RESUMEN
Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy.
Asunto(s)
Ácido N-Acetilneuramínico , Neoplasias , Humanos , Ratones , Animales , Ácido N-Acetilneuramínico/metabolismo , Neutrófilos/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Anticuerpos , Ácidos Siálicos/metabolismo , Receptores ErbB , Microambiente TumoralRESUMEN
Therapeutic antibodies can elicit an immune response through different mechanisms, either cell independent via complement activation (CDC) or through activation of immune-effector cells (such as macrophages and NK cells). After target binding, the Fc part of the antibody will interact with Fc receptors on the surface of effector cells, leading to activation and lysis of the target cells by a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC). The ADCC of an antibody can be increased by modifying the carbohydrates on the Fc part. If the fucose on the first N-acetylglucosamine is absent, the affinity for the FcγRIIIa is increased and the ADCC enhanced. We describe the development of a chromatography method that is based on the differential affinity of the Fc receptor FcγRIIIa (high affinity V158 variant) for fucosylated and a-fucosylated antibodies. Immobilized FcγRIIIa can be used for the separation of immunoglobulins carrying these glycosylation variants for both, analytical and preparative purposes. The biological activity and fucose content of three pools enriched for fully fucosylated, mono-fucosylated or a-fucosylated carbohydrates could be characterized. Mono-fucosylated and a-fucosylated immunoglobulins have the same enhanced biological activity compared to fully fucosylated IgGs. A direct, label- and modification-free analytical method for screening of IgGs from culture supernatant was developed and was amenable to high-throughput screening. Clones producing antibodies with a high content of a-fucosylated oligosaccharides could be successfully selected.
Asunto(s)
Anticuerpos/uso terapéutico , Cromatografía/métodos , Fucosa/metabolismo , Ingeniería de Proteínas , Receptores de IgG/metabolismo , Secuencia de Aminoácidos , Anticuerpos/química , Citotoxicidad Celular Dependiente de Anticuerpos , Células Cultivadas , Glicosilación , Humanos , Inmunoglobulina G/metabolismo , Oligosacáridos/metabolismo , Receptores de IgG/químicaRESUMEN
Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.
RESUMEN
The antibody Fc domain engages the small family of Fc receptors, expressed on cells of the immune system and beyond, to stimulate a rich diversity of positive and negative cell-mediated effector functions. The emergence of monoclonal antibodies for the treatment of various pathologic conditions has provided additional insights into Fc receptor biology, and has suggested new strategies to exploit Fc receptor interactions to create improved therapeutics. While most therapeutic IgGs approved to date have retained a native IgG Fc domain, the knowledge gained over the last decades has provided the opportunity to design tailored and more efficacious immunotherapies exhibiting fewer side effects and longer half-life. This review summarizes recent advances made in the design of biologics that modulate or exploit Fc receptor-IgG interactions, and describes innovative drugs currently under investigation in clinical trials that have been precisely tuned to achieve a desired therapeutic effect.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Inmunoterapia/métodos , Receptores Fc/metabolismo , Proteínas Recombinantes de Fusión/uso terapéutico , Animales , Diseño de Fármacos , Humanos , Inmunoterapia/tendencias , Ingeniería de Proteínas , Receptores Fc/genética , Transducción de SeñalRESUMEN
FcγRs are a crucial component of the antibody response as they mediate the cellular effector functions in response to IgG-containing immune complexes (ICs). Therefore, they also play a central role in the pathogenesis of autoimmune diseases which offers an attractive option to specifically target this class of molecules and their interaction with IgG for treatment of immune disorders. In detail, two strategies are discussed in this article. SM101, a soluble FcγR that is already in clinical development competes with the interaction of IgG with membrane FcγRs. Oppositely, SM201 recruits the inhibitory FcγRIIB for a broad down-modulation of the immune system. The presented approaches for the treatment of autoimmune diseases have the potential be more efficacious with fewer side effects than the currently used therapeutic options.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Receptores de IgG/metabolismo , Animales , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Enfermedades Autoinmunes/terapia , Humanos , Inmunomodulación , Terapia de Inmunosupresión , Terapia Molecular Dirigida , Unión Proteica , Receptores de IgG/química , Receptores de IgG/genéticaRESUMEN
Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with wild-type IgA. In vitro, Fab- and Fc-mediated effector functions, such as inhibition of ligand binding, receptor modulation, and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity, were similar between wild-type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy because the novel IgA antibody demonstrated therapeutic activity also in non-FcαRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Receptores ErbB/inmunología , Inmunoterapia/métodos , Células Mieloides/metabolismo , Animales , Anticuerpos Antiidiotipos/administración & dosificación , Diferenciación Celular , Receptores ErbB/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Ratones Transgénicos , TransfecciónAsunto(s)
Progresión de la Enfermedad , Epidermólisis Ampollosa Adquirida/prevención & control , Receptores de IgG/uso terapéutico , Animales , Complejo Antígeno-Anticuerpo/metabolismo , Modelos Animales de Enfermedad , Epidermólisis Ampollosa Adquirida/metabolismo , Humanos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Immunoglobulins recognize and clear microbial pathogens and toxins through the coupling of variable region specificity to Fc-triggered cellular activation. These proinflammatory activities are regulated, thus avoiding the pathogenic sequelae of uncontrolled inflammation by modulating the composition of the Fc-linked glycan. Upon sialylation, the affinities for Fcγ receptors are reduced, whereas those for alternative cellular receptors, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)/CD23, are increased. We demonstrate that sialylation induces significant structural alterations in the Cγ2 domain and propose a model that explains the observed changes in ligand specificity and biological activity. By analogy to related complexes formed by IgE and its evolutionarily related Fc receptors, we conclude that this mechanism is general for the modulation of antibody-triggered immune responses, characterized by a shift between an "open" activating conformation and a "closed" anti-inflammatory state of antibody Fc fragments. This common mechanism has been targeted by pathogens to avoid host defense and offers targets for therapeutic intervention in allergic and autoimmune disorders.
Asunto(s)
Moléculas de Adhesión Celular/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Lectinas Tipo C/inmunología , Receptores de Superficie Celular/inmunología , Receptores de IgE/inmunología , Receptores de IgG/inmunología , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Dicroismo Circular , Cricetinae , Cricetulus , Glicosilación , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Modelos Moleculares , Unión Proteica , Estructura Terciaria de Proteína , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de IgE/genética , Receptores de IgE/metabolismo , Receptores de IgG/metabolismo , Ácidos Siálicos/metabolismo , Espectrofotometría Ultravioleta , TermodinámicaRESUMEN
Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate-carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.
Asunto(s)
Anticuerpos/inmunología , Carbohidratos/inmunología , Fucosa/inmunología , Receptores de IgG/inmunología , Animales , Anticuerpos/química , Anticuerpos/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Unión Competitiva/inmunología , Células CHO , Carbohidratos/química , Células Cultivadas , Cricetinae , Cricetulus , Cristalografía por Rayos X , Fucosa/química , Fucosa/metabolismo , Glicosilación , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/química , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Cinética , Leucocitos Mononucleares/inmunología , Modelos Moleculares , Estructura Molecular , Unión Proteica/inmunología , Estructura Terciaria de Proteína , Receptores de IgG/química , Receptores de IgG/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Resonancia por Plasmón de SuperficieRESUMEN
Antibody-dependent cellular cytotoxicity (ADCC) contributes to clinical efficacy of a broad range of antibody therapeutics. However, reproducible quantitation of ADCC activity on a cellular level remains highly challenging, as ADCC assays rely on primary effector cells associated with laborious cell purification procedures, resulting in highly donor-dependent results. Here, we report the development of an in vitro ADCC method based on an engineered human natural killer cell line as effectors. While eliminating the limitations of primary cells, this assay exhibits all the hallmarks of traditional ADCC assay systems. We have used this assay to measure the ADCC activity of a humanized IgG1 antibody directed against the human CD20 antigen. Our data show that this assay is capable to measure small changes in ADCC and can therefore be used to test therapeutic antibodies against cell-surface targets for their depleting activity.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos , Células Asesinas Naturales/inmunología , Anticuerpos Monoclonales/inmunología , Antígenos CD20/inmunología , Línea Celular , Citometría de Flujo , Humanos , Inmunoglobulina G/inmunologíaRESUMEN
CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell-depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders.
