RESUMO
We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 microg MT110 on days 0-4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 microg doses of MT110 on days 8-12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.
Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Especificidade de Anticorpos , Antígenos CD19/metabolismo , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Cinética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/patologia , Proteínas Recombinantes/isolamento & purificação , Anticorpos de Cadeia ÚnicaRESUMO
To define the early events that determine the outcome of acute hepatitis C virus (HCV) infection, we compared the course of viremia with the peripheral and intrahepatic T cell response and intrahepatic cytokine profile in six acutely infected chimpanzees. Three different outcomes were observed after peak viral titers were reached: sustained viral clearance, transient viral clearance followed by chronic infection, and chronic infection that persisted at initial peak titers. The results indicate that HCV spread outpaces the T cell response and that HCV rapidly induces but is not controlled by IFN-alphabeta; that viral clearance follows the entry and accumulation of HCV-specific IFN-gamma-producing T cells in the liver; and that it may not require the destruction of infected cells.