British journal of cancer · 2026
Potency and safety of novel [225Ac]Ac-labeled pertuzumab-PEGylated emtansine drug conjugate against HER2-positive breast cancer.
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Pougoue Ketchemen Jessica, Monzer Alissar, Njotu Fabrice Ngoh, Babeker Hanan, Tikum Anjong Florence, Nwangele Emmanuel, Henning Nikita, Hassani Nava, Ngong Amy Futela, Doroudi Alireza, Fonge Humphrey
Аннотация
PURPOSE: Approved therapeutics targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) have unacceptably high recurrence rates. HER2 is amplified and overexpressed in 25-30% of BC. Actinium-225 (225Ac) has ideal decay characteristics for targeted alpha therapy. To improve the therapeutic index, we describe the effectiveness and safety of an anti-HER2 antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1.
AIM: To evaluate the effectiveness and safety of [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 against HER2-positive BC.
EXPERIMENTAL DESIGN: The antibody-drug conjugate (ADC) pertuzumab-PEG6-DM1 and the ADR [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 were developed. Safety and biodistribution were carried out in healthy female Balb/C mice and in mice bearing HCC1954/JIMT-1 xenografts, respectively. Radioimmunotherapy was done in nude mice bearing trastuzumab-resistant HCC1954 (high HER2-density), T-DM1/trastuzumab-resistant JIMT-1 (medium HER2-density) and MDA-MB-468 (negative control with very low HER2-density) xenografts.
RESULTS: Internalisation in HCC1954 and JIMT-1 cells was HER2 density-dependent, with pertuzumab-PEG6-DM1 2.5-22-fold higher than unconjugated pertuzumab. Pertuzumab-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 (18 kBq) administered separately in healthy Balb/C mice, 10-days apart was well tolerated biochemically and haematologically for 20-days. Mice bearing HCC1954 tumours treated using [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 and pertuzumab-PEG6-DM1 all had complete remissions, whereas those bearing JIMT-1 tumour showed significant % tumour growth inhibition of 72.1 and 29.4%, respectively.
CONCLUSION: [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 is more potent than pertuzumab-PEG6-DM1 against trastuzumab or T-DM1-resistant BC necessitating clinical investigation.
AIM: To evaluate the effectiveness and safety of [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 against HER2-positive BC.
EXPERIMENTAL DESIGN: The antibody-drug conjugate (ADC) pertuzumab-PEG6-DM1 and the ADR [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 were developed. Safety and biodistribution were carried out in healthy female Balb/C mice and in mice bearing HCC1954/JIMT-1 xenografts, respectively. Radioimmunotherapy was done in nude mice bearing trastuzumab-resistant HCC1954 (high HER2-density), T-DM1/trastuzumab-resistant JIMT-1 (medium HER2-density) and MDA-MB-468 (negative control with very low HER2-density) xenografts.
RESULTS: Internalisation in HCC1954 and JIMT-1 cells was HER2 density-dependent, with pertuzumab-PEG6-DM1 2.5-22-fold higher than unconjugated pertuzumab. Pertuzumab-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 (18 kBq) administered separately in healthy Balb/C mice, 10-days apart was well tolerated biochemically and haematologically for 20-days. Mice bearing HCC1954 tumours treated using [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 and pertuzumab-PEG6-DM1 all had complete remissions, whereas those bearing JIMT-1 tumour showed significant % tumour growth inhibition of 72.1 and 29.4%, respectively.
CONCLUSION: [225Ac]Ac-Macropa-pertuzumab-PEG6-DM1 is more potent than pertuzumab-PEG6-DM1 against trastuzumab or T-DM1-resistant BC necessitating clinical investigation.