89Zr/177Lu-labeled claudin-6 antibody exhibits effective targeted radiodiagnostic and therapeutic efficacy in gynecological cancers

• 6 (CLDN6) is highly expressed in ovarian cancer (OV) and uterine corpus endometrial cancer (UCEC) but silenced in normal tissues, holding promise as an attractive target for radioimmunotherapy (RIT). • This study aimed to develop zirconium-89 (⁸⁹Zr)/lutetium-177 (¹⁷⁷Lu)-labeled CLDN6 antibody (IMAB027) for immuno-positron emission tomography (immuno-PET) and RIT for OV and UCEC. • We demonstrated that immuno-PET with [⁸⁹Zr]Zr-DFO-IMAB027 enables specific and precise non-invasive assessment of CLDN6 expression in OV and UCEC models. • [ 177 Lu]Lu-DOTA-IMAB027 exhibited significant tumor suppressive effects with low toxicity, holding promise as a potentially viable therapeutic approach for clinical management of gynecological cancers. Claudin 6 (CLDN6) is highly expressed in ovarian cancer (OV) and uterine corpus endometrial cancer (UCEC) but silenced in normal tissues, holding promise as an attractive target for radioimmunotherapy (RIT). This study aimed to develop zirconium-89 (⁸⁹Zr)/lutetium-177 (¹⁷⁷Lu)-labeled CLDN6 antibody (IMAB027) for immuno-positron emission tomography (immuno-PET) and RIT for OV and UCEC subcutaneous tumor models. IMAB027 was conjugated with p-SCN-Bn-DFO and DOTA- maleimide, followed by radiolabeling with 89 Zr/ 177 Lu. In immuno-PET, [⁸⁹Zr]Zr-DFO- IMAB027 specifically accumulated in tumor regions, reaching maximum uptake at 96 hours post-injection and maintaining elevated levels, consistent with biodistribution results. [¹⁷⁷Lu]Lu-DOTA- IMAB027 exhibited high radioactive binding efficiency through cell binding, blocking, and internalization assays. And the 11.1 MBq [¹⁷⁷Lu]Lu-DOTA- IMAB027 group significantly inhibited tumor growth, prolonged survival, and showed lower toxicity than non-radioactive drug treatment groups. ⁸⁹Zr/¹⁷⁷Lu-labeled IMAB027 holding promise as a potentially viable therapeutic approach for clinical management of gynecological cancers. Scheme of the experiment. IMAB027(CLDN6 antibody) was conjugated with DFO and DOTA, subsequently labeled with 89 Zr/ 177 Lu for immuno-PET imaging and radioimmunotherapy experiments in two gynecological cancers preclinical models, respectively.