Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies
SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00233/full |
| _version_ | 1818524705714339840 |
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| author | Philipp eHaselmayer Montserrat eCamps Mathilde eMuzerelle Mathilde eMuzerelle Samer eEl Bawab Caroline eWaltzinger Caroline eWaltzinger Lisa eBruns Nada eAbla Mark ePolokoff Carole eJond-Necand Marilène eGaudet Audery eBenoit Dominique eBertschy Meier Catherine eMartin Denise eGretener Maria Stella Lombardi Maria Stella Lombardi Roland eGrenningloh Christoph eLadel Jørgen Søberg Petersen Jørgen Søberg Petersen Pascale eGaillard Pascale eGaillard Hong eJi Hong eJi |
| author_facet | Philipp eHaselmayer Montserrat eCamps Mathilde eMuzerelle Mathilde eMuzerelle Samer eEl Bawab Caroline eWaltzinger Caroline eWaltzinger Lisa eBruns Nada eAbla Mark ePolokoff Carole eJond-Necand Marilène eGaudet Audery eBenoit Dominique eBertschy Meier Catherine eMartin Denise eGretener Maria Stella Lombardi Maria Stella Lombardi Roland eGrenningloh Christoph eLadel Jørgen Søberg Petersen Jørgen Søberg Petersen Pascale eGaillard Pascale eGaillard Hong eJi Hong eJi |
| author_sort | Philipp eHaselmayer |
| collection | DOAJ |
| description | SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune complex deposition as well as reduced inflammation, fibrosis and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant Mycophenolate mofetil (MMF). Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis. |
| first_indexed | 2024-12-11T06:00:26Z |
| format | Article |
| id | doaj.art-c398c4f28c9740c99b5b10200732c270 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T06:00:26Z |
| publishDate | 2014-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c398c4f28c9740c99b5b10200732c2702022-12-22T01:18:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242014-05-01510.3389/fimmu.2014.0023389577Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studiesPhilipp eHaselmayer0Montserrat eCamps1Mathilde eMuzerelle2Mathilde eMuzerelle3Samer eEl Bawab4Caroline eWaltzinger5Caroline eWaltzinger6Lisa eBruns7Nada eAbla8Mark ePolokoff9Carole eJond-Necand10Marilène eGaudet11Audery eBenoit12Dominique eBertschy Meier13Catherine eMartin14Denise eGretener15Maria Stella Lombardi16Maria Stella Lombardi17Roland eGrenningloh18Christoph eLadel19Jørgen Søberg Petersen20Jørgen Søberg Petersen21Pascale eGaillard22Pascale eGaillard23Hong eJi24Hong eJi25Merck Serono S.A.Merck Serono S.A.Merck Serono S.A.Debiopharm Research and Manufacturing S.AMerck Serono S.A.Merck Serono S.A.Roche Glycart AGMerck Serono S.A.Merck Serono S.A.DiscoveRx CorporationMerck Serono S.A.Merck Serono S.A.Merck Serono S.A.Merck Serono S.A.Merck Serono S.A.Merck Serono S.A.Merck Serono S.A.University of GenevaEMD SeronoMerck Serono S.A.Merck Serono S.A.Novo Nordisk A/SMerck Serono S.A.ALAXIA SASMerck Serono S.A.Novo Nordisk A/SSLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune complex deposition as well as reduced inflammation, fibrosis and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant Mycophenolate mofetil (MMF). Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00233/fullLupus Nephritisimmune responseDrug DevelopmentSLEpharmacokinetic/pharmacodynamic modelingPI3Kδ inhibitor |
| spellingShingle | Philipp eHaselmayer Montserrat eCamps Mathilde eMuzerelle Mathilde eMuzerelle Samer eEl Bawab Caroline eWaltzinger Caroline eWaltzinger Lisa eBruns Nada eAbla Mark ePolokoff Carole eJond-Necand Marilène eGaudet Audery eBenoit Dominique eBertschy Meier Catherine eMartin Denise eGretener Maria Stella Lombardi Maria Stella Lombardi Roland eGrenningloh Christoph eLadel Jørgen Søberg Petersen Jørgen Søberg Petersen Pascale eGaillard Pascale eGaillard Hong eJi Hong eJi Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies Frontiers in Immunology Lupus Nephritis immune response Drug Development SLE pharmacokinetic/pharmacodynamic modeling PI3Kδ inhibitor |
| title | Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies |
| title_full | Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies |
| title_fullStr | Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies |
| title_full_unstemmed | Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies |
| title_short | Characterization of novel PI3Kδ inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies |
| title_sort | characterization of novel pi3kδ inhibitors as potential therapeutics for sle and lupus nephritis in pre clinical studies |
| topic | Lupus Nephritis immune response Drug Development SLE pharmacokinetic/pharmacodynamic modeling PI3Kδ inhibitor |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2014.00233/full |
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