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1.
Brain Nerve ; 76(9): 1011-1017, 2024 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-39251220

RESUMO

Amyloid-related imaging abnormalities (ARIA) represent the most frequent adverse effect of lecanemab, a monoclonal antibody drug that targets amyloid beta. ARIA is observed in approximately 20% of patients who receive lecanemab. Most patients are asymptomatic; however, some develop serious neurological symptoms, and optimal management remains clinically challenging in such cases. In this review, I summarize the pathomechanism underlying ARIA and associated disorders, in addition to countermeasures for ARIA.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/administração & dosagem
2.
Biochemistry (Mosc) ; 89(8): 1451-1473, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39245455

RESUMO

High-affinity and specific agents are widely applied in various areas, including diagnostics, scientific research, and disease therapy (as drugs and drug delivery systems). It takes significant time to develop them. For this reason, development of high-affinity agents extensively utilizes computer methods at various stages for the analysis and modeling of these molecules. The review describes the main affinity and specific agents, