Complete remissions of HER2-positive trastuzumab-resistant xenografts using a potent [225Ac]Ac-labeled anti-HER2 antibody-drug radioconjugate.

Autor:	Pougoue Ketchemen J; Université Laval, Quebec, QC, Canada., Njotu FN; University of Saskatchewan, saskatoon, SK, Canada., Babeker H; University of Saskatchewan, saskatoon, SK, Canada., Monzer A; University of Saskatchewan, saskatoon, SK, Canada., Nwangele E; University of Saskatchewan, saskatoon, SK, Canada., Tikum AF; University of Saskatchewan, saskatoon, SK, Canada., Henning N; University of Saskatchewan, saskatoon, SK, Canada., Hassani N; University of Saskatchewan, saskatoon, SK, Canada., Frye S; Canadian nuclear labs, Chalk River, Ontario, Canada., Perron R; Canadian Nuclear Labs, Chalk River, Ontario, Canada., Byrne C; Canadian nuclear labs, Chalk River, Ontario, Canada., Didychuk C; Canadian Nuclear Labs, Chalk River, Ontario, Canada., Qi Q; Canadian Nuclear Labs, Chalk River, Onatrio, Canada., Bannister L; canadian nuclear laboratories, Chalk River, Ontario, Canada., Doroudi A; University of Saskatchewan, saskatoon, SK, Canada., Fonge H; Université Laval, Quebec City, QC, Canada.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Dec 13. Date of Electronic Publication: 2024 Dec 13.
DOI:	10.1158/1078-0432.CCR-24-1779
Abstrakt:	Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted alpha therapies. Antibody-drug conjugates (ADCs) are highly cytotoxic. Combining [225Ac]Ac with ADC to develop an antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, is expected to be more effective than its ADC (trastuzumab-PEG6-DM1) against breast cancer (BC). Experimental Design: [89Zr]Zr-DFO-trastuzumab-PEG6-DM1 (imaging) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluation of [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 were carried out in non-tumor bearing Balb/C mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-trastuzumab-PEG6-DM1, and radiotherapy using [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was carried-out in athymic Balb/C nude mice bearing trastuzumab-resistant HCC1954 and T-DM1/trastuzumab resistant JIMT-1 tumor bearing mice. Results: After 7-days (d) of incubation at 37ºC, [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was stable in both human serum (89.2 ± 0.9%) and phosphate buffered saline (82.8 ± 0.4%). Trastuzumab-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (3 x 18 kBq) administered separately in non-tumor bearing mice, 10-d apart was well tolerated biochemically and haematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-trastuzumab-PEG6-DM1 in tumor-bearing mice at 120 h post 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 CR) indicative of the responsiveness of the xenograft to T-DM1-based treatments, while for JIMT-1 xenograft (having 1/8 CR) at 23-d post 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), trastuzumab-PEG6-DM1 and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, respectively. Conclusion: [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 is more potent than ADC against trastuzumab-resistant BC and necessitates clinical translation.
Databáze:	MEDLINE
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