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1.
Adv Ther ; 41(1): 364-378, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37971653

RESUMO

INTRODUCTION: Accurate predictions of pharmacokinetics and efficacious doses for biologics in humans are critical for selecting appropriate first-in-human starting doses and dose ranges and for estimating clinical material needs and cost of goods. This also impacts clinical feasibility, particularly for subcutaneously administered biologics. METHODS: We performed a comprehensive comparison between predicted and observed clearances and doses in humans for a set of 22 biologic drugs developed at Boehringer Ingelheim (BI) over the last 2 decades. The analysis included biologics across three therapeutic areas comprising a wide variety of modalities: mono- and bispecific monoclonal antibodies (mAbs) and nanobodies and a Fab fragment. RESULTS: Our analysis showed that observed clearances in humans were within twofold of predicted clearances for 17 out of 20 biologics (85%). Six biologics had uncharacteristically high observed human clearances (range 32-280 mL/h) for their respective molecular classes, impacting their clinical developability. For three molecules, molecular characteristics contributed to the high clearance. Clinically selected doses were within twofold of predicted for 58% of projects. With 42% and 25% of projects selecting clinical doses higher than two- or threefold the predicted value, respectively, the importance of better understanding not only the pharmacokinetic (PK) but also the predictivity of pharmacodynamic models is highlighted. CONCLUSIONS: We provide a clinical pharmacology perspective on the commonly accepted twofold range of human clearance predictions as well as the implications of higher than predicted targeted efficacious plasma concentration on clinical development. Finally, an analysis of key success factors for biologics at BI was conducted, which may be relevant for the entire pharmaceutical industry. This is one of the largest retrospective analyses for biologics and provides further evidence that successful predictions of human PK and efficacious dose will be further facilitated by gathering key translational data early in research.


Assuntos
Anticorpos Biespecíficos , Produtos Biológicos , Humanos , Produtos Biológicos/uso terapêutico , Estudos Retrospectivos , Relação Dose-Resposta a Droga
2.
Int J Pharm ; 609: 121162, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34624444

RESUMO

Antibodies targeting the CD40-CD40L pathway have great potential for treating autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), and inflammatory bowel diseases (IBD). However, in addition to the known difficulty in generating a purely antagonistic CD40 antibody, the presence of CD40 and CD40L on platelets creates additional unique challenges for the safety, target coverage, and clearance of antibodies targeting this pathway. Previously described therapeutic antibodies targeting this pathway have various shortcomings, and the full therapeutic potential of this axis has yet to be realized. Herein, we describe the generation and characterization of BI 655064, a novel, purely antagonistic anti-CD40 antibody that potently neutralizes CD40-CD40L-dependent B-cell stimulation without evidence of impacting platelet functions. This uniquely optimized antibody targeting a highly challenging pathway was obtained by applying stringent functional and biophysical criteria during the lead selection process. BI 655064 has favorable target-mediated drug disposition (TMDD)-saturation pharmacokinetics, consistent with that of a high-quality therapeutic monoclonal antibody.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Doenças Autoimunes/tratamento farmacológico , Linfócitos B , Antígenos CD40 , Ligante de CD40 , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico
3.
Bioanalysis ; 13(8): 621-629, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33829873

RESUMO

Volumetric absorptive microsampling (VAMS) is increasingly utilized for both nonclinical and clinical pharmacokinetic studies. Currently, VAMS is employed as the sampling method for the detection of antibodies for coronavirus disease 2019. Biotherapeutics whole blood stability on VAMS presents as a critical concern for the health and pharmaceutical industries. In this follow-up to our previous publication, we evaluated daclizumab and trastuzumab whole blood sample stability on VAMS. The drug recovery data we observed at room temperature for short term and -80°C for long term was very encouraging. The knowledge could help us better understand and plan important investigation timelines, especially pandemic situations where human whole blood samples from a large population are collected and in urgent need of data analysis.


