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

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2024-12-13 DOI:10.1158/1078-0432.CCR-24-1779

Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Alissar Monzer, Emmanuel Nwangele, Anjong Florence Tikum, Nikita Henning, Nava Hassani, Sarah Frye, Randy Perron, Chris Byrne, Candice Didychuk, Qi Qi, Laura Bannister, Alireza Doroudi, Humphrey Fonge

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引用次数: 0

Abstract

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.

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.