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1.
PLoS One ; 15(7): e0236172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726321

RESUMO

There are several broadly neutralizing monoclonal antibodies that neutralize influenza viruses with different mechanisms from traditional polyclonal antibodies induced by vaccination. CT149, which is one of the broadly neutralizing antibodies, was also previously reported to neutralize group 2 and some of group 1 influenza viruses (13 out of 13 tested group 2 viruses and 5 out of 11 group 1 viruses). In this study, we developed another antibody with the aim of compensating partial coverage of CT149 against group 1 influenza viruses. CT120 was screened among different antibody candidates and mixed with CT149. Importantly, although the binding sites of CT120 and CT149 are close to each other, the two antibodies do not interfere. The mixture of CT120 and CT149, which we named as CT-P27, showed broad efficacy by neutralizing 37 viruses from 11 different subtypes, of both group 1 and 2 influenza A viruses. Moreover, CT-P27 showed in vivo therapeutic efficacy, long prophylactic potency, and synergistic effect with oseltamivir in influenza virus-challenged mouse models. Our findings provide a novel therapeutic opportunity for more efficient treatment of influenza.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/farmacologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos/imunologia , Antígenos Virais/imunologia , Hemaglutinação/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Camundongos , Testes de Neutralização , Vacinação
2.
Aliment Pharmacol Ther ; 52(2): 292-302, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32506695

RESUMO

BACKGROUND: Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited. AIMS: To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab. METHODS: GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59µg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250µg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag). RESULTS: Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 µg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 µg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 µg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 µg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66). CONCLUSIONS: GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 µg/mL at week 6 and 2.4 µg/mL during maintenance.


Assuntos
Anticorpos Monoclonais/sangue , Antirreumáticos/sangue , Colite Ulcerativa/sangue , Adulto , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Área Sob a Curva , Colite Ulcerativa/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Indução de Remissão , Adulto Jovem
3.
Nat Med ; 26(4): 519-528, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32284611

RESUMO

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.


Assuntos
Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/imunologia , Receptor de Morte Celular Programada 1/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Animais , Antirretrovirais/imunologia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Antígeno CTLA-4/antagonistas & inibidores , Macaca mulatta , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Viremia/induzido quimicamente , Replicação Viral/efeitos dos fármacos , Suspensão de Tratamento
4.
Cancer Chemother Pharmacol ; 85(5): 831-842, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222808

RESUMO

PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais , Imunoconjugados , Linfoma de Células B , Rituximab , Administração Intravenosa , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinética
6.
Proc Natl Acad Sci U S A ; 117(11): 6086-6091, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123080

RESUMO

Recombinant immunotoxins (RITs) are chimeric proteins composed of an Fv and a protein toxin being developed for cancer treatment. The Fv brings the toxin to the cancer cell, but most of the RITs do not reach the tumor and are removed by other organs. To identify cells responsible for RIT removal, and the pathway by which RITs reach these cells, we studied SS1P, a 63-kDa RIT that targets mesothelin-expressing tumors and has a short serum half-life. The major organs that remove RIT were identified by live mouse imaging of RIT labeled with FNIR-Z-759. Cells responsible for SS1P removal were identified by immunohistochemistry and intravital two-photon microscopy of kidneys of rats. The primary organ of SS1P removal is kidney followed by liver. In the kidney, SS1P passes through the glomerulus, is taken up by proximal tubular cells, and transferred to lysosomes. In the liver, macrophages are involved in removal. The short half-life of SS1P is due to its very rapid filtration by the kidney followed by degradation in proximal tubular cells of the kidney. In mice treated with SS1P, proximal tubular cells are damaged and albumin in the urine is increased. SS1P uptake by kidney is reduced by coadministration of l-lysine. Our data suggests that l-lysine administration to humans might prevent SS1P-mediated kidney damage, reduce albumin loss in urine, and alleviate capillary leak syndrome.