Assuntos
Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Teste em Amostras de Sangue Seco/métodos , Animais , Coleta de Amostras Sanguíneas/métodos , Daclizumabe/sangue , Daclizumabe/farmacocinética , Armazenamento de Medicamentos , Luz , Ratos , Espectrometria de Massas em Tandem , Temperatura , Trastuzumab/sangue , Trastuzumab/farmacocinética
4.
MAbs ; 12(1): 1709322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31924119

RESUMO

CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have been identified. Here we describe the lead finding and engineering approach that lead to the identification of BI 655088, a potent biotherapeutic antagonist to CX3CR1. BI 655088 is a potent CX3CR1 antagonist that, upon therapeutic dosing, significantly inhibits plaque progression in the standard mouse model of atherosclerosis. BI 655088 represents a novel and highly selective biotherapeutic that could reduce inflammation in the atherosclerotic plaque when added to standard of care treatment including statins, which could result in a significant decrease in atherothrombotic events in patients with existing cardiovascular disease.


Assuntos
Aterosclerose/patologia , Receptor 1 de Quimiocina CX3C/antagonistas & inibidores , Anticorpos de Domínio Único/farmacologia , Animais , Progressão da Doença , Humanos , Macaca fascicularis , Camundongos
5.
MAbs ; 11(5): 956-964, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31068073

RESUMO

Accurate prediction of the human pharmacokinetics (PK) of a candidate monoclonal antibody from nonclinical data is critical to maximize the success of clinical trials. However, for monoclonal antibodies exhibiting nonlinear clearance due to target-mediated drug disposition, PK predictions are particularly challenging. That challenge is further compounded for molecules lacking cross-reactivity in a nonhuman primate, in which case a surrogate antibody selective for the target in rodent may be required. For these cases, prediction of human PK must account for any interspecies differences in binding kinetics, target expression, target turnover, and potentially epitope. We present here a model-based method for predicting the human PK of MAB92 (also known as BI 655130), a humanized IgG1 κ monoclonal antibody directed against human IL-36R. Preclinical PK was generated in the mouse with a chimeric rat anti-mouse IgG2a surrogate antibody cross-reactive against mouse IL-36R. Target-specific parameters such as antibody binding affinity (KD), internalization rate of the drug target complex (kint), target degradation rate (kdeg), and target abundance (R0) were integrated into the model. Two different methods of assigning human R0 were evaluated: the first assumed comparable expression between human and mouse and the second used high-resolution mRNA transcriptome data (FANTOM5) as a surrogate for expression. Utilizing the mouse R0 to predict human PK, AUC0-∞ was substantially underpredicted for nonsaturating doses; however, after correcting for differences in RNA transcriptome between species, AUC0-∞ was predicted largely within 1.5-fold of observations in first-in-human studies, demonstrating the validity of the modeling approach. Our results suggest that semi-mechanistic models incorporating RNA transcriptome data and target-specific parameters may improve the predictivity of first-in-human PK.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Receptores de Interleucina-1/imunologia , Animais , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Ratos , Receptores de Interleucina-1/metabolismo , Estudos Retrospectivos , Transcriptoma
6.
Bioanalysis ; 11(1): 13-20, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30461295

RESUMO

AIM: Volumetric absorptive microsampling (VAM) is being increasingly applied in nonclinical pharmacokinetic studies. Although there are published results for VAM use in small molecule pharmacokinetics (PK) studies, there is limited data on the utility of VAM for protein therapeutics. RESULTS: We describe the use of Mitra® microsampler for blood sampling, ELISA quantitation and PK analysis of two marketed therapeutic monoclonal antibodies administered to rat. Results generated for these monoclonal antibodies using Mitra® were compared with both serum and whole blood sampling methods in the same study. CONCLUSION: The low relative standard deviation among the three sets of PK data suggest that Mitra® microsampler could be useful in early nonclinical PK studies for protein therapeutics where reduction and refinement of animal use is desirable.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Daclizumabe/farmacocinética , Trastuzumab/farmacocinética , Animais , Coleta de Amostras Sanguíneas/instrumentação , Calibragem , Daclizumabe/administração & dosagem , Daclizumabe/sangue , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Ratos Wistar , Trastuzumab/administração & dosagem , Trastuzumab/sangue
7.
Bioanalysis ; 10(6): 397-406, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29451404

