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1.
Structure ; 31(8): 958-967.e3, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37279757

RESUMO

B and T lymphocyte attenuator (BTLA) is an attractive target for a new class of therapeutics that attempt to rebalance the immune system by agonizing checkpoint inhibitory receptors (CIRs). Herpesvirus entry mediator (HVEM) binds BTLA in both trans- and cis-orientations. We report here the development and structural characterization of three humanized BTLA agonist antibodies, 22B3, 25F7, and 23C8. We determined the crystal structures of the antibody-BTLA complexes, showing that these antibodies bind distinct and non-overlapping epitopes of BTLA. While all three antibodies activate BTLA, 22B3 mimics HVEM binding to BTLA and shows the strongest agonistic activity in functional cell assays and in an imiquimod-induced mouse model of psoriasis. 22B3 is also capable of modulating HVEM signaling through the BTLA-HVEM cis-interaction. The data obtained from crystal structures, biochemical assays, and functional studies provide a mechanistic model of HVEM and BTLA organization on the cell surface and informed the discovery of a highly active BTLA agonist.


Assuntos
Receptores Imunológicos , Linfócitos T , Camundongos , Animais , Linfócitos T/metabolismo , Receptores Imunológicos/metabolismo , Anticorpos/metabolismo
2.
J Allergy Clin Immunol ; 121(2): 441-447.e5, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17949802

RESUMO

BACKGROUND: A human Fcgamma-Fcepsilon fusion protein (GE2) designed to inhibit FcepsilonRI signaling by coaggregating FcepsilonRI with the inhibitory receptor FcgammaRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcgammaRIIB. OBJECTIVE: Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. METHODS: The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow-derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum-sensitized cynomolgus monkeys. RESULTS: mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcgammaRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcgammaRIIB phosphorylation and the subsequent recruitment of SH2 domain-containing inositol polyphosphate 5' phosphatase (SHIP) 1 and SH2 domain-containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. CONCLUSION: mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcgammaRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.


Assuntos
Mastócitos/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de IgG/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Domínios de Homologia de src , Anafilaxia/prevenção & controle , Animais , Ascaris suum , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Imunização , Imunoglobulina E/metabolismo , Inositol Polifosfato 5-Fosfatases , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/química , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Quinases/metabolismo , Receptores de IgE/metabolismo , Proteínas Recombinantes de Fusão/genética , Quinase Syk , Receptor 4 Toll-Like/metabolismo
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