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1.
J Immunol ; 194(1): 84-92, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25416807

RESUMO

Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor a subunit (IL-2R a or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ~50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN- g, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2R bg signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Interleucina-2/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Contagem de Linfócito CD4 , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Daclizumabe , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Subunidade gama Comum de Receptores de Interleucina/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Interleucina-2/biossíntese , Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade beta de Receptor de Interleucina-2/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Fosforilação , Regiões Promotoras Genéticas , Fator de Transcrição STAT5/metabolismo , Tolerância a Antígenos Próprios/efeitos dos fármacos , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/imunologia
2.
Mult Scler ; 17(12): 1441-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21807759

RESUMO

OBJECTIVE: The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS). METHODS: DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion. RESULTS: Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNß)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNß, 2.01 [1.25]; DAC low/IFNß, 2.29 [1.06]; placebo/IFNß, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029). CONCLUSION: CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno CD56/análise , Imunoglobulina G/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Células Matadoras Naturais/imunologia , Esclerose Múltipla/imunologia , Proliferação de Células/efeitos dos fármacos , Daclizumabe , Humanos , Células Matadoras Naturais/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo
3.
Clin Cancer Res ; 26(10): 2308-2317, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31969330

RESUMO

PURPOSE: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel. RESULTS: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively. CONCLUSIONS: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Imunoconjugados/farmacocinética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Terapia de Salvação , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Distribuição Tecidual
4.
Clin Pharmacokinet ; 55(1): 121-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26242380

RESUMO

BACKGROUND AND OBJECTIVE: Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood. METHODS: Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200-400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody. RESULTS: CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005-0.073); IC50(desaturation) 0.86 µg/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8). CONCLUSIONS: Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Imunoglobulina G/administração & dosagem , Receptores de Interleucina-2/antagonistas & inibidores , Administração Intravenosa , Daclizumabe , Método Duplo-Cego , Esquema de Medicação , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Modelos Biológicos , Dinâmica não Linear
5.
MAbs ; 8(7): 1417-1424, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27367933

RESUMO

The CD25-binding antibody daclizumab high-yield process (DAC HYP) is an interleukin (IL)-2 signal modulating antibody that shares primary amino acid sequence and CD25 binding affinity with Zenapax®, a distinct form of daclizumab, which was approved for the prevention of acute organ rejection in patients receiving renal transplants as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. Comparison of the physicochemical properties of the two antibody forms revealed the glycosylation profile of DAC HYP differs from Zenapax in both glycan distribution and the types of oligosaccharides, most notably high-mannose, galactosylated and galactose-α-1,3-galactose (α-Gal) oligosaccharides, resulting in a DAC HYP antibody material that is structurally distinct from Zenapax. Although neither antibody elicited complement-dependent cytotoxicity in vitro, DAC HYP antibody had significantly reduced levels of antibody-dependent cell-mediated cytotoxicity (ADCC). The ADCC activity required natural killer (NK) cells, but not monocytes, suggesting the effects were mediated through binding to Fc-gamma RIII (CD16). Incubation of each antibody with peripheral blood mononuclear cells also caused the down-modulation of CD16 expression on NK cells and the CD16 down-modulation was greater for Zenapax in comparison to that observed for DAC HYP. The substantive glycosylation differences between the two antibody forms and corresponding greater Fc-mediated effector activities by Zenapax, including cell killing activity, manifest as a difference in the biological function and pharmacology between DAC HYP and Zenapax.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Imunoglobulina G/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Daclizumabe , Glicosilação , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologia
6.
Expert Rev Clin Pharmacol ; 7(1): 9-19, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24308792

RESUMO

Daclizumab is a monoclonal antibody specific for the IL-2R α chain (CD25). Daclizumab has been observed to have multiple mechanisms of action, which may contribute to beneficial effects in immune-related disease and particularly in relapsing and remitting multiple sclerosis (RRMS). These include inhibition of activated immune cells, increase of regulatory natural killer cells, effects on dendritic cells, inhibition of innate lymphoid tissue inducer cells and altered responses involving IL-2 transpresentation. The antibody has shown considerable promise in open-label and early Phase II clinical trials when used as a monotherapy, or in combination with IFN-ß. In recently completed randomized trials in RRMS, treatment with daclizumab monotherapy compared with placebo resulted in clinically meaningful and statistically significant reductions in relapses, active lesions on brain MRI and slowing of disability progression. A large Phase III trial in RRMS is ongoing.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoglobulina G/uso terapêutico , Interleucina-2/imunologia , Esclerose Múltipla/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Encéfalo/fisiopatologia , Daclizumabe , Progressão da Doença , Humanos , Imunoglobulina G/farmacologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Esclerose Múltipla/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia
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