HER3-Targeted Affibodies with Optimized Formats Reduce Ovarian Cancer Progression in a Mouse Xenograft Model
Expression of the receptor tyrosine kinase HER3 is negatively correlated with survival in ovarian cancer, and HER3 overexpression is associated with cancer progression and therapeutic resistance. Thus, improvements in HER3-targeted therapy could lead to significant clinical impact for ovarian cancer patients. Previous work from our group established multivalency as a potential strategy to improve the therapeutic efficacy of HER3-targeted ligands, including affibodies. Others have established HER3 affibodies as viable and potentially superior alternatives to monoclonal antibodies for cancer therapy. Here, bivalent HER3 affibodies were engineered for optimized production, specificity, and function as evaluated in an ovarian cancer xenograft model. Enhanced inhibition of HER3-mediated signaling and increased HER3 downregulation associated with multivalency could be achieved with a simplified construct, potentially increasing translational potential. Additionally, functional effects of affibodies due to multivalency were found to be specific to HER3 targeting, suggesting a unique molecular mechanism. Further, HER3 affibodies demonstrated efficacy in ovarian cancer xenograft mouse models, both as single agents and in combination with carboplatin. Overall, these results reinforce the potential of HER3-targeted affibodies for cancer therapy and establish treatment of ovarian cancer as an application where multivalent HER3 ligands may be useful. Further, this work introduces the potential of HER3 affibodies to be utilized as part of clinically relevant combination therapies (e.g., with carboplatin).
KEY WORDSHER3 ErbB3 affibody carboplatin ovarian cancer
This work was supported by funding from the National Institutes of Health (R00 HL112905 to SMJ), the Elsa U. Pardee Foundation (SMJ), the NCI-UMD Partnership for Integrative Cancer Research (JSS, SMJ and SL), the University of Maryland Greenebaum Comprehensive Care Center seed grant (SMJ, AH, and RGL), the Rivkin Center for Ovarian Cancer (SMJ), and the American Association of Pharmaceutical Scientists Foundation Graduate Student Fellowship (JSS). AH was supported by a Merit Review Award from the U.S. Department of Veterans Affairs (I01 BX000545). This research was also supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (SL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with Ethical Standards
All animal work was carried out in accordance with the NIH guidelines and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Maryland Medical School.
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