癌胚抗原（CEA）已成为结直肠癌（CRC）治疗和诊断应用中的一个有吸引力的靶点。在本研究中，人源化的抗CEA抗体hT84.66-M5A（M5A）被标记为177Lu以用于潜在的CRC治疗。此外，首次评估了177Lu-DOTA-M5A与热休克蛋白90抑制剂onalespib的新组合，后者被认为具有放射增敏性质。使用SPECT / CT成像在体内评估了M5A抗体的摄取和治疗效果，单独或与onalespib联合应用于人源CRC移植瘤模型。尽管177Lu-DOTA-M5A和onalespib单独治疗都有效地减缓了肿瘤生长速率，但联合治疗产生了最显著的影响，与对照组相比，肿瘤生长减少了四倍。与单独使用177Lu-DOTA-M5A相比，中位生存期增加了33％，与对照组和onalespib组相比，生存期延长了三倍。重要的是，联合治疗比双剂量的177Lu-DOTA-M5A单独治疗产生了相似或更好的效果。177Lu-DOTA-M5A增加了凋亡细胞水平，表明其可能诱导肿瘤细胞死亡。这些结果显示了177Lu-DOTA-M5A作为CRC治疗药物的潜力，并且其与onalespib的联合应用可以显著增强治疗效果。有必要进行进一步的体内研究，以充分验证这些发现并探索该治疗方法在临床应用中的潜力。

Carcinoembryonic antigen (CEA) has emerged as an attractive target for theranostic applications in colorectal cancers (CRCs). In the present study, the humanized anti-CEA antibody hT84.66-M5A (M5A) was labeled with 177Lu for potential CRC therapy. Moreover, the novel combination of 177Lu-DOTA-M5A with the heat shock protein 90 inhibitor onalespib, suggested to mediate radiosensitizing properties, was assessed in vivo for the first time. M5A antibody uptake and therapeutic effects, alone or in combination with onalespib, were assessed in human CRC xenografts and visualized using SPECT/CT imaging. Although both 177Lu-DOTA-M5A and onalespib monotherapies effectively reduced tumor growth rates, the combination therapy demonstrated the most substantial impact, achieving a fourfold reduction in tumor growth compared to the control group. Median survival increased by 33% compared to 177Lu-DOTA-M5A alone, and tripled compared to control and onalespib groups. Importantly, combination therapy yielded comparable or superior effects to the double dose of 177Lu-DOTA-M5A monotherapy. 177Lu-DOTA-M5A increased apoptotic cell levels, indicating its potential to induce tumor cell death. These findings show promise for 177Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Further in vivo studies are warranted to validate these findings fully and explore the treatment's potential for clinical use.