肿瘤细胞治疗研究
英文原题：Targeted antibody-drug conjugates for rhabdomyosarcoma and other FGFR4-expressing cancers.
与嵌合抗原受体（CAR）T细胞疗法相比，抗体-药物偶联物（ADCs）具有明显优势。
与嵌合抗原受体（CAR）T细胞疗法相比，抗体药物偶联物（ADC）具有明显优势。在此，我们报告了两种靶向FGFR4的ADC，使用高亲和力单克隆抗体3A11，该结合物与正在NCI（NCT06865664）评估用于复发/难治性横纹肌肉瘤（RMS）患者的CAR T细胞形式中所用的结合物相同。这些ADC分别偶联单甲基澳瑞他汀E（MMAE）或一种依沙替康衍生物，可迅速内化，在体外引起强效的成纤维细胞生长因子受体4（FGFR4）依赖性细胞毒性。在皮下RMS异种移植模型中，两种ADC均表现出强大的抗肿瘤活性，显著延长生存期。值得注意的是，依沙替康-ADC在侵袭性融合阴性（FN）RMS559和融合阳性（FP）RH4 RMS细胞系来源异种移植（CDX）以及患者来源RMS异种移植（PDX）中显示出更好的疗效，并实现持久肿瘤控制。此外，依沙替康-ADC在表达FGFR4的MDA-MB-453乳腺癌小鼠模型中有效控制肿瘤，并通过再治疗根除复发肿瘤。这些发现凸显了靶向FGFR4的ADC作为针对侵袭性FGFR4表达恶性肿瘤的有效治疗药物，支持其进一步的临床开发。
Compared with chimeric antigen receptor (CAR) T cell therapy, antibody-drug conjugates (ADCs) offer distinct advantages. Here, we report on two FGFR4-targeted ADCs, using the high-affinity monoclonal antibody 3A11, the same binder used in a CAR T cell format that is being evaluated at the NCI (NCT06865664) for patients with relapsed/refractory rhabdomyosarcoma (RMS). These ADCs, conjugated to monomethyl auristatin E (MMAE) or an exatecan derivative, are rapidly internalized, causing potent fibroblast growth factor receptor 4 (FGFR4)-dependent cytotoxicity in vitro. In subcutaneous RMS xenograft models, both ADCs demonstrated robust anti-tumor activities, significantly prolonging survival. Notably, exatecan-ADC showed better efficacy, with durable tumor control, in aggressive fusion-negative (FN) RMS559 and fusion-positive (FP) RH4 RMS cell-line-derived xenografts (CDXs) and a patient-derived RMS xenograft (PDX). Furthermore, exatecan-ADC effectively controls tumors in an FGFR4-expressing MDA-MB-453 breast cancer mouse model, eradicating relapsed tumors with retreatment. These findings highlight FGFR4-targeted ADCs as potent therapeutic agents against aggressive FGFR4-expressing malignancies, supporting their further clinical development.
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