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Purpose <p>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 (<sup>225</sup>Ac) 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) [<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-DM1.</p> Aim <p>To evaluate the effectiveness and safety of [<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-DM1 against HER2-positive BC.</p> Experimental design <p>The antibody-drug conjugate (ADC) pertuzumab-PEG<sub>6</sub>-DM1 and the ADR [<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-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.</p> Results <p>Internalisation in HCC1954 and JIMT-1 cells was HER2 density-dependent, with pertuzumab-PEG<sub>6</sub>-DM1 2.5-22-fold higher than unconjugated pertuzumab. Pertuzumab-PEG<sub>6</sub>-DM1 (8 mg/kg) and [<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-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 [<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-DM1 and pertuzumab-PEG<sub>6</sub>-DM1 all had complete remissions, whereas those bearing JIMT-1 tumour showed significant % tumour growth inhibition of 72.1 and 29.4%, respectively.</p> Conclusion <p>[<sup>225</sup>Ac]Ac-Macropa-pertuzumab-PEG<sub>6</sub>-DM1 is more potent than pertuzumab-PEG<sub>6</sub>-DM1 against trastuzumab or T-DM1-resistant BC necessitating clinical investigation.</p>

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Potency and safety of novel [225Ac]Ac-labeled pertuzumab-PEGylated emtansine drug conjugate against HER2-positive breast cancer

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Jessica Pougoue Ketchemen,
  • Alissar Monzer,
  • Fabrice Ngoh Njotu,
  • Hanan Babeker,
  • Anjong Florence Tikum,
  • Emmanuel Nwangele,
  • Nikita Henning,
  • Nava Hassani,
  • Amy Futela Ngong,
  • Alireza Doroudi,
  • Humphrey Fonge

摘要

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.