Asunto(s)
Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/farmacología , Antígenos CD20/inmunología , Linfocitos B/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino , Citotoxicidad Celular Dependiente de Anticuerpos , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunidad Celular , Fragmentos Fc de Inmunoglobulinas/genética , Región Variable de Inmunoglobulina/genética , Técnicas In Vitro , Depleción Linfocítica/métodos , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/terapia , Macaca fascicularis , Ratones , Ratones SCID , Trasplante de Neoplasias , Ingeniería de Proteínas , Receptores de IgG/inmunología , Rituximab , Trasplante HeterólogoRESUMEN
Immune complex (IC) binding to Fc gamma receptors (FcgammaRs) is central for inflammatory reactions seen in autoimmune diseases. Consequently, a therapeutic agent with a possibility to interfere with binding of pathogenic IC to FcgammaRs would be valuable in autoimmune disorders such as rheumatoid arthritis (RA). Here we have explored the therapeutic effect of a recombinant soluble human FcgammaRIIb (sFcgammaRIIb) protein in collagen-induced arthritis (CIA). In vitro studies of the sFcgammaRIIb demonstrated binding to mouse IgG, suggesting that sFcgammaRIIb can absorb pathogenic IgG anti-collagen type II (CII) IC in vivo. Hence, administration of sFcgammaRIIb significantly reduced CIA severity compared to control treated mice. The sFcgammaRIIb treated mice had significantly less IgG anti-CII antibodies in serum and lower mRNA levels of inflammatory cytokines compared to control mice. In conclusion, sFcgammaRIIb treatment ameliorates CIA by reducing IC-stimulated inflammation and joint swelling. This suggests that recombinant sFcgammaRIIb may be useful as therapeutic agent in RA.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Receptores de IgG/inmunología , Animales , Citocinas/genética , Citocinas/inmunología , Relación Dosis-Respuesta Inmunológica , Ensayo de Inmunoadsorción Enzimática , Pie/patología , Histocitoquímica , Humanos , Inmunización , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos DBA , ARN Mensajero/química , ARN Mensajero/genética , Proteínas Recombinantes/farmacología , Ribonucleasas/químicaRESUMEN
FcgammaRIIIa plays a prominent role in the elimination of tumor cells by antibody-based cancer therapies. Non-fucosylated bisected IgGs bind this receptor with increased affinity and trigger FcgammaRIII-mediated effector functions more efficiently than native, fucosylated antibodies. In this study the contribution of the carbohydrates of both binding partners to the strength of the complex was analyzed. Glycoengineering of the antibody increased affinity for two polymorphic forms of soluble human FcgammaRIIIa (by up to 50-fold) but did not affect binding to the inhibitory FcgammaRIIb receptor. While the absence of carbohydrate at FcgammaRIIIa's Asn-162 increased affinity for native IgG, presumably due to the removal of steric hindrance caused by the bulky sugars, it unexpectedly reduced affinity for glycoengineered (GE) antibodies by over one order of magnitude, bringing the affinity down to the same level as for native IgG. We conclude that the high affinity between GE antibodies and FcgammaRIII is mediated by productive interactions formed between the receptor carbohydrate attached at Asn-162 and regions of the Fc that are only accessible when it is nonfucosylated. As FcgammaRIIIa and FcgammaRIIIb are the only human Fcgamma receptors glycosylated at this position, the proposed interactions explain the observed selective affinity increase of GE antibodies for only these receptors. Furthermore, we predict from our structural model that only one of the two Fc-fucose residues needs to be absent for increased binding affinity toward FcgammaRIII. This information can be exploited for the design of new antibodies with altered Fc receptor binding affinity and enhanced therapeutic potential.
