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Fab quimérico que incorpora el dominio IgM Cμ1: perspectivas sobre las propiedades fisicoquímicas

Rara Sugimoto¹, Masato Kiyoshi², Hitomi Nakamura¹

¹Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.

Journal of biochemistry

|February 5, 2026

Resumen

La investigación del dominio IgM Cμ1 en fragmentos de anticuerpos (Fab) reveló que la glicosilación ligada a N es crucial para la estabilidad. Esta glicosilación suprime la agregación y mejora la estabilidad térmica en los Fab diseñados.

Área de la Ciencia:

Bioquímica
Inmunología
Ingeniería de Proteínas

Sus antecedentes:

La mayoría de las investigaciones sobre fragmentos de anticuerpos (Fab) se centran en IgG, con una comprensión limitada de otros isotipos.
El papel del dominio constante Cμ1 de IgM en la estructura y función del Fab está en gran medida sin explorar.

Objetivo del estudio:

Investigar el impacto del dominio humano IgM Cμ1 en las propiedades fisicoquímicas del Fab.
Determinar el papel de la glicosilación ligada a N dentro del dominio Cμ1 en la estabilidad y agregación del Fab.

Principales métodos:

Se diseñó un Fab quimérico (Cμ1Fab) reemplazando el dominio IgG1 CH1 con el dominio humano IgM Cμ1.
Se expresó el Cμ1Fab en células CHO y se evaluaron sus propiedades mediante SDS-PAGE, tratamiento con PNGase F, SPR y DSC.
Se creó un mutante de motivo de N-glicosilación (N166A) para análisis comparativo.

Principales resultados:

El Cμ1Fab conservó la actividad de unión al antígeno comparable al Fab de tipo salvaje.
La glicosilación ligada a N dentro del dominio Cμ1 suprimió significativamente la agregación y mejoró la estabilidad térmica (Tm = 66,0 °C para Cμ1Fab frente a 60,5 °C para el mutante N166A).
El mutante N166A exhibió una marcada agregación y su estabilidad térmica se redujo sustancialmente en comparación con el Cμ1Fab.

Conclusiones:

La glicosilación nativa ligada a N dentro del dominio IgM Cμ1 juega un papel crítico en el mantenimiento de la estabilidad del Fab.
Estos hallazgos proporcionan información valiosa para la ingeniería de anticuerpos, particularmente para el desarrollo de terapias basadas en anticuerpos más estables.

Palabras clave:

Fab IgM Análisis de mutaciones adalimumab estabilidad térmica

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