Publication: Aplicaciones terapéuticas de inmunotoxinas: cáncer y alergia
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2021-01-21
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Universidad Complutense de Madrid
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Abstract
Las inmunotoxinas son moléculas quiméricas que se incluyen dentro del grupo de los agentes terapéuticos biológicos. Constan de un dominio marcador, formado habitualmente por un anticuerpo o un fragmento de éste, aunque también por otras moléculas con capacidad de unión celular específica, como interleuquinas o factores de crecimiento, fusionados a un dominio tóxico, normalmente compuesto por una toxina proteica capaz de producir muerte una vez en el interior celular. De este modo, el dominio marcador dirige específicamente la actividad enzimática del dominio tóxico sobre sus células diana. En conjunto, su elevada especificidad de acción, combinada con su extraordinaria potencia citotóxica y la ausencia de mecanismos específicos de resistencia dotan a las inmunotoxinas de unas características óptimas para su aplicación como agentes terapéuticos frente al cáncer y otras enfermedades. Treinta años después del desarrollo de las primeras inmunotoxinas, los avances realizados en el diseño, producción y efectividad de estas moléculas están permitiendo superar las limitaciones que en los orígenes de su investigación restringían sus posibilidades de aplicación clínica; entre ellas su elevada inmunogenicidad, su excesivo tamaño molecular o la aparición de efectos adversos asociados a cierta citotoxicidad inespecífica. De este modo, aunque todavía existen algunos impedimentos que dificultan la expansión de sus aplicaciones terapéuticas, principalmente relacionados con una limitada efectividad antitumoral in vivo; en los últimos años ha surgido un renovado interés en el estudio, optimización funcional y aplicación clínica de las inmunotoxinas, cuya consecuencia más importante ha sido la aprobación por la FDA de las tres primeras inmunotoxinas antitumorales para uso clínico. Así, actualmente, la investigación sobre estas moléculas bifuncionales se centra en aspectos como el desarrollo de nuevos formatos optimizados para el tratamiento de tumores sólidos, la mejora de sus propiedades farmacocinéticas y el diseño de nuevas construcciones con especificidad por nuevas dianas terapéuticas, encaminadas no sólo al tratamiento del cáncer, sino también al de otras patologías de tipo infeccioso, parasitario e inflamatorio. La Tesis doctoral que se presenta, se centra en el desarrollo de varios diseños de inmunotoxinas recombinantes basadas en la fusión de la ribotoxina α-sarcina a diversos dominios marcadores con especificidad por antígenos celulares relevantes en algunos procesos tumorales o alérgicos, incluyendo el desarrollo de formatos estructurales novedosos. En este sentido, los objetivos concretos se han dividido en dos bloques independientes: 1) Generación de una nueva línea de inmunotoxinas antitumorales CEA-específicas, utilizando diversos formatos de anticuerpo -VHH, scFv o scFv-20 trimerbody-, tratando de conseguir la optimización de su capacidad citotóxica antígeno-específica y de su efecto antitumoral in vivo; y 2) Desarrollo de dos estrategias novedosas, alérgeno-dependiente e independiente, basadas en inmunotoxinas para el tratamiento de la enfermedad alérgica. La primera, mediante un formato alérgeno-toxina, Der p 1-α-sarcina, centra su acción en las células efectoras de la alergia (mastocitos y basófilos) que presenten como diana terapéutica IgE Der p 1-específica en su membrana plasmática. La segunda, IL-33-dirigida, es una estrategia alérgeno-independiente cuya diana celular son las células ST2-positivas, en especial las células ILC2s, implicadas en el desarrollo y mantenimiento de la inflamación Th2 durante la respuesta alérgica respiratoria crónica...