Assuntos
Albuminúria/patologia , Anticorpos Monoclonais/farmacocinética , Síndrome de Vazamento Capilar/patologia , Imunotoxinas/farmacocinética , Túbulos Renais Proximais/efeitos dos fármacos , Albuminúria/induzido quimicamente , Albuminúria/prevenção & controle , Albuminúria/urina , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/toxicidade , Síndrome de Vazamento Capilar/induzido quimicamente , Síndrome de Vazamento Capilar/prevenção & controle , Síndrome de Vazamento Capilar/urina , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes/química , Meia-Vida , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/química , Imunotoxinas/toxicidade , Microscopia Intravital , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/diagnóstico por imagem , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Lisina/administração & dosagem , Camundongos , Microscopia de Fluorescência , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/toxicidade , Eliminação Renal/efeitos dos fármacos , Albumina Sérica/análise , Albumina Sérica/metabolismo , Coloração e Rotulagem
7.
Ann Pharmacother ; 54(8): 795-803, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32019317

RESUMO

Objective: To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. Data Sources: A literature search was performed in PubMed (January 2009 to November 2019) using the terms migraine, calcitonin gene-related peptide (CGRP), erenumab, fremanezumab, and galcanezumab for clinical trials and studies. Study Selection and Data Extraction: Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. Data Synthesis: In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. Relevance to Patient Care and Clinical Practice: This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Conclusions: Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/prevenção & controle , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Transtornos de Enxaqueca/metabolismo , Qualidade de Vida
8.
Drug Metab Rev ; 52(1): 66-124, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32045530

RESUMO

Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker. The linkage of the active component to a carrier molecule enhances the therapeutic window through a targeted delivery and by reducing toxicity. Bioconjugates also possess improved pharmacokinetic properties such as a long half-life, increased stability, and cleavage by intracellular enzymes/environment. However, premature cleavage of the bioconjugates and the resulting metabolites/catabolites may produce undesirable toxic effects and, hence, it is critical to understand cleavage mechanisms, metabolism of bioconjugates, and translatability to human in the discovery stages. This article provides a comprehensive overview of linker cleavage pathways and catabolism/metabolism of antibody-drug conjugates, glycoconjugates, polymer-drug conjugates, lipid-drug conjugates, folate-targeted small molecule-drug conjugates, and drug-drug conjugates.


Assuntos
Imunoconjugados/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Reagentes para Ligações Cruzadas/metabolismo , Reagentes para Ligações Cruzadas/farmacocinética , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia
9.
Paediatr Drugs ; 22(2): 199-216, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32052309

RESUMO

Monoclonal antibodies (mAbs) and their derivatives are increasingly used in pediatric pharmacotherapy, and the number of antibody-based drug products with approved pediatric indications is continuously growing. In most instances, pediatric use is being pursued after the efficacy and safety of novel antibody medications have been established in adult indications. The pediatric extrapolation exercise that is frequently used in this context to bridge efficacy and safety from adults to children is oftentimes challenged through uncertainties and knowledge gaps in how to reliably extrapolate pharmacokinetics and clinical pharmacology of mAbs to different pediatric age groups, and how to derive age-appropriate dosing regimens that strike a balance between precision dosing and practicability. The article highlights some of the pharmacokinetic and clinical pharmacology challenges with regard to therapeutic use of mAbs and antibody derivatives in children, including immunogenicity events. Although considering body size-based differences in drug disposition can account for many of the perceived and actual differences in the distribution and elimination of antibody-based therapeutics between children and adults, increasing evidence suggests potential or actual age-associated differences beyond size differences, especially for young pediatric patients such as newborns and infants. To overcome age-associated differences in antibody disposition, various different dosing approaches have been applied to ensure safe and efficacious antibody exposure for pediatric populations of different ages. The development of such dosing regimens and the associated pathway to pediatric indication approval is illustrated in more detail for two antibody-based biologics, the fusion protein abatacept and the mAb tocilizumab.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Neoplasias/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido
10.
Am J Hematol ; 95(5): 510-520, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32052473

