RESUMO
Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas.
Assuntos
Terapia Biológica/métodos , Biotecnologia/métodos , Fragmentos Fc das Imunoglobulinas/farmacologia , Medicina Molecular/métodos , Proteínas Recombinantes de Fusão/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Proteínas Recombinantes de Fusão/genéticaRESUMO
The success of Fc-fusion bio-therapeutics has spurred the development of other Fc-fusion products for treating and/or vaccinating against a range of diseases. We describe a method to modulate their function by converting them into well-defined stable polymers. This strategy resulted in cylindrical hexameric structures revealed by tapping mode atomic force microscopy (AFM). Polymeric Fc-fusions were significantly less immunogenic than their dimeric or monomeric counterparts, a result partly owing to their reduced ability to interact with critical Fc-receptors. However, in the absence of the fusion partner, polymeric IgG1-Fc molecules were capable of binding selectively to FcγRs, with significantly increased affinity owing to their increased valency, suggesting that these reagents may prove of immediate utility in the development of well-defined replacements for intravenous immunoglobulin (IVIG) therapy. Overall, these findings establish an effective IgG Fc-fusion based polymeric platform with which the therapeutic and vaccination applications of Fc-fusion immune-complexes can now be explored.
Assuntos
Fragmentos Fc das Imunoglobulinas/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sequência de Bases , Terapia Biológica , Proteínas do Sistema Complemento/metabolismo , Primers do DNA/genética , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunização , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoglobulina G/química , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Malária/imunologia , Malária/parasitologia , Malária/terapia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Plasmodium berghei , Ligação Proteica , Multimerização Proteica , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Parasite drug resistance and difficulties in developing effective vaccines have precipitated the search for alternative therapies for malaria. The success of passive immunization suggests that immunoglobulin (Ig)-based therapies are effective. To further explore the mechanism(s) by which antibody mediates its protective effect, we generated human chimeric IgG1 and IgA1 and a single-chain diabody specific for the C-terminal 19-kDa region of Plasmodium yoelii merozoite surface protein 1 (MSP119), a major target of protective immune responses. These novel human reagents triggered in vitro phagocytosis of merozoites but, unlike their parental mouse IgG2b, failed to protect against parasite challenge in vivo. Therefore, the Fc region appears critical for mediating protection in vivo, at least for this MSP119 epitope. Such antibodies may serve as prototype therapeutic agents, and as useful tools in the development of in vitro neutralization assays with Plasmodium parasites.