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1.
Gene Ther ; 31(3-4): 128-143, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37833563

RESUMO

Adeno-associated virus (AAV) vector gene therapy is a promising approach to treat rare genetic diseases; however, an ongoing challenge is how to best modulate host immunity to improve transduction efficiency and therapeutic outcomes. This report presents two studies characterizing multiple prophylactic immunosuppression regimens in male cynomolgus macaques receiving an AAVrh10 gene therapy vector expressing human coagulation factor VIII (hFVIII). In study 1, no immunosuppression was compared with prednisolone, rapamycin (or sirolimus), rapamycin and cyclosporin A in combination, and cyclosporin A and azathioprine in combination. Prednisolone alone demonstrated higher mean peripheral blood hFVIII expression; however, this was not sustained upon taper. Anti-capsid and anti-hFVIII antibody responses were robust, and vector genomes and transgene mRNA levels were similar to no immunosuppression at necropsy. Study 2 compared no immunosuppression with prednisolone alone or in combination with rapamycin or methotrexate. The prednisolone/rapamycin group demonstrated an increase in mean hFVIII expression and a mean delay in anti-capsid IgG development until after rapamycin taper. Additionally, a significant reduction in the plasma cell gene signature was observed with prednisolone/rapamycin, suggesting that rapamycin's tolerogenic effects may include plasma cell differentiation blockade. Immunosuppression with prednisolone and rapamycin in combination could improve therapeutic outcomes in AAV vector gene therapy.


Assuntos
Ciclosporina , Sirolimo , Masculino , Humanos , Animais , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sirolimo/metabolismo , Ciclosporina/metabolismo , Plasmócitos , Prednisolona/farmacologia , Prednisolona/uso terapêutico , Prednisolona/metabolismo , Terapia Genética , Vetores Genéticos/genética , Macaca/genética , Dependovirus
2.
Mol Plant Microbe Interact ; 35(6): 477-487, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35266808

RESUMO

Pitch canker, caused by the fungal pathogen Fusarium circinatum, is a global disease affecting many Pinus spp. Often fatal, this disease causes significant mortality in both commercially grown and natural pine forests and is an issue of current and growing concern. F. circinatum isolates collected from three locations in the U.S. state of Florida were shown to be virulent on both slash and loblolly pine, with two of the isolates causing equivalent and significantly larger lesions than those caused by the third isolate during pathogenicity trials. In addition, significant genetic variation in lesion length in the pedigreed slash pine population was evident and rankings of parents for lesion length were similar across isolates. Experimental data demonstrate that both host and pathogen genetics contribute to disease severity. High-quality genomic assemblies of all three isolates were created and compared for structural differences and gene content. No major structural differences were observed among the isolates; however, missing or altered genes do contribute to genomic variation in the pathogen population. This work evaluates in planta virulence among three isolates of F. circinatum, provides genomic resources to facilitate study of this organism, and details comparative genomic methods that may be used to explore the pathogen's contribution to disease development.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Assuntos
Fusarium , Pinus , Fusarium/genética , Genômica , Doenças das Plantas/microbiologia
3.
Plant Dis ; 103(3): 538-545, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30667322

RESUMO

Defining host-pathogen interactions between species of root-rotting Phytophthora and Abies in Christmas tree production areas is important for tailoring management activities on a regional scale and for developing molecular tools for identifying resistant host species. Classifying Abies species as resistant or susceptible is complicated by regional variation in abundance and aggressiveness of Phytophthora species and the influence of environment on symptom expression and host vigor. Because previous studies performed to assess host response to Phytophthora root rot (PRR) have focused on one or a few species of either the host or pathogen, a multifactorial experiment was conducted to assess the responses of seven species of Abies challenged with three isolates each of four Phytophthora species under contrasting temperature conditions. Evaluation of mortality, root rot severity, and remaining root biomass after 16 weeks of exposure to the pathogen confirmed prior inferences regarding inherent variation in the resistance responses of various species of Abies and demonstrated evidence of variation in aggressiveness among species of Phytophthora as well as different isolates of the same Phytophthora species. The ambient temperatures at which studies were conducted had a conspicuous effect on host mortality, root rot severity, and radial growth of Phytophthora. Understanding how host responses differ under variable pathogen attack and ambient environment will improve efforts to control PRR using host species substitutions on infested ground.


