title: Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells.
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.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Schardt
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Jinan M
authors.initials: JM
authors.lastname: Oubaid
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Williams
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Howard
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Chloe M
authors.initials: CM
authors.lastname: Aloimonos
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Bookstaver
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Tek N
authors.initials: TN
authors.lastname: Lamichhane
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sokic
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Mariya S
authors.initials: MS
authors.lastname: Liyasova
authors.affiliation: Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
authors.forename: Maura
authors.initials: M
authors.lastname: O'Neill
authors.affiliation: Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andresson
authors.affiliation: Baltimore VA Medical Center , Baltimore, Maryland 21201, United States.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Stanley
authors.initials: S
authors.lastname: Lipkowitz
authors.affiliation: Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.|Program in Molecular and Cellular Biology, University of Maryland , College Park, Maryland 20742, United States.
authors.forename: Steven M
authors.identifier: 0000-0002-3827-5988
authors.initials: SM
authors.lastname: Jay
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015202:Protein Engineering / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C581292:ERBB3 protein, human
keywords: HER3; affibody; antibody; cancer; multivalent