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Published on: June 13, 2014
Biparatopic anti-HER2 drug radioconjugates as breast cancer theranostics
Jessica Pougoue Ketchemen1, Hanan Babeker1,2, Anjong Florence Tikum1
1Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada.
Background:
HER2 is overexpressed in 25-30% of breast cancer. Multiple domains targeting of a receptor can have synergistic/additive therapeutic effects.
Methods:
Two domain-specific ADCs trastuzumab-PEG6-DM1 (domain IV) and pertuzumab-PEG6-DM1 (domain II) were developed, characterised and radiolabeled to obtain [89Zr]Zr-trastuzumab-PEG6-DM1 and [67Cu]Cu-pertuzumab-PEG6-DM1 to study their in vitro (binding assay, internalisation and cytotoxicity) and in vivo (pharmacokinetics, biodistribution and immunoPET/SPECT imaging) characteristics.
Results:
The ADCs had an average drug-to-antibody ratio of 3. Trastuzumab did not compete with [67Cu]Cu-pertuzumab-PEG6-DM1 for binding to HER2. The highest antibody internalisation was observed with the combination of ADCs in BT-474 cells compared with single antibodies or ADCs. The combination of the two ADCs had the lowest IC50 compared with treatment using the single ADCs or controls. Pharmacokinetics showed biphasic half-lives with fast distribution and slow elimination, and an AUC that was five-fold higher for [89Zr]Zr-trastuzumab-PEG6-DM1 compared with [67Cu]Cu-pertuzumab-PEG6-DM1. Tumour uptake of [89Zr]Zr-trastuzumab-PEG6-DM1 was 51.3 ± 17.3% IA/g (BT-474), and 12.9 ± 2.1% IA/g (JIMT-1) which was similarly to [67Cu]Cu-pertuzumab-PEG6-DM1. Mice pre-blocked with pertuzumab had [89Zr]Zr-trastuzumab-PEG6-DM1 tumour uptakes of 66.3 ± 33.9% IA/g (BT-474) and 25.3 ± 4.9% IA/g (JIMT-1) at 120 h p.i.
Conclusion:
Using these biologics simultaneously as biparatopic theranostic agents has additive benefits.
Insights
Targeting multiple HER2 domains with antibody-drug conjugates (ADCs) showed enhanced efficacy in breast cancer models. Simultaneous administration of trastuzumab-PEG-DM1 and pertuzumab-PEG-DM1 offers additive therapeutic benefits.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- HER2 is overexpressed in 25-30% of breast cancer cases.
- Targeting multiple HER2 domains can yield synergistic or additive therapeutic effects.
Purpose of the Study:
- To develop and characterize domain-specific antibody-drug conjugates (ADCs) for HER2-targeted therapy.
- To evaluate the in vitro and in vivo performance of radiolabeled ADCs for immunoPET/SPECT imaging and therapeutic assessment.
Main Methods:
- Two domain-specific ADCs, trastuzumab-PEG-DM1 (domain IV) and pertuzumab-PEG-DM1 (domain II), were synthesized and radiolabeled with 89Zr and 67Cu, respectively.
- In vitro studies included binding assays, cellular internalisation, and cytotoxicity assays.
- In vivo studies involved pharmacokinetic analysis, biodistribution, and immunoPET/SPECT imaging in relevant cancer models.
Main Results:
- The ADCs exhibited an average drug-to-antibody ratio of 3.
- Combined ADC treatment demonstrated the highest antibody internalisation and lowest IC50 in BT-474 cells.
- Pharmacokinetics revealed biphasic half-lives, with [89Zr]Zr-trastuzumab-PEG-DM1 showing a five-fold higher AUC than [67Cu]Cu-pertuzumab-PEG-DM1.
- Significant tumor uptake was observed for both radiolabeled ADCs, with [89Zr]Zr-trastuzumab-PEG-DM1 showing substantial uptake in BT-474 and JIMT-1 xenografts.
Conclusions:
- Simultaneous administration of these HER2-targeting biologics as biparatopic theranostic agents provides additive therapeutic benefits.
- This dual-targeting approach holds promise for enhanced breast cancer treatment and imaging.