RESUMO

AIM: The fully automated microfluidics-based Gyrolab is a popular instrument for the bioanalysis of protein therapeutics; requiring minimal sample and reagent volumes. Gyros offers affinity software for determining binding affinity in solution using a high-throughput method and miniaturized reactions. RESULTS: Using this affinity software, multiple CTGF-targeting reagents were characterized on the Gyrolab after <100% target coverage was seen in a cynomolgus pharmacokinetic/PD study dosed with anti-CTGF antibodies. The results uncovered magnitude differences in binding affinities between the dosed antibody, target and assay reagents. CONCLUSION: The binding affinity values were used to investigate reduced target coverage and results highlight potential of the affinity software for incorporation into the bioanalyst's existing Gyrolab workflow for characterizing reagents and optimizing pharmacokinetic/PD bioanalytical assays.


Assuntos
Anticorpos Monoclonais/imunologia , Bioensaio/métodos , Imunoensaio/métodos , Humanos , Fluxo de Trabalho
8.
MAbs ; 9(7): 1105-1117, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28786732

RESUMO

Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the "know-how" of therapeutic modality by design.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/farmacologia , Antígenos de Histocompatibilidade Classe I/imunologia , Receptores Fc/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Afinidade de Anticorpos/imunologia , Humanos , Concentração de Íons de Hidrogênio , Macaca fascicularis
9.
MAbs ; 9(7): 1143-1154, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28726542

RESUMO

Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP). We report the discovery and characterization of MAB92, a potent, high affinity anti-human IL-36 receptor antagonistic antibody that blocks human IL-36 ligand (α, ß and γ)-mediated signaling. In vitro treatment with MAB92 directly inhibits human IL-36R-mediated signaling and inflammatory cytokine production in primary human keratinocytes and dermal fibroblasts. MAB92 shows exquisite species specificity toward human IL-36R and does not cross react to murine IL-36R. To enable in vivo pharmacology studies, we developed a mouse cross-reactive antibody, MAB04, which exhibits overlapping binding and pharmacological activity as MAB92. Epitope mapping indicates that MAB92 and MAB04 bind primarily to domain-2 of the human and mouse IL-36R proteins, respectively. Treatment with MAB04 abrogates imiquimod and IL-36-mediated skin inflammation in the mouse, further supporting an important role for IL-36R signaling in epithelial cell-mediated inflammation.


Assuntos
Anticorpos Monoclonais/imunologia , Receptores de Interleucina/antagonistas & inibidores , Animais , Especificidade de Anticorpos , Humanos , Camundongos , Psoríase/imunologia
10.
AAPS J ; 19(2): 431-437, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27924614

RESUMO

Loss of skeletal muscle mass and function results in loss of mobility for elderly patients. Novel therapies that can protect and/or restore muscle function during aging would have profound effects on the quality of life for this population. Growth differentiation factor 11 (GDF11) has been proposed as a "youthful" circulating factor that can restore cardiac, neural, and skeletal muscle functions in aging animals. However, conflicting data has been recently published that casts doubt on these assertions. We used a complex rat model of skeletal muscle injury that physiologically mimics injuries seen in patients; to investigate the ability of GDF11 and to enhance skeletal muscle regeneration after injury in older rats. Our data showed that GDF11 treatment resulted in a significant increase in tissue fibrosis, accompanied by attenuated functional recovery, as compared to animals treated with vehicle alone. GDF11 impaired the recovery of skeletal muscle function in older rats after injury.


