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1.
Nat Immunol ; 18(8): 889-898, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28604720

RESUMO

Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.


Assuntos
Complemento C1q/imunologia , Citotoxicidade Imunológica/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Imunoterapia , Neoplasias/tratamento farmacológico , Fagocitose/imunologia , Receptores de IgG/imunologia , Animais , Anticorpos Monoclonais , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/imunologia , Linhagem Celular Tumoral , Cromatografia em Gel , Cromatografia Líquida , Complemento C1q/metabolismo , Cristalização , Cristalografia por Raios X , Ensaio de Imunoadsorção Enzimática , Humanos , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Técnicas In Vitro , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Espectrometria de Massas , Camundongos , Neoplasias/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de IgG/metabolismo , Ressonância de Plasmônio de Superfície , Espectrometria de Massas em Tandem
3.
Eur J Immunol ; 52(5): 753-759, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35133670

RESUMO

IgG is the predominant antibody class generated during infections and used for the generation of therapeutic antibodies. Antibodies are mainly characterized in or generated from animal models that support particular infections, respond to particular antigens or allow the generation of hybridomas. Due to the availability of numerous transgenic mouse models and the ease of performing bioassays with human blood cells in vitro, most antibodies from species other than mice and humans are tested in vitro using human cells and/or in vivo using mice. In this process, it is expected, but not yet systematically documented, that IgG from these species interact with human or mouse IgG receptors (FcγRs). In this study, we undertook a systematic assessment of binding specificities of IgG from various species to the families of mouse and human FcγRs including their polymorphic variants. Our results document the specific binding patterns for each of these IgG (sub)classes, reveal possible caveats of antibody-based immunoassays, and will be a useful reference for the transition from one animal model to preclinical mouse models or human cell-based bioassays.


Assuntos
Imunoglobulina G , Receptores de IgG , Animais , Proteínas de Transporte/metabolismo , Humanos , Hibridomas , Camundongos , Camundongos Transgênicos
4.
Sci Transl Med ; 16(764): eado4463, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39259810

RESUMO

Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.


Assuntos
Anafilaxia , Rocurônio , Rocurônio/efeitos adversos , Animais , Humanos , Anafilaxia/imunologia , Anticorpos , Camundongos , Período Perioperatório , Androstanóis/efeitos adversos , Sugammadex/efeitos adversos , Imunoglobulina E/imunologia , Especificidade de Anticorpos , Feminino , Modelos Animais de Doenças , Masculino
5.
J Clin Invest ; 130(3): 1330-1335, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31770111

RESUMO

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.


Assuntos
Anafilaxia/imunologia , Toxidermias/imunologia , Mutação , Omalizumab/efeitos adversos , Receptores de IgG/imunologia , Anafilaxia/induzido quimicamente , Anafilaxia/genética , Anafilaxia/patologia , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Toxidermias/genética , Toxidermias/patologia , Camundongos , Camundongos Knockout , Omalizumab/genética , Omalizumab/farmacologia , Receptores de IgG/genética
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