Design, creation and in vitro testing of a reduced immunogenicity humanized anti-CD25 monoclonal antibody that retains functional activity.

Humanized and fully human sequence-derived therapeutic antibodies retain the capacity to induce anti-drug antibodies. Daclizumab (humanized version of the murine anti-Tac antibody; E.HAT) was selected for a proof of concept application of engineering approaches to reduce potential immunogenicity due to its demonstrated immunogenicity in the clinic. Reduced immunogenicity variants of E.HAT were created by identifying and modifying a CD4+ T cell epitope region in the VH region. Variant epitope region peptides were selected for their reduced capacity to induce CD4+ T cell proliferative responses in vitro. Variant antibody molecules were created, and CD25 affinity and potency were similar to the unmodified parent antibody. Fab fragments from the variant antibodies induced a lower frequency and magnitude of responses in human peripheral blood mononuclear cells proliferation tests. By the empirical selection of two amino acid mutations, fully functional humanized E.HAT antibodies with reduced potential to induce immune responses in vitro were created.

Daclizumab in multiple sclerosis. / Daclizumab en la esclerosis multiple.

INTRODUCTION: Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety. DEVELOPMENT: Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells. CONCLUSIONS: Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.

TITLE: Daclizumab en la esclerosis multiple.Introduccion. El daclizumab es un anticuerpo monoclonal dirigido contra la subunidad CD25 del receptor de la interleucina-2, investigado como terapia modificadora de la evolucion de la enfermedad en la esclerosis multiple. La presente revision aborda como se desarrollo el farmaco, cual es su mecanismo de accion conocido y los datos que se han obtenido hasta la fecha acerca de su eficacia y seguridad. Desarrollo. El daclizumab ha mostrado superioridad en prevencion de brotes frente a placebo e interferon beta-1a de baja dosis en un nivel que lo situa a la par del resto de farmacos de primera linea actuales. El efecto sobre la progresion de la enfermedad y sobre parametros de neurodegeneracion, no obstante, no esta aclarado. Por otro lado, presenta problemas de seguridad (riesgo de reacciones autoinmunes que incluyen hepatopatia fulminante y encefalitis) que han supuesto finalmente su retirada del mercado. El daclizumab introduce un nuevo mecanismo de accion a traves del bloqueo de una interleucina clave en la regulacion inmune y por su efecto sobre una poblacion de celulas con capacidad reguladora, como son las celulas NK CD56(bright). Conclusiones. El daclizumab ha demostrado eficacia para frenar el proceso inflamatorio de la esclerosis multiple, aunque la aparicion de efectos secundarios potencialmente graves no ha permitido que su uso impacte de manera significativa en la practica clinica actual. El desarrollo de nuevos farmacos en la esclerosis multiple debe estar supeditado a mantener o mejorar el perfil riesgo-beneficio respecto a los ya en uso.