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 with177Lu for potential CRC therapy. Moreover, the novel combination of177Lu-DOTA-M5A with the heat shock protein 90 inhibitor onalespib, suggested to mediate radiosensitizing properties, was assessedin vivofor 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 both177Lu-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 to177Lu-DOTA-M5A alone, and tripled compared to control and onalespib groups. Importantly, combination therapy yielded comparable or superior effects to the double dose of177Lu-DOTA-M5A monotherapy.177Lu-DOTA-M5A increased apoptotic cell levels, indicating its potential to induce tumor cell death. These findings show promise for177Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Furtherin vivostudies are warranted to validate these findings fully and explore the treatment’s potential for clinical use.
癌胚抗原（CEA）已成为结直肠癌诊疗一体化应用中极具吸引力的靶点。本研究将人源化抗CEA抗体hT84.66-M5A（M5A）用¹⁷⁷Lu标记，探索其用于结直肠癌治疗的潜力。此外，本研究首次在体内评估了¹⁷⁷Lu-DOTA-M5A与热休克蛋白90抑制剂onalespib的新型联合方案——该方案被认为可能介导放射增敏效应。通过SPECT/CT成像技术，我们在人结直肠癌异种移植模型中观察了M5A抗体的摄取情况，并评估了其单独或联合onalespib的治疗效果。虽然¹⁷⁷Lu-DOTA-M5A和onalespib单药治疗均能有效降低肿瘤生长速率，但联合疗法显示出最显著的效果，与对照组相比肿瘤生长减缓了四倍。与单独使用¹⁷⁷Lu-DOTA-M5A相比，中位生存期延长了33%；与对照组及onalespib单药组相比，生存期延长至三倍。重要的是，联合疗法达到了与双剂量¹⁷⁷Lu-DOTA-M5A单药治疗相当或更优的效果。¹⁷⁷Lu-DOTA-M5A能提升凋亡细胞水平，表明其具有诱导肿瘤细胞死亡的潜力。这些发现揭示了¹⁷⁷Lu-DOTA-M5A作为结直肠癌治疗药物的前景，且与onalespib联用可显著提升疗效。需要开展进一步的体内研究以全面验证这些发现，并探索该治疗方案在临床应用中的潜力。
肿瘤(癌症)患者之家