Asunto(s)
Asparagina/química , Carbohidratos/química , Inmunoglobulina G/química , Receptores de IgG/química , Anticuerpos/química , Línea Celular , Fucosa/química , Vectores Genéticos , Glicosilación , Humanos , Células Jurkat , Cinética , Ligandos , Modelos Moleculares , Oligosacáridos/química , Unión Proteica , Isoformas de Proteínas , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Resonancia por Plasmón de SuperficieRESUMEN
Pathogenic bacteria have developed complex and diverse virulence mechanisms that weaken or disable the host immune defense system. IdeS (IgG-degrading enzyme of Streptococcus pyogenes) is a secreted cysteine endopeptidase from the human pathogen S. pyogenes with an extraordinarily high degree of substrate specificity, catalyzing a single proteolytic cleavage at the lower hinge of human IgG. This proteolytic degradation promotes inhibition of opsonophagocytosis and interferes with the killing of group A Streptococcus. We have determined the crystal structure of the catalytically inactive mutant IdeS-C94S by x-ray crystallography at 1.9-A resolution. Despite negligible sequence homology to known proteinases, the core of the structure resembles the canonical papain fold although with major insertions and a distinct substrate-binding site. Therefore IdeS belongs to a unique family within the CA clan of cysteine proteinases. Based on analogy with inhibitor complexes of papain-like proteinases, we propose a model for substrate binding by IdeS.
Asunto(s)
Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Inmunoglobulina G/metabolismo , Streptococcus pyogenes/enzimología , Secuencia de Aminoácidos , Sitios de Unión , Catálisis , Cristalografía por Rayos X , Cisteína/genética , Cisteína/metabolismo , Cisteína Endopeptidasas/genética , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/química , Modelos Moleculares , Datos de Secuencia Molecular , Papaína/química , Papaína/metabolismo , Estructura Terciaria de Proteína , Alineación de Secuencia , Streptococcus pyogenes/genética , Especificidad por SustratoRESUMEN
A method for the determination of the stoichiometry of protein complexes has been developed, which is based on proteolytic digestion of the complex, labeling with a fluorescent reagent, specific for amino or sulfhydryl groups, and separation by liquid chromatography with fluorescence and mass spectrometric detection. The intensity of the fluorescence signal of the labeled peptides resulting from different proteins is directly proportional to the stoichiometry of these proteins in the complex. The performance of the method was evaluated with standard peptides and proteins to ensure that accurate molar ratios can be obtained from the fluorescence chromatogram. Standard deviations of the measured molar ratio from the expected molar ratio were below 10% for both peptides and proteins. The method was finally employed for the determination of the stoichiometry of the 1:1 complex of sFc gamma RIII and hFc1. Using the described methodology, a stoichiometry of 1:1.1 was measured, which agrees well with a 1:1 complex.
Asunto(s)
Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Péptidos/química , Angiotensinas/química , Bradiquinina/química , Cromatografía , Cromatografía Líquida de Alta Presión , Fluoresceínas/farmacología , Humanos , Ligandos , Unión Proteica , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Factores de TiempoRESUMEN
FcalphaRI is the predominant receptor for IgA in the serum. Nevertheless, the interaction between the molecules that finally leads to an immune response is poorly understood. To investigate the structural requirements for IgA binding, the extracellular region of FcalphaRI was cloned and overexpressed in Escherichia coli. The resulting inclusion-body protein was refolded and purified. Despite its deglycosylated state, this recombinant FcalphaRI retained its ability to bind human IgA. The protein crystallized spontaneously as microcrystalline needles. Recrystallization yielded crystals belonging to a primitive monoclinic space group. A complete 2.8 A resolution X-ray diffraction data set was collected using synchrotron radiation.
Asunto(s)
Antígenos CD/química , Receptores Fc/química , Antígenos CD/genética , Antígenos CD/aislamiento & purificación , Antígenos CD/metabolismo , Cristalización , Cristalografía por Rayos X/métodos , Escherichia coli/metabolismo , Espacio Extracelular/química , Humanos , Inmunoglobulina A/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Unión Proteica , Receptores Fc/genética , Receptores Fc/aislamiento & purificación , Receptores Fc/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , SincrotronesRESUMEN
Recently, Fc receptors for immunoglobulins moved further into the focus of pure and applied research as a role in the induction and development of autoimmune diseases and allergies is becoming more probable. Indeed by connecting the humoral with the cellular immune response FcRs possess an important role in the immune system in which the initial, crucial step is the binding of an immunoglobulin to the cell bound receptor. Thereafter a variety of effector functions depending on the cell and the receptor is triggered. This key event could recently be visualised with the solution of the crystal structure of a human Fc receptor in complex with its native ligand the Fc fragment of IgG1. In this paper the reasons for a 1:1 stoichiometry between Fc receptor and Fc Fragment and the medical applications of potential inhibitors of complex formation are highlighted.