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Synergy between trastuzumab and pertuzumab for human epidermal growth factor 2 (Her2) from colocalization: an in
Gloria Fuentes1, Maurizio Scaltriti, José Baselga
1Bioinformatics Institute, A*STAR, Singapore. gfuentes@bii.a-star.edu.sg
Introduction:
Human epidermal growth factor 2 (Her2), a receptor tyrosine kinase, is overexpressed in breast cancers. It has been successfully targeted by small molecule kinase inhibitors and by antibodies. Recent clinical data show a synergistic response in patients when two antibodies, trastuzumab and pertuzumab, are given in combination.
Methods:
This unexpected effect is rationalized through computer models and molecular dynamic simulations by hypothesizing that the two antibodies can co-localize on the same molecule of the Her2 extracellular domain.
Results:
Simulations suggest that the clinical synergism observed for the two antibodies arises partly from enhanced affinity that originates in cooperative interactions between these two antibodies when they are co-localized on Her2 and "clamp" it; this may inhibit dimerization and possibly higher oligomerizations with neighboring receptors. In the presence of trastuzumab, the receptor becomes highly plastic, especially domains I to III, and this appears to promote increased association with pertuzumab. Further, the presence of pertuzumab evokes novel interactions between the receptor and trastuzumab. Indeed, splicing out of this region in silico results in a big reduction in the interactions of the antibody with the receptor.
Conclusions:
If validated, these findings will bring about a new direction in the design of antibodies whereby different epitopes on the same antibody may be targeted to lead to synergistic/cooperative inhibition and contribute to generate more potent therapeutics and to increase clinical efficacy.
Insights
Two antibodies targeting Human Epidermal Growth Factor 2 (Her2) show synergistic effects in breast cancer by co-localizing and enhancing binding affinity. This cooperative action may lead to more potent antibody therapeutics.
Area of Science:
- Oncology
- Immunology
- Computational Biology
Background:
- Human Epidermal Growth Factor 2 (Her2) is a receptor tyrosine kinase overexpressed in breast cancers.
- Her2 has been targeted by small molecule inhibitors and antibodies, with recent data showing synergy with combined trastuzumab and pertuzumab antibodies.
Purpose of the Study:
- To rationalize the synergistic response observed with combined Her2 antibody therapy.
- To investigate the molecular mechanisms behind the enhanced efficacy of trastuzumab and pertuzumab combination therapy.
Main Methods:
- Utilized computer models and molecular dynamic simulations.
- Hypothesized and simulated co-localization of trastuzumab and pertuzumab on the Her2 extracellular domain.
Main Results:
- Simulations suggest cooperative interactions between co-localized antibodies enhance binding affinity, "clamping" Her2 and inhibiting dimerization.
- Trastuzumab binding induces receptor plasticity, promoting pertuzumab association, while pertuzumab evokes novel interactions with trastuzumab.
- In silico removal of specific receptor regions significantly reduced antibody-receptor interactions.
Conclusions:
- Findings suggest a new antibody design strategy targeting different epitopes on the same antibody for synergistic inhibition.
- This approach could lead to more potent therapeutics and increased clinical efficacy in cancer treatment.
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