Publication: Nuevos diseños nanobiotecnológicos frente a cáncer basados en inmunotoxinas
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2022-03-15
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Universidad Complutense de Madrid
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Abstract
En la actualidad, y pese al desarrollo de tecnologías biomédicas avanzadas y de nuevos métodos diagnósticos, la incidencia y mortalidad del cáncer constituyen uno de los principales riesgos para la salud y la esperanza de vida. Dentro de los tipos de cáncer, el cáncer colorrectal ocupa la tercera posición en incidencia y la segunda posición en mortalidad para la población global. La terapia suele consistir en cirugía, acompañada de quimioterapia y radioterapia como terapia adyuvante. No obstante, estos tratamientos no son específicos, ocasionando toxicidades inespecíficas y comprometiendo directamente la calidad de vida de los pacientes. Por ello, la inmunoterapia y el uso de anticuerpos monoclonales ha constituido un avance primordial en el tratamiento de esta enfermedad, al tratarse de terapias dirigidas de gran especificidad, presentando resultados clínicos prometedores. Dentro de la inmunoterapia pasiva basada en anticuerpos monoclonales destacan las inmunotoxinas. Las inmunotoxinas son proteínas quiméricas que presentan un dominio marcador (normalmente un anticuerpo o derivado suyo) que dirige específicamente la acción de un dominio tóxico (formado por una toxina de naturaleza proteica) hacia la célula diana o tumoral, provocando la muerte de la misma. Desde los diseños iniciales, las inmunotoxinas han experimentado una evolución, tanto en su dominio marcador, mediante la incorporación de dominios de menor tamaño, como los formatos scFv (fragmento variable de cadena única) o VHH (nanobody), o con formatos triméricos (trimerbody); como en su dominio tóxico, mediante la utilización de toxinas de diferente origen o con variantes menos inmunogénicas. En este sentido, es destacable la utilización de ribotoxinas fúngicas como dominio tóxico de inmunotoxinas, y en particular de su miembro mejor caracterizado, la α-sarcina, debido a su elevada estabilidad térmica, a su pequeño tamaño, a su baja inmunogenicidad y a su elevada eficacia catalítica...
Nowadays, the incidence and mortality of cancer remain one of the main risks to human health and lifespan, in spite of the development of biomedical technology and new diagnostic methods. Among the cancer classification, colorectal cancer remains in third place considering incidence, and second place considering mortality for global population. Current therapy consists of surgery, followed by chemotherapy or radiotherapy as adjuvant treatment. However, these are non-specific therapies, leading to systemic toxicity and affecting directly the quality of life of patients. That is why immunotherapy and the advent of monoclonal antibodies have arisen as a breakthrough in the treatment of this disease, as they are target therapies with great specificity and promising clinical results.Regarding passive immunotherapy based on monoclonal antibodies, immunotoxins are a type of immunoconjugates. Immunotoxins are chimeric molecules, with a target domain (usually an antibody or a derived from it) that targets specifically the action of a toxic domain (a toxic protein) towards the cancerous cell, leading to its death. Since immunotoxins were first conceived, they have undergone an evolution in its designs, with the use of smaller target domains, such as scFv (single chain fragment variable), VHH (nanobody) or trimeric formats (trimerbody) or using toxins from different sources, being less immunogenic. Regarding the latter, the use of fungal ribotoxins, being α-sarcin the most characterized member of fungal ribotoxins, has earned quite interest because of its high thermal stability, small size, low immunogenicity and high catalytic efficiency...
Nowadays, the incidence and mortality of cancer remain one of the main risks to human health and lifespan, in spite of the development of biomedical technology and new diagnostic methods. Among the cancer classification, colorectal cancer remains in third place considering incidence, and second place considering mortality for global population. Current therapy consists of surgery, followed by chemotherapy or radiotherapy as adjuvant treatment. However, these are non-specific therapies, leading to systemic toxicity and affecting directly the quality of life of patients. That is why immunotherapy and the advent of monoclonal antibodies have arisen as a breakthrough in the treatment of this disease, as they are target therapies with great specificity and promising clinical results.Regarding passive immunotherapy based on monoclonal antibodies, immunotoxins are a type of immunoconjugates. Immunotoxins are chimeric molecules, with a target domain (usually an antibody or a derived from it) that targets specifically the action of a toxic domain (a toxic protein) towards the cancerous cell, leading to its death. Since immunotoxins were first conceived, they have undergone an evolution in its designs, with the use of smaller target domains, such as scFv (single chain fragment variable), VHH (nanobody) or trimeric formats (trimerbody) or using toxins from different sources, being less immunogenic. Regarding the latter, the use of fungal ribotoxins, being α-sarcin the most characterized member of fungal ribotoxins, has earned quite interest because of its high thermal stability, small size, low immunogenicity and high catalytic efficiency...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 16-12-2021