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Published on: November 9, 2017
Neu antigen-negative variants can be generated after neu-specific antibody therapy in neu transgenic mice
Keith L Knutson1, Bond Almand, Yushe Dang
1University of Washington, Tumor Vaccine Group, Department of Oncology, Seattle, Washington, USA. kknutson@u.washington.edu
Abstract:
Prolonged administration of HER-2/neu-specific monoclonal antibody therapy is now widely used for the treatment of HER-2/neu-overexpressing tumors in advanced-stage breast cancer patients. Monoclonal antibody therapy has the potential to promote reduced tumor expression of HER-2/neu by receptor down-modulation and/or the generation of antigen-negative variants. Loss of antigen by either mechanism could potentially impact subsequent therapeutic strategies targeting HER-2/neu. In this study, the effects of chronic neu-specific monoclonal antibody therapy on tumor growth and neu protein expression were examined in a murine model of neu-overexpressing breast cancer. Treatment of neu-overexpressing tumors with neu-specific antibody, in vitro or in vivo, resulted in significant tumor growth inhibition. When neu antibody was used to treat neu-overexpressing tumor cells both in vitro and in vivo in tumor-bearing mice, neu receptor expression was not diminished after cessation of therapy. However, in the setting of clinically undetectable disease in a fraction of animals, antigen-negative variants were generated. An understanding of the effects of monoclonal antibodies on target antigen expression is critical for the future design and testing of novel HER-2/neu-targeted therapies administered in combination with or after HER-2/neu-specific monoclonal antibody therapy.
Insights
Chronic HER-2/neu antibody therapy inhibits tumor growth in breast cancer models. While receptor expression is maintained post-therapy, antigen-negative variants can emerge in some cases, impacting future treatment strategies.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- HER-2/neu-specific monoclonal antibody therapy is a standard treatment for HER-2/neu-overexpressing breast cancer.
- This therapy may reduce HER-2/neu expression through receptor down-modulation or antigen-negative variant generation.
- Changes in HER-2/neu expression can affect subsequent targeted therapies.
Purpose of the Study:
- To investigate the impact of chronic HER-2/neu-specific monoclonal antibody therapy on tumor growth and HER-2/neu expression.
- To evaluate the potential for antigen loss during prolonged antibody treatment in a preclinical model.
Main Methods:
- Utilized a murine model of HER-2/neu-overexpressing breast cancer.
- Administered HER-2/neu-specific monoclonal antibody therapy both in vitro and in vivo.
- Assessed tumor growth inhibition and HER-2/neu protein expression levels post-therapy.
Main Results:
- Neu-specific antibody treatment significantly inhibited tumor growth in vitro and in vivo.
- HER-2/neu receptor expression remained undiminished after therapy cessation in most cases.
- Antigen-negative variants were generated in a subset of animals with clinically undetectable disease.
Conclusions:
- Prolonged HER-2/neu antibody therapy effectively controls tumor growth.
- While HER-2/neu expression is generally preserved, antigen loss can occur, leading to variant generation.
- Understanding these effects is crucial for designing future combination or sequential HER-2/neu-targeted therapies.
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