Title | Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Schardt JS, Oubaid JM, Williams SC, Howard JL, Aloimonos CM, Bookstaver ML, Lamichhane TN, Sokic S, Liyasova MS, O'Neill M, Andresson T, Hussain A, Lipkowitz S, Jay SM |
Journal | Mol Pharm |
Volume | 14 |
Issue | 4 |
Pagination | 1047-1056 |
Date Published | 2017 Apr 03 |
ISSN | 1543-8392 |
Keywords | Antibodies, Monoclonal, Cell Line, Tumor, Cell Proliferation, Dimerization, Down-Regulation, Humans, Neoplasms, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Engineering, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Receptor, ErbB-3 |
Abstract | The receptor tyrosine kinase HER3 has emerged as a therapeutic target in ovarian, prostate, breast, lung, and other cancers due to its ability to potently activate the PI3K/Akt pathway, especially via dimerization with HER2, as well as for its role in mediating drug resistance. Enhanced efficacy of HER3-targeted therapeutics would therefore benefit a wide range of patients. This study evaluated the potential of multivalent presentation, through protein engineering, to enhance the effectiveness of HER3-targeted affibodies as alternatives to monoclonal antibody therapeutics. Assessment of multivalent affibodies on a variety of cancer cell lines revealed their broad ability to improve inhibition of Neuregulin (NRG)-induced HER3 and Akt phosphorylation compared to monovalent analogues. Engineered multivalency also promoted enhanced cancer cell growth inhibition by affibodies as single agents and as part of combination therapy approaches. Mechanistic investigations revealed that engineered multivalency enhanced affibody-mediated HER3 downregulation in multiple cancer cell types. Overall, these results highlight the promise of engineered multivalency as a general strategy for enhanced efficacy of HER3-targeted therapeutics against a variety of cancers. |
DOI | 10.1021/acs.molpharmaceut.6b00919 |
Alternate Journal | Mol. Pharm. |
PubMed ID | 28248115 |
PubMed Central ID | PMC5433087 |
Grant List | I01 BX000545 / BX / BLRD VA / United States R00 HL112905 / HL / NHLBI NIH HHS / United States T32 AI089621 / AI / NIAID NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:11pm