物来预测疗效。基于线性预测评分（LPS）制定了生物标志物预测指标，以估计患者或肿瘤模型对TAVO412治疗反应的概率。
TAVO412的这种疗效预测指标在CDX训练模型中的准确率为78%。该生物标志物模型在PDX数据集中进一步得到验证，结果准确率相当。
在利用临床前模型数据实施精准医学的过程中，我们鉴定了一种由下一代测序赋能的预测性转录组学生物标志物，该标志物可优化选择可能从TAVO412治疗中获益最大的患者。
