Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity.

Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1beta (IL-1beta) antibody XOMA 052 is a potent inhibitor of IL-1beta activity that reduces the affinity of IL-1beta for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1beta bound by XOMA 052 is 20-100-fold lower than that of IL-1beta in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1beta while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1beta activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody.target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.

Lupus, «un cáncer pero más chiquito¼. Percepciones del lupus eritematoso sistémico en adolescentes próximos a la transición / Lupus: like a cancer but tinier-. Perceptions of systemic lupus erythematosus among adolescents nearing transition to adult care

Resumen Introducción: Se espera que pacientes con lupus pediátrico próximos a la transición asuman responsabilidades de su cuidado, pero muchos no están preparados, lo cual empobrece su pronóstico. Según el modelo autorregulatorio, las percepciones de la enfermedad determinan las respuestas emocionales, guían las conductas de afrontamiento, su evaluación, retroalimentación y estrategias de asimilación. Objetivo: Describir las percepciones sobre el lupus en adolescentes próximos a la transición. Materiales y métodos: Desde un enfoque hermenéutico y utilizando técnicas de la teoría fundada, se realizaron 11 entrevistas semiestructuradas entre junio de 2013 y septiembre de 2014 a 9 adolescentes con diagnóstico de lupus. Resultados: Se obtuvieron 1.800 códigos. Emergieron como categorías preliminares: «Intentando explicar el origen¼, donde se interpreta la causa de la enfermedad en términos de inmunosupresión y autoinmunidad, asociación con cáncer, culpa e influencia de factores emocionales, además el proceso diagnóstico. «Lo que se pierde¼, enmarcado en cambios, trato diferencial y límites. Finalmente, los «aspectos positivos¼: enfermedad como modulador de la conducta, adquisición de cualidades, aprendizaje sobre el funcionamiento corporal y ganancia secundaria. Conclusión: Las percepciones de la enfermedad en estos adolescentes, expresan en la experiencia de cambio las implicaciones del diagnóstico, las cuales impactan múltiples aspectos de sus vidas y traen consigo incertidumbre y necesidad de ajustes que les llevan a la búsqueda de explicaciones. Se requiere mayor conciencia sobre estas percepciones, debido a que, junto con otros factores, determinarán las estrategias que los adolescentes desarrollen para garantizar su autocuidado y adaptación a situaciones derivadas del vivir con la enfermedad.

Abstract Introduction: Patients with paediatric lupus nearing transition to adult care are expected to take responsibility for their care. Nevertheless, many are not prepared for this, and thus have a poorer prognosis. Using the self-regulation model, the perception of a condition determines the emotional responses and guides coping efforts, appraisal, feedback, and assimilation strategies. Objective: To describe how adolescents nearing transition perceive lupus. Materials and methods: Eleven semi-structured interviews were conducted using a hermeneutic approach with techniques from grounded theory. Interviews took place between July 2013 and September 2014. The participants were nine adolescents with diagnosed lupus. Results: A total of 1,800 codes were obtained that emerged as the following preliminary categories: "Attempting to explain the origin", where the cause of the disease is interpreted as immunosuppression, autoimmunity, association with cancer, guilt and influence of emotional factors, along with the diagnosis process. "What is lost", which includes changes, being treated differently, and having limitations. The last category was "positive aspects" deals with illness as a behavioural moderator, acquiring qualities, learning about bodily functioning and secondary gain. Conclusion: Adolescents perceive their condition based on the implications of the changes experienced in their lives as a result of the diagnosis. Lupus affects several aspects of their lives and brings uncertainty and a need to adjust, leading them to look for explanations. More awareness of these perceptions is required because the latter, along with other factors, determine the strategies that adolescents develop to ensure their self-care and adaptation to any situations arising from living with the condition.