Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody-Drug Radioconjugate.

• Tác giả: Hanan Babeker, Laura Bannister, Chris Byrne, Candice Didychuk, Alireza Doroudi, Humphrey Fonge, Sarah Frye, Nava Hassani, Nikita Henning, Alissar Monzer, Fabrice Ngoh Njotu, Emmanuel Nwangele, Randy Perron, Jessica Pougoue Ketchemen, Qi Qi, Anjong Florence Tikum
• Ngôn ngữ: eng
• Ký hiệu phân loại: 363.232 Patrol and surveillance
• Thông tin xuất bản: United States : Clinical cancer research : an official journal of the American Association for Cancer Research , 2025
• Bộ sưu tập: NCBI
• ID: 159855

Tóm tắt

PURPOSE: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody-drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody-drug radioconjugate [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine (DM1), is expected to be more effective than its ADC (T-PEG6-DM1) against breast cancer. EXPERIMENTAL DESIGN: [89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 (imaging) and [225Ac]Ac-macropa-T-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac-macropa-T-PEG6-DM1 were carried out in non-tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-T-PEG6-DM1, and radiotherapy using [225Ac]Ac-macropa-T-PEG6-DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice. RESULTS: After 7 days of incubation at 37°C, [225Ac]Ac-macropa-T-PEG6-DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-macropa-T-PEG6-DM1 (3 × 18 kBq) administered separately in non-tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-T-PEG6-DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1-based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T-PEG6-DM1, and [225Ac]Ac-macropa-T-PEG6-DM1, respectively. CONCLUSIONS: [225Ac]Ac-macropa-T-PEG6-DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.