RESUMEN
Combining different treatment strategies offers the possibility of improving treatment results for cancer patients. The aim of our study was therefore to investigate the combination of treatment of established s.c. human B non-Hodgkin's lymphoma in severe immune deficient mice using a recombinant bispecific CD19 x CD16 diabody (targeting natural killer cells to CD19 cells) and the angiogenesis inhibitor thalidomide. Monotherapy with either thalidomide or diabody caused an approximate 50% reduction in tumor growth rate. The combined treatment showed evidence for a synergistic effect resulting in a 74% reduction in median tumor size. In the combined treatment group, two of five animals had complete remissions of their s.c. tumor. These results suggest that a combination treatment with recombinant diabodies and angiogenesis inhibition represents a useful approach in cancer therapy.
Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD19/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Receptores de IgG/inmunología , Talidomida/farmacología , Animales , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Inhibidores de Crecimiento/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Proteínas Recombinantes/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
To target NK cells against non-Hodgkin's lymphoma, we constructed a bispecific diabody (BsDb) with reactivity against both human CD19 and FcgammaRIII (CD16). Bacterially produced CD19 x CD16 BsDb specifically interacted with both CD19(+) and CD16(+) cells and exhibited significantly higher apparent affinity and slower dissociation from the tumor cells than from effector cells. It was able to induce specific lysis of tumor cells in the presence of isolated human NK cells or nonfractionated PBLs. The combination of the CD19 x CD16 BsDb with a previously described CD19 x CD3 BsDb and CD28 costimulation significantly increased the lytic potential of human PBLs. Treatment of SCID mice bearing an established Burkitt's lymphoma (5 mm in diameter) with human PBLs, CD19 x CD16 BsDb, CD19 x CD3 BsDb, and anti-CD28 mAb resulted in the complete elimination of tumors in 80% of animals. In contrast, mice receiving human PBLs in combination with either diabody alone showed only partial tumor regression. These data clearly demonstrate the synergistic effect of small recombinant bispecific molecules recruiting different populations of human effector cells to the same tumor target.