Immunotoxins are a novel class of therapeutic agents consisting of a targeting domain (usually an antibody, a cytokine or growth factor, but also another cell-binding proteins) recombinantly fused to a cytotoxic domain, which is composed by protein toxin capable of promoting cell death once inside the cell. In this way, targeting domain marker directs the enzymatic activity of the toxic domain to specifically cause the death of its target cells. Taking together, the high specificity of their action, combined with their extraordinary cytotoxic potency and the absence of any specific resistance mechanisms endow immunotoxins with optimal properties for their application as therapeutic agents against cancer and other diseases. After thirty years since the development of the first immunotoxins, the advances made in the design, production and effectiveness of these molecules have allowed us to overcome the main limitations that restricted their previous possibilities of clinical application (e.g. high immunogenicity, excessive molecular size and certain cytotoxicity nonspecific). Thereby, although there are still some impediments that hinder the expansion of its therapeutic applications (e.g. inefficient cytotoxic capacity or limited antitumor effectiveness in vivo), in recent years there has been renewed interest in the study, functional implementation and clinical application of immunotoxins. One of whose most important consequences has been the FDA approval of the first three antitumor immunotoxins for clinical use. As a consequence, current immunotoxin research focuses on aspects such as the development of optimized formats for enhancing the treatment of solid tumors and the improvement of their pharmacokinetic properties; but also searching for new designs with specificity for innovative therapeutic targets, aimed not just at the treatment of cancer, but also infectious, parasitic and inflammatory disorders. Regarding the objective of this project we proposed the development of multiple recombinant immunotoxins based on the ribotoxin α-sarcin and various marker domains with specificity for cellular antigens relevant in the pathology of some tumor processes or allergic disease. The first is based on an allergen-dependent strategy (Der p 1-targeted) directed against allergy effector cells (mast cells and basophils) presenting IgE Der p 1-specific in their plasma membrane. The second one belongs to a allergen independent strategy (IL-33-targeted) acting on ST2-positive cells, especially ILC2s cells, that are involved in the development and maintenance of Th2 inflammation occurring during chronic respiratory allergic disease...
Immunotoxins are a novel class of therapeutic agents consisting of a targeting domain (usually an antibody, a cytokine or growth factor, but also another cell-binding proteins) recombinantly fused to a cytotoxic domain, which is composed by protein toxin capable of promoting cell death once inside the cell. In this way, targeting domain marker directs the enzymatic activity of the toxic domain to specifically cause the death of its target cells. Taking together, the high specificity of their action, combined with their extraordinary cytotoxic potency and the absence of any specific resistance mechanisms endow immunotoxins with optimal properties for their application as therapeutic agents against cancer and other diseases. After thirty years since the development of the first immunotoxins, the advances made in the design, production and effectiveness of these molecules have allowed us to overcome the main limitations that restricted their previous possibilities of clinical application (e.g. high immunogenicity, excessive molecular size and certain cytotoxicity nonspecific). Thereby, although there are still some impediments that hinder the expansion of its therapeutic applications (e.g. inefficient cytotoxic capacity or limited antitumor effectiveness in vivo), in recent years there has been renewed interest in the study, functional implementation and clinical application of immunotoxins. One of whose most important consequences has been the FDA approval of the first three antitumor immunotoxins for clinical use. As a consequence, current immunotoxin research focuses on aspects such as the development of optimized formats for enhancing the treatment of solid tumors and the improvement of their pharmacokinetic properties; but also searching for new designs with specificity for innovative therapeutic targets, aimed not just at the treatment of cancer, but also infectious, parasitic and inflammatory disorders. Regarding the objective of this project we proposed the development of multiple recombinant immunotoxins based on the ribotoxin α-sarcin and various marker domains with specificity for cellular antigens relevant in the pathology of some tumor processes or allergic disease. The first is based on an allergen-dependent strategy (Der p 1-targeted) directed against allergy effector cells (mast cells and basophils) presenting IgE Der p 1-specific in their plasma membrane. The second one belongs to a allergen independent strategy (IL-33-targeted) acting on ST2-positive cells, especially ILC2s cells, that are involved in the development and maintenance of Th2 inflammation occurring during chronic respiratory allergic disease...
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Tesis inédita de la Universidad Complutense de Madrid. Facultad de Ciencias Químicas, leída el 8-06-2020