RESUMO

Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Rituximab/farmacocinética , Rituximab/farmacologia
11.
Molecules ; 25(3)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991858

RESUMO

Characterization of pharmacokinetic (PK) properties and target tissue distribution of therapeutic fusion proteins (TFPs) are critical in supporting in vivo efficacy. We evaluated the pharmacokinetic profile of an investigational TFP consisting of human immunoglobulin G4 fused to the modified interferon alpha by orthogonal bioanalytical assays and applied minimal physiologically based pharmacokinetic (PBPK) modeling to characterize the TFP pharmacokinetics in mouse. The conventional ligand binding assay (LBA), immunocapture-liquid chromatography/tandem mass spectrometry (IC-LC/MS) detecting the human IgG4 peptide or the interferon alpha peptide were developed to measure the TFP concentrations in mouse plasma and tumor. The minimal PBPK model incorporated a tumor compartment model was used for data fitting. The plasma clearance measured by LBA and IC-LC/MS was comparable in the range of 0.5-0.6 mL/h/kg. However, the tumor exposure measured by the generic human IgG4 IC-LC/MS was significantly underestimated compared with the interferon alpha specific IC-LC/MS and LBA. Furthermore, the minimal PBPK model simultaneously captured the relationship between plasma and tissue exposure. We proposed the streamlined practical strategy to characterize the plasma exposure and tumor distribution of a TFP by both LBA and IC-LC/MS. The minimal PBPK modeling was established for better understanding of pharmacokinetic profile of investigational TFPs in the biotherapeutic discovery.


Assuntos
Monitoramento de Medicamentos/métodos , Modelos Teóricos , Proteínas Recombinantes de Fusão/farmacocinética , Algoritmos , Animais , Anticorpos Monoclonais/farmacocinética , Bioensaio , Cromatografia Líquida , Humanos , Imunoglobulina G , Camundongos , Espectrometria de Massas em Tandem , Distribuição Tecidual
12.
Clin Ther ; 42(1): 157-174.e4, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982148

RESUMO

PURPOSE: Golimumab is a fully human monoclonal antibody to tumor necrosis factor-α and is indicated for the treatment of moderately to severely active ulcerative colitis (UC). This study analyzed the population pharmacokinetic (PK) properties of golimumab and exposure-response for efficacy and safety, using data from combined Phase II/III UC studies. METHODS: Data on serum golimumab concentration following IV and subcutaneous (SC) administration were fitted simultaneously using nonlinear mixed-effects modeling for the development of a population PK model. Logistic regression models were used for assessing relationships between serum golimumab concentrations and clinical efficacy outcomes in SC induction and maintenance studies. The percentages of patients developing infections, serious infections, and serious adverse events were assessed by golimumab exposure metric quartiles. FINDINGS: The PK properties of golimumab are well described by a 2-compartment model with first-order absorption and elimination. Typical values of PK parameters in a 70-kg patient were clearance, 0.544 L/d; central and peripheral compartment Vd, 3.43 and 2.27 L, respectively; and intercompartmental clearance, 0.291 L/d. Golimumab t1/2 was 10.5 days; bioavailability following SC administration was 52.2%. Body weight, anti-golimumab antibodies, serum albumin, C-reactive protein, and alkaline phosphatase affected golimumab disposition. A positive exposure-response relationship was established between golimumab concentration and efficacy outcomes. No apparent correlation between golimumab exposure and rate of infections, serious infections, or serious adverse events was observed in patients receiving golimumab 50 or 100 mg SC every 4 weeks through 1 year. IMPLICATIONS: Body weight, serum albumin, and anti-golimumab antibodies explain some of the variability observed in the PK properties of golimumab, and exposure-response findings support the recommended posology of golimumab in UC. ClinicalTrials.gov identifiers: NCT00488774, NCT00487539, and NCT00488631.