Assuntos
Abies , Meio Ambiente , Interações Hospedeiro-Parasita , Phytophthora , Abies/parasitologia , Phytophthora/fisiologia , Doenças das Plantas/parasitologia , Raízes de Plantas/parasitologia
4.
Oncologist ; 20(6): 653-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25964306

RESUMO

BACKGROUND: First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). MATERIALS AND METHODS: A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. RESULTS: The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8-500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5-55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. CONCLUSION: One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials. IMPLICATIONS FOR PRACTICE: Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters.


Assuntos
Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Humanos , Dose Máxima Tolerável , Neoplasias/patologia
5.
Toxicol Appl Pharmacol ; 279(2): 230-9, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24937321

RESUMO

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥30mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress.


Assuntos
Anticorpos Monoclonais/toxicidade , Antirreumáticos/toxicidade , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Testes de Toxicidade/métodos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antirreumáticos/administração & dosagem , Antirreumáticos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Células Espumosas/efeitos dos fármacos , Células Espumosas/patologia , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macaca fascicularis , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Modelos Animais , Nível de Efeito Adverso não Observado , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Medição de Risco
6.
Clin Pharmacol Drug Dev ; 11(11): 1264-1272, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35908210

RESUMO

Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC-FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first-order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one-compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC-FAOD. The typical CL/F in adult subjects with LC-FAOD was ≈19% lower than that in healthy subjects. Model-estimated elimination half-life for LC-FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.


Assuntos
Heptanoatos , Erros Inatos do Metabolismo Lipídico , Adulto , Humanos , Criança , Erros Inatos do Metabolismo Lipídico/metabolismo , Voluntários Saudáveis , Triglicerídeos , Ácidos Graxos/metabolismo
7.
J Clin Pharmacol ; 62(1): 87-98, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34352114

RESUMO

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fósforo/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais Humanizados/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Lactente , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
8.
Mol Ther Methods Clin Dev ; 24: 292-305, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35211641

RESUMO

Ornithine transcarbamylase deficiency is a rare X-linked genetic urea cycle disorder leading to episodes of acute hyperammonemia, adverse cognitive and neurological effects, hospitalizations, and in some cases death. DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized. This study sought to describe the impact of sex and immunosuppression in adult, sexually mature female and male cynomolgus macaques through day 140 after DTX301 administration. Four study groups (n = 3/group) were included: male non-immunosuppressed; male immunosuppressed; female non-immunosuppressed; and female immunosuppressed. DTX301 was well tolerated with and without immunosuppression; no notable differences were observed between female and male groups across outcome measures. Prednisolone-treated animals exhibited a trend toward greater vector genome and transgene expression, although the differences were not statistically significant. The hepatic interferon gene signature was significantly decreased in prednisolone-treated animals, and a significant inverse relationship was observed between interferon gene signature levels and hepatic vector DNA and transgene RNA. These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged.

9.
Clin Pharmacol Drug Dev ; 10(11): 1325-1334, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33789001

RESUMO

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Ácidos Graxos/metabolismo , Heptanoatos/metabolismo , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Triglicerídeos/farmacocinética , Adolescente , Adulto , Criança , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Erros Inatos do Metabolismo Lipídico/metabolismo , Masculino , Pessoa de Meia-Idade , Oxirredução , Adulto Jovem
10.
Clin Pharmacokinet ; 58(5): 673-683, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30467742

RESUMO

INTRODUCTION: Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of ß-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I-III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects' body weight as the only significant covariate. RESULTS: Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of Kuptake (the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose. CONCLUSION: The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII. CLINICAL TRIAL REGISTRATION: NCT01856218, NCT02418455, NCT02230566.


