RESUMEN

BACKGROUND: CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis. METHODOLOGY: Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies. SIGNIFICANCE: For the first time, successful generation of anti- G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.

Asunto(s)

Antineoplásicos/farmacología , Quimiotaxis/efectos de los fármacos , Receptores CCR4/antagonistas & inhibidores , Anticuerpos de Cadena Única/farmacología , Animales , Antineoplásicos/uso terapéutico , Señalización del Calcio , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quimiocina CCL17/fisiología , Células HEK293 , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Masculino , Ratones Desnudos , Biblioteca de Péptidos , Agregación Plaquetaria/efectos de los fármacos , Receptores CCR4/inmunología , Anticuerpos de Cadena Única/uso terapéutico , Especificidad de la Especie , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

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