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A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or
John Y Li1, Samuel R Perry1, Vanessa Muniz-Medina1
1Biosuperiors, MedImmune LLC, Gaithersburg, MD 20878, USA.
Abstract:
Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.
Insights
A novel biparatopic antibody-drug conjugate (ADC) targeting HER2 shows enhanced cancer cell destruction. This new HER2-targeting ADC offers superior anti-tumor activity compared to T-DM1 for a wider patient population.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Antibody-drug conjugates (ADCs) are an effective cancer therapy, delivering cytotoxic drugs to targeted cells.
- HER2-positive cancers are a significant clinical challenge, necessitating novel therapeutic strategies.
- Existing HER2-targeting ADCs have limitations in efficacy and patient population coverage.
Purpose of the Study:
- To develop and evaluate a novel bivalent biparatopic antibody-drug conjugate (ADC) targeting two distinct epitopes on HER2.
- To assess the efficacy of this biparatopic ADC compared to ado-trastuzumab emtansine (T-DM1) in preclinical tumor models.
- To determine the potential of this biparatopic ADC to overcome resistance and expand treatment options for HER2-positive cancers.
Main Methods:
- Designed a bivalent biparatopic antibody targeting two non-overlapping HER2 epitopes.
- Conjugated the antibody with a tubulysin-based microtubule inhibitor to create the biparatopic ADC.
- Evaluated the ADC's ability to induce HER2 receptor clustering, internalization, lysosomal trafficking, and degradation.
- Assessed anti-tumor activity in various preclinical models, including T-DM1-resistant and refractory settings.
Main Results:
- The biparatopic antibody induced significant HER2 receptor clustering, promoting enhanced internalization and lysosomal degradation.
- The biparatopic ADC demonstrated superior anti-tumor activity compared to T-DM1 across diverse tumor models.
- Efficacy was observed in models representing T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory patient subpopulations.
Conclusions:
- Bivalent biparatopic HER2 targeting enhances ADC-mediated cellular drug delivery and anti-tumor efficacy.
- This novel biparatopic ADC exhibits promising potential for treating metastatic breast cancer.
- The unique targeting mechanism may benefit a broader patient population, including those resistant to current therapies.
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