Assuntos
Envelhecimento/fisiologia , Proteínas Morfogenéticas Ósseas/toxicidade , Fatores de Diferenciação de Crescimento/toxicidade , Músculo Esquelético/metabolismo , Regeneração/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/administração & dosagem , Modelos Animais de Doenças , Fibrose , Fatores de Diferenciação de Crescimento/administração & dosagem , Humanos , Masculino , Músculo Esquelético/lesões , Qualidade de Vida , Ratos , Ratos Endogâmicos Lew
11.
MAbs ; 8(8): 1606-1611, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27598372

RESUMO

Prior to clinical studies, the pharmacokinetics (PK) of antibody-based therapeutics are characterized in preclinical species; however, those species can elicit immunogenic responses that can lead to an inaccurate estimation of PK parameters. Immunodeficient (SCID) transgenic hFcRn and C57BL/6 mice were used to characterize the PK of three antibodies that were previously shown to be immunogenic in mice and cynomolgus monkeys. Four mouse strains, Tg32 hFcRn SCID, Tg32 hFcRn, SCID and C57BL/6, were administered adalimumab (Humira®), mAbX and mAbX-YTE at 1 mg/kg, and in SCID strains there was no incidence of immunogenicity. In non-SCID strains, drug-clearing ADAs appeared after 4-7 days, which affected the ability to accurately calculate PK parameters. Single species allometric scaling of PK data for Humira® in SCID and hFcRn SCID mice resulted in improved human PK predictions compared to C57BL/6 mice. Thus, the SCID mouse model was demonstrated to be a useful tool for assessing the preclinical PK of immunogenic therapeutics.


Assuntos
Anticorpos Monoclonais/farmacocinética , Modelos Animais , Adalimumab/farmacologia , Animais , Antígenos de Histocompatibilidade Classe I , Humanos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Receptores Fc
12.
Bioanalysis ; 8(6): 511-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26917343

RESUMO

BACKGROUND: Four bioanalytical platforms were evaluated to optimize sensitivity and enable detection of recombinant human GDF11 in biological matrices; ELISA, Meso Scale Discovery, Gyrolab xP Workstation and Simoa HD-1. Results & methodology: After completion of custom assay development, the single-molecule ELISA (Simoa) achieved the greatest sensitivity with a lower limit of quantitation of 0.1 ng/ml, an improvement of 100-fold over the next sensitive platform (MSD). DISCUSSION & CONCLUSION: This improvement was essential to enable detection of GDF11 in biological samples, and without the technology the sensitivity achieved on the other platforms would not have been sufficient. Other factors such as ease of use, cost, assay time and automation capability can also be considered when developing custom immunoassays, based on the requirements of the bioanalyst.


Assuntos
Proteínas Morfogenéticas Ósseas/análise , Ensaio de Imunoadsorção Enzimática/métodos , Fatores de Diferenciação de Crescimento/análise , Animais , Anticorpos/imunologia , Biotinilação , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Ensaio de Imunoadsorção Enzimática/economia , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Humanos , Limite de Detecção , Camundongos , Ratos , Proteínas Recombinantes/análise , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia
13.
MAbs ; 7(4): 778-91, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25905918

RESUMO

Herein, we describe the generation and characterization of BI 655066, a novel, highly potent neutralizing anti-interleukin-23 (IL23) monoclonal antibody in clinical development for autoimmune conditions, including psoriasis and Crohn's disease. IL23 is a key driver of the differentiation, maintenance, and activity of a number of immune cell subsets, including T helper 17 (Th17) cells, which are believed to mediate the pathogenesis of several immune-mediated disorders. Thus, IL23 neutralization is an attractive therapeutic approach. Designing an antibody for clinical activity and convenience for the patient requires certain properties, such as high affinity, specificity, and solubility. These properties were achieved by directed design of the immunization, lead identification, and humanization procedures. Favorable substance and pharmacokinetic properties were established by biophysical assessments and studies in cynomolgus monkeys.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/farmacologia , Sistemas de Liberação de Medicamentos , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Humanos , Subunidade p19 da Interleucina-23/imunologia , Macaca fascicularis , Psoríase/tratamento farmacológico , Psoríase/imunologia , Células Th17/imunologia
14.
Bioorg Med Chem Lett ; 19(6): 1588-91, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19246196

RESUMO

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.


Assuntos
Benzimidazóis/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Benzimidazóis/farmacologia , Complexo CD3/biossíntese , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
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