RESUMO
The enhancement of immune effector functions has been proposed as a potential strategy for increasing the efficacy of therapeutic antibodies. Here, we show that removing fucose from trastuzumab (Herceptin) increased its binding to FcgammaRIIIa, enhanced antibody-dependent cell-mediated cytotoxicity, and more than doubled the median progression-free survival when compared with conventional trastuzumab in treating preclinical models of HER2-amplified breast cancer. Our results show that afucosylated trastuzumab has superior efficacy in treating in vivo models of HER2-amplified breast cancer and support the development of effector function-enhanced antibodies for solid tumor therapy.
Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Receptor ErbB-2/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Fucose/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Camundongos Transgênicos , Receptores de IgG/biossíntese , Receptores de IgG/genética , Receptores de IgG/metabolismo , TrastuzumabRESUMO
Pathogenic factors associated with chronic obstructive pulmonary disease (COPD), such as cigarette smoke, proinflammatory cytokines, and bacterial infections, can individually induce respiratory mucins in vitro and in vivo. Since co-presence of these factors is common in lungs of patients with COPD, we hypothesized that cigarette smoke can amplify mucin induction by bacterial exoproducts and proinflammatory cytokines, resulting in mucin hyperproduction. We demonstrated that cigarette smoke extract (CSE) synergistically increased gene expression and protein production of MUC5AC mucin induced by LPS or TNF-alpha in human airway epithelial NCI-H292 cells. CSE also enhanced expression and production of MUC5AC mucin induced by epidermal growth factor receptor (EGFR) ligands TGF-alpha and amphiregulin, as well as LPS- and TNF-alpha- induced expression and/or release of TGF-alpha and amphiregulin. Furthermore, (4-[(3-bromophenyl)amino]-6,7-diaminoquinazoline), a potent inhibitor of EGFR, blocked synergistic induction of MUC5AC mucin. H(2)O(2) mimicked the synergistic effects of CSE, while antioxidant N-acetyl-L-cysteine prevented synergistic induction of MUC5AC mucin by CSE. In a rat model of LPS-induced airway inflammation, concurrent cigarette smoke inhalation enhanced mucin content of the bronchoalveolar lavage fluid, muc5AC gene expression, and mucous cell metaplasia in the airways. These results suggest that cigarette smoke has the potential to synergistically amplify induction of respiratory mucins by proinflammatory stimuli relevant to COPD pathogenesis and contribute to mucin hyperproduction observed in patients with COPD.