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.