RESUMEN
Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been described in the literature but none of them completely eliminates binding to all of the Fcγ receptors. Here we describe a set of novel variants having specific amino acid substitutions in the Fc region at L234 and L235 combined with the substitution G236R. They show no detectable binding to Fcγ receptors or to C1q, are inactive in functional cell-based assays and do not elicit inflammatory cytokine responses. Meanwhile, binding to FcRn, manufacturability, stability and potential for immunogenicity are unaffected. These variants have the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Complemento C1q/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/metabolismo , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Sustitución de Aminoácidos , Afinidad de Anticuerpos , Complemento C1q/genética , Complemento C1q/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Unión Proteica , Ingeniería de Proteínas , Receptores Fc/genética , Receptores Fc/inmunología , Receptores de IgG/genética , Receptores de IgG/inmunologíaRESUMEN
A conceptually and practically simple alternative approach to the use of arylboron species as the organometallic component in cross-coupling processes is described whereby trihydroxyborate salts are isolated and directly employed. The protocol derives practical benefit from the ease and convenience of the isolation and subsequent use of the discrete borate salts, eliminates the need for additional base, and aids the use of correct reaction stoichiometry.