Assuntos
Anticorpos Monoclonais/farmacocinética , Colite Ulcerativa , Modelos Biológicos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Fosfatase Alcalina/sangue , Anticorpos/sangue , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Peso Corporal , Proteína C-Reativa/análise , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Infecções/sangue , Infecções/metabolismo , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise , Resultado do Tratamento , Adulto Jovem
14.
Anal Bioanal Chem ; 412(3): 739-752, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31832706

RESUMO

RMP1-14 is a monoclonal antibody that targets the murine PD-1 protein, and has been used extensively to probe the effects of PD-1 inhibition in preclinical murine models. However, to date, no quantitative analytical methods have been published for RMP1-14. To evaluate its anti-tumor activity in BALB/c mice inoculated with CT26.WT murine colon cancer cells, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify RMP1-14 in BALB/c mouse K3EDTA plasma was developed and validated. The methodology used a signature peptide (GFYPPDIYTEWK) as a surrogate for RMP1-14 quantitation and an isotopically labeled analog of the signature peptide as the internal standard. Initial method development focused on a hybrid LC-MS/MS assay involving Protein G immunoprecipitation, but this strategy was abandoned due to lack of selectivity. The final validated method consisted of dilution with Tris-buffered saline, trypsin digestion, and desalting using micro solid-phase extraction. Analytical run time was 3.50 min, and the method demonstrated linearity between 0.500 and 50.0 µg/mL of intact RMP1-14. Accuracy, precision, and robustness were all acceptable, and the method was demonstrated to be comparable to a commercially available fit-for-purpose enzyme-linked immunosorbent assay (ELISA) capable of measuring RMP1-14. The validated method was used to generate pharmacokinetic parameters from tumor-bearing BALB/c mice dosed with RMP1-14 at either 2.50 or 7.50 mg/kg. Overall, the validated method represents a novel tool that can be used to evaluate RMP1-14 activity in future immuno-oncology studies.


Assuntos
Anticorpos Monoclonais/sangue , Cromatografia Líquida/métodos , Receptor de Morte Celular Programada 1/imunologia , Espectrometria de Massas em Tandem/métodos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Calibragem , Limite de Detecção , Camundongos , Camundongos Endogâmicos BALB C
15.
Scand J Immunol ; 91(1): e12839, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630416

RESUMO

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI-322.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antígenos CD2/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores , Biópsia , Citocinas/sangue , Feminino , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Depleção Linfocítica , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pan troglodytes , Ratos
16.
Handb Exp Pharmacol ; 260: 81-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820172

RESUMO

Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by the variable domains of the heavy and light chains and contains the complementarity-determining region that imparts the high specificity for the target antigen. The pharmacokinetics of mAbs involves target-mediated and non-target-related factors that influence their disposition.Preclinical safety evaluation of mAbs differs substantially from that of small molecular (chemical) entities. Immunogenicity of mAbs has implications for their pharmacokinetics and safety. Early studies of mAbs in humans require careful consideration of the most suitable study population, route/s of administration, starting dose, study design and the potential difference in pharmacokinetics in healthy subjects compared to patients expressing the target antigen.Of the ever-increasing diversity of therapeutic indications for mAbs, we have concentrated on two that have proved dramatically successful. The contribution that mAbs have made to the treatment of inflammatory conditions, in particular arthritides and inflammatory bowel disease, has been nothing short of revolutionary. Their benefit has also been striking in the treatment of solid tumours and, most recently, as immunotherapy for a wide variety of cancers. Finally, we speculate on the future with various new approaches to the development of therapeutic antibodies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Artrite/terapia , Humanos , Imunoterapia , Doenças Inflamatórias Intestinais/terapia , Neoplasias/terapia
17.
EBioMedicine ; 49: 247-257, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31680000

RESUMO

BACKGROUND: Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. METHODS: Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. FINDINGS: A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8+T cells and increased TNF-α, granzyme B production. INTERPRETATION: The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Imunização Passiva , Vacinação , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Hidrodinâmica , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Injeções , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Camundongos Endogâmicos C57BL
18.
Int J Mol Sci ; 20(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717302

