Abstract
Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.
Highlights
Of the 207,000 women diagnosed with breast cancer in the United States in 2010, one-fourth had tumors overexpressing the transmembrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; known as HER-2/neu)
Human HER2-expressing tumor cells coated with trastuzumab induce the expression of CD137 on human NK cells
Anti-CD137 mAbs enhance the therapeutic activity of trastuzumab against One in 5 women with HER2-overexpressing breast cancer will a human HER2-overexpressing primary breast tumor
Summary
Of the 207,000 women diagnosed with breast cancer in the United States in 2010, one-fourth had tumors overexpressing the transmembrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; known as HER-2/neu). ADCC is dependent upon immune effector cells, mainly NK cells, binding via their Fc receptor (FcγRIII, CD16) to the IgG1 Fc, heavy-chain portion of trastuzumab [3]. This leads to the activation of the NK cells, release of their cytotoxic granules, and lysis of the trastuzumab-bound breast cancer cell [6]. Clinical results have shown that patients harboring an FcγRIIIA polymorphism with higher NK affinity for IgG1 have a better response to trastuzumab, further
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