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Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do
David Kiewlich1, Jianhuan Zhang, Cynthia Gross
1Corporate Research Oncology, Berlex Biosciences, Richmond, CA 94804, USA.
Abstract:
The EphA2 receptor tyrosine kinase has been shown to be over-expressed in cancer and a monoclonal antibody (mAb) that activates and down-modulates EphA2 was reported to inhibit the growth of human breast and lung tumor xenografts in nude mice. Reduction of EphA2 levels by treatment with anti-EphA2 siRNA also inhibited tumor growth, suggesting that the anti-tumor effects of these agents are mediated by decreasing the levels of EphA2. As these studies employed human tumor xenograft models in nude mice with reagents whose cross reactivity with murine EphA2 is unknown, we generated a mAb (Ab20) that preferentially binds, activates, and induces the degradation of murine EphA2. Treatment of established murine CT26 colorectal tumors with Ab20 reduced EphA2 protein levels to approximately 12% of control tumor levels, yet had no effect on tumor growth. CT26 tumor cell colonization of the lung was also not affected by Ab20 administration despite having barely detectable levels of EphA2. We also generated and tested a potent agonistic mAb against human EphA2 (1G9-H7). No inhibition of humanMDA-231 breast tumor xenograft growth was observed despite evidence for >85% reduction of EphA2 protein levels in the tumors. These results suggest that molecular characteristics of the tumors in addition to EphA2 over-expression may be important for predicting responsiveness to EphA2-directed therapies.
Insights
Monoclonal antibodies targeting the EphA2 receptor tyrosine kinase showed limited efficacy in preclinical cancer models. Tumor-specific factors beyond EphA2 levels may influence treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- EphA2 receptor tyrosine kinase is over-expressed in various cancers.
- Previous studies indicated that antibodies and siRNA targeting EphA2 inhibit tumor growth in human xenograft models.
- The cross-reactivity of these agents with murine EphA2 was not established.
Purpose of the Study:
- To investigate the efficacy of EphA2-targeting monoclonal antibodies (mAbs) in murine cancer models.
- To determine if reducing EphA2 levels impacts tumor growth and metastasis in mice.
- To assess the role of tumor-specific factors in response to EphA2-directed therapies.
Main Methods:
- Generation of a murine-specific anti-EphA2 mAb (Ab20) that activates and degrades murine EphA2.
- Treatment of established murine CT26 colorectal tumors with Ab20.
- Evaluation of tumor growth, EphA2 protein levels, and lung colonization.
- Testing of a potent agonistic human-specific anti-EphA2 mAb (1G9-H7) on human MDA-231 breast tumor xenografts.
Main Results:
- Ab20 treatment significantly reduced murine EphA2 levels in CT26 tumors but did not affect tumor growth or lung metastasis.
- The human-specific mAb 1G9-H7 reduced human EphA2 levels in MDA-231 tumors by over 85% without inhibiting xenograft growth.
- These findings indicate that EphA2 down-modulation alone is insufficient to inhibit tumor progression in these models.
Conclusions:
- EphA2 over-expression alone may not be sufficient to predict response to EphA2-targeted therapies.
- Tumor-specific molecular characteristics, beyond EphA2 levels, are likely critical for therapeutic efficacy.
- Further research is needed to identify predictive biomarkers for EphA2-directed cancer treatments.
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