RESUMO

Combination radioimmunotherapy is an emerging approach for the treatment of solid tumors where radio immunotherapy alone has proven to be reasonably ineffective. Radioimmunotherapy (RIT) using monoclonal antibodies (mAbs) labeled with radionuclides is an attractive approach for cancer treatment because tumor-associated mAbs with cytotoxic radionuclides can selectively bind to tumor antigens. However, due to various limitations, mAbs cannot reach solid tumors, consequently reducing RIT efficacy. Combination RIT is a pragmatic approach through which the addition of drugs or other agents not only help mAbs to reach the targeted site but also improves its efficacy. Thus, the combination of drugs or moieties with RIT can be applied to overcome the barriers that RIT faces for solid tumors. This review covers the RIT approach, along with the mechanism of action of mAb used in RIT, limitations of solid tumors, and strategies that can be used in combination RIT to enhance the treatment regimen for solid tumors.


Assuntos
Neoplasias/terapia , Radioimunoterapia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Isótopos
19.
Pharm Res ; 36(12): 169, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654236

RESUMO

PURPOSE: The purpose of this study was to validate a ligand binding assay for the quantitation of a monoclonal antibody-based biotherapeutics (PF-57781346) in samples collected via capillary microsampling to support a regulated mouse toxicity study. METHOD: A quantitative ligand binding assay on the Gyrolab platform was developed to quantify PF-57781346 in blood samples derived from capillary mouse serial sampling. The method validation evaluated assay characteristics including accuracy and precision, influence of sample processing on drug quantitation, whole blood matrix selectivity, dilution linearity and the stability of the drug in the study sample matrix. RESULTS: The method validation demonstrated acceptable analytical characteristics. The whole blood selectivity testing demonstrated accuracy between -4.8% and 13.9% in 10 out of 10 individual whole blood samples, suggesting that drug quantitation from whole blood is not impacted by the serial sampling procedure. Short-term and long-term drug stability in study sample matrix were established to cover required stability for sample storage and analysis (accuracy between -7.3% and 6.1%). CONCLUSION: We reported a successful validation of a bioanalytical method that quantifies PF-55781346 in samples collected via capillary microsampling. The experience shared in this study could serve as a model process for bioanalytical method validation when capillary microsampling is used.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/toxicidade , Imunoensaio/métodos , Animais , Coleta de Amostras Sanguíneas/métodos , Estabilidade de Medicamentos , Ligantes , Camundongos , Modelos Animais , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Toxicocinética
20.
PLoS One ; 14(10): e0223899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618250

RESUMO

Post-translational modifications (PTMs) of therapeutic monoclonal antibodies (mAbs) are important product quality attributes (PQAs) that can potentially impact drug stability, safety, and efficacy. The PTMs of a mAb may change remarkably in the bloodstream after drug administration compared to in vitro conditions. Thus, monitoring in vivo PTM changes of mAbs helps evaluate the criticality of PQAs during the product risk assessment. In addition, quantitation of the subject exposures to PTM variants helps assess the impact of PTMs on the safety and efficacy of therapeutic mAbs. Here, we developed an immunocapture-liquid chromatography/mass spectrometry (LC/MS) method to quantify in vivo PTM changes a therapeutic mAb overtime in single- and multiple-dose monkey pharmacokinetic (PK) studies. We also built mathematical models to predict the in vivo serum concentrations of PQAs, the subject exposures to PQAs, and the relative abundance of PQAs in single- and multiple-dose regimens. The model predictions are in good agreement with the experimental results. The immunocapture-LC/MS method and mathematical models enable bioanalytical chemists to quantitatively assess the criticality of PQAs during drug development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/metabolismo , Animais , Anticorpos Monoclonais/farmacocinética , Cromatografia Líquida/métodos , Esquema de Medicação , Estabilidade de Medicamentos , Feminino , Haplorrinos , Humanos , Modelos Teóricos , Processamento de Proteína Pós-Traducional , Espectrometria de Massas em Tandem/métodos
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