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

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Drug Development

Background:

• Actinium-225 ([225Ac]Ac) is of significant interest for targeted alpha therapies.
• Antibody-drug conjugates (ADC) are highly cytotoxic agents used in cancer treatment.
• Combining [225Ac]Ac with an ADC offers a potential strategy to enhance therapeutic efficacy.

Purpose of the Study:

• To develop and evaluate a novel antibody-drug radioconjugate, [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine ([225Ac]Ac-macropa-T-PEG6-DM1), for targeted alpha therapy.
• To compare the efficacy of [225Ac]Ac-macropa-T-PEG6-DM1 with its non-radiolabeled counterpart (T-PEG6-DM1) against breast cancer models, including trastuzumab-resistant cell lines.

Main Methods:

• Development of [89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 for imaging and [225Ac]Ac-macropa-T-PEG6-DM1 for radiotherapy.
• Biodistribution and safety evaluations in non-tumor-bearing mice.
• MicroPET imaging and biodistribution studies in tumor-bearing mice using the [89Zr]-labeled conjugate.
• Radiotherapy efficacy assessment in mice bearing trastuzumab-resistant HCC1954 and JIMT-1 tumors.

Main Results:

• The radioconjugate [225Ac]Ac-macropa-T-PEG6-DM1 demonstrated stability in human serum and PBS.
• Biochemical and hematological safety evaluations showed good tolerability in mice.
• High tumor uptake of the imaging conjugate was observed in both HCC1954 and JIMT-1 xenografts.
• Complete remission was achieved in HCC1954 tumors, and significant tumor growth inhibition was observed in JIMT-1 tumors treated with [225Ac]Ac-macropa-T-PEG6-DM1 compared to controls.

Conclusions:

• [225Ac]Ac-macropa-T-PEG6-DM1 exhibits superior potency compared to the non-radiolabeled ADC against trastuzumab-resistant breast cancer models.
• The preclinical data support the clinical translation of [225Ac]Ac-macropa-T-PEG6-DM1 for targeted alpha therapy in breast cancer.