Assuntos
Glucuronidase/farmacocinética , Modelos Biológicos , Mucopolissacaridose VII/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Simulação por Computador , Estudos Cross-Over , Terapia de Reposição de Enzimas , Feminino , Glucuronidase/administração & dosagem , Glucuronidase/sangue , Glicosaminoglicanos/urina , Humanos , Lactente , Masculino , Mucopolissacaridose VII/sangue , Mucopolissacaridose VII/tratamento farmacológico , Adulto Jovem
13.
MAbs ; 10(1): 1-17, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28991509

RESUMO

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Primatas , Animais , Anticorpos Monoclonais/efeitos adversos , Qualidade de Produtos para o Consumidor , Humanos , Modelos Animais , Medição de Risco , Fatores de Risco , Especificidade da Espécie
14.
Reprod Toxicol ; 74: 116-133, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28916434

RESUMO

MEDI-570 is a fully human afucosylated monoclonal antibody (MAb) against Inducible T-cell costimulator (ICOS), highly expressed on CD4+ T follicular helper (TFH) cells. Effects of MEDI-570 were evaluated in an enhanced pre-postnatal development toxicity (ePPND) study in cynomolgus monkeys. Administration to pregnant monkeys did not cause any abortifacient effects. Changes in hematology and peripheral blood T lymphocyte subsets in maternal animals and infants and the attenuated infant IgG immune response to keyhole limpet hemocyanin (KLH) were attributed to MEDI-570 pharmacology. Adverse findings included aggressive fibromatosis in one dam and two infant losses in the high dose group with anatomic pathology findings suggestive of atypical lymphoid hyperplasia. The margin of safety relative to the no observed adverse effect level (NOAEL) for the highest planned clinical dose in the Phase 1a study was 7. This study suggests that women of child bearing potential employ effective methods of contraception while being treated with MEDI-570.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Depleção Linfocítica , Linfócitos T/imunologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Embrião de Mamíferos/imunologia , Desenvolvimento Embrionário/imunologia , Feminino , Desenvolvimento Fetal/imunologia , Feto/efeitos dos fármacos , Hemocianinas/farmacologia , Imunoglobulina G/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Contagem de Linfócitos , Macaca fascicularis , Masculino , Troca Materno-Fetal , Gravidez
15.
Vet J ; 171(3): 556-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16624725

RESUMO

Targeting the CD20 receptor that is common to many B-cell Non-Hodgkin's Lymphoma subtypes in people, rituximab is a chimeric monoclonal antibody which has significantly improved disease-free survival rates compared with the use of cytotoxic agents alone. This study evaluated ex vivo canine B cell binding and depletion by rituximab with flow cytometric technique as possible proof of concept for treatment of canine lymphoma. Despite immunohistochemistry supporting CD20 expression, rituximab did not bind or deplete canine B cells and it is unlikely that it will be added to the armamentarium of treatment options for canine lymphoma.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Linfoma de Células B/veterinária , Animais , Anticorpos Monoclonais Murinos , Cães , Citometria de Fluxo/veterinária , Linfoma de Células B/tratamento farmacológico , Rituximab , Resultado do Tratamento , Células Tumorais Cultivadas
16.
Arthritis Res Ther ; 18(1): 131, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27267753

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a clinically heterogeneous, life-threatening disease characterized by fibrosis, microvasculopathy, and autoimmunity. Extensive nonclinical and clinical data implicate B cells in the pathogenesis of SSc. MEDI-551 is an investigational humanized monoclonal antibody that targets the B cell surface antigen CD19 and mediates antibody-dependent, cell-mediated cytotoxicity of B cells. This clinical study evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of MEDI-551 in subjects with SSc. METHODS: This phase I multicenter, randomized, double-blind, placebo-controlled, single escalating dose study enrolled adult subjects with either limited or diffuse cutaneous SSc. A single intravenous dose of MEDI-551 was administered, and safety and tolerability were evaluated. MEDI-551 pharmacokinetics (PK), pharmacodynamics, and immunogenicity were also assessed. Safety assessments included the incidence of adverse events and changes in clinical and laboratory results. MEDI-551 serum concentrations, effects on circulating and tissue B cells and plasma cells (PCs), and antidrug antibodies were analyzed. Modified Rodnan skin score (MRSS) and pulmonary function tests were used to explore the clinical effect of MEDI-551. RESULTS: The study enrolled 28 subjects with SSc (mean age, 47.3 years; 67.9 % female). Twenty-four received a single dose of MEDI-551 (0.1-10.0 mg/kg) and four received placebo. Treatment-emergent adverse events (TEAEs) occurred in 95.8 % of subjects in the MEDI-551 group and in 75.0 % of subjects in the placebo group; the majority of TEAEs were mild or moderate in severity. Two serious adverse events were considered possibly related to the study drug. One death, deemed not related to the study drug, occurred in a MEDI-551-treated subject. MEDI-551 exhibited linear PK in the dose range of 1.0 to 10.0 mg/kg, and more rapid clearance at lower doses. Dose-dependent depletion of circulating B cells and plasma cells was observed. MRSS assessments suggest a possible clinical effect of MEDI-551 on affected skin. CONCLUSIONS: A single escalating dose of MEDI-551 was tolerable and safe in this subject population. B cell depletion was achieved and was dose dependent. A signal of clinical effect was observed. Based on these results, further investigation of MEDI-551 as a disease-modifying treatment for SSc is warranted. TRIAL REGISTRATION: www.clinicaltrials.gov identifier, NCT00946699 ; registered 23 July 2009.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19 , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
17.
Int Immunopharmacol ; 3(10-11): 1477-81, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12946444

