Schardt John S, Oubaid Jinan M, Williams Sonya C, Howard James L, Aloimonos Chloe M, Bookstaver Michelle L, Lamichhane Tek N, Sokic Sonja, Liyasova Mariya S, O'Neill Maura, Andresson Thorkell, Hussain Arif, Lipkowitz Stanley, Jay Steven M
Fischell Department of Bioengineering, University of Maryland , College Park, Maryland 20742, United States.
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
Mol Pharm. 2017 Apr 3;14(4):1047-1056. doi: 10.1021/acs.molpharmaceut.6b00919. Epub 2017 Mar 8.
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.
受体酪氨酸激酶HER3已成为卵巢癌、前列腺癌、乳腺癌、肺癌和其他癌症的治疗靶点，这是因为它能够有效激活PI3K/Akt信号通路，特别是通过与HER2二聚化来实现，此外它还在介导耐药性方面发挥作用。因此，提高HER3靶向治疗药物的疗效将使广泛的患者受益。本研究通过蛋白质工程评估了多价展示增强HER3靶向亲合体有效性的潜力，以替代单克隆抗体治疗药物。对多种癌细胞系的多价亲合体评估显示，与单价类似物相比，它们具有广泛的能力来增强对神经调节蛋白（NRG）诱导的HER3和Akt磷酸化的抑制作用。工程化多价性还促进了亲合体作为单一药物以及作为联合治疗方法的一部分对癌细胞生长抑制作用的增强。机制研究表明，工程化多价性增强了亲合体在多种癌细胞类型中介导的HER3下调。总体而言，这些结果突出了工程化多价性作为一种提高HER3靶向治疗药物对多种癌症疗效的通用策略的前景。