RESUMO

Cynomolgus monkeys (Macaca fascicularis) are widely used animal models in biomedical research and have been used to study new therapeutics aimed at B-cell depletion. We have recently identified two different B-cell subsets in cynomolgus monkey, with the CD20lowCD40highCD21+ subset being phenotypically closer to human B cells and having a similar responsivness to anti-CD20 mAb, rituximab, in in vitro depletion assays. Here, we show that similar to in vitro findings CD20highCD40lowCD21- and CD20lowCD40highCD21+ cynomolgus monkey B cells differ significantly in their in vivo susceptibility to rituximab, as the low dose of 0.05 mg/kg of rituximab resulted in more than 70% depletion of the former B-cell subset and virtually no depletion of the latter B-cell subset. Our data suggest that for the B-cell-targeting anti-CD20 therapeutics, depletion of CD20lowCD40highCD21+ subset rather than depletion of all cynomolgus monkey B cells is more relevant to dose-efficacy projections for humans. In addition, we show that differential cell surface expression of CD80/CD86 costimulatory molecules on the two different cynomolgus monkey B-cell subsets is similar to that identified in rhesus monkeys, suggesting that our in vivo study may be relevant to other monkey models.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfócitos B/efeitos dos fármacos , Animais , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Antígenos CD40/imunologia , Depleção Linfocítica , Macaca fascicularis , Masculino , Receptores de Complemento 3d/imunologia , Rituximab
18.
Arthritis Rheumatol ; 66(1): 173-84, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24431284

RESUMO

OBJECTIVE: Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response. METHODS: We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases. RESULTS: The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r = 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs. CONCLUSION: This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.


Assuntos
Plasmócitos/metabolismo , Escleroderma Sistêmico/genética , Transcriptoma/genética , Autoanticorpos/biossíntese , Doenças Autoimunes/genética , Antígeno de Maturação de Linfócitos B/genética , Humanos , Cadeias J de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Imunoglobulinas/genética , Análise Serial de Tecidos
19.
Arthritis Res Ther ; 15 Suppl 1: S4, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23566679

RESUMO

B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system. However, B cells can also be pathogenic and the origin of disease. Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies. DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response. B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients. Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development. This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development. Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/patologia , Fatores Imunológicos/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Murinos/farmacologia , Anticorpos Monoclonais Murinos/uso terapêutico , Doenças Autoimunes/imunologia , Fator Ativador de Células B/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Seleção de Pacientes , Rituximab
20.
Toxicol Sci ; 119(1): 116-25, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20937725

RESUMO

Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy.


Assuntos
Anticorpos Monoclonais Murinos/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais Murinos/sangue , Anticorpos Monoclonais Murinos/farmacocinética , Formação de Anticorpos/imunologia , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/imunologia , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Desenvolvimento Fetal/imunologia , Idade Gestacional , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/embriologia , Macaca fascicularis , Troca Materno-Fetal/efeitos dos fármacos , Leite/química , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Rituximab , Testes de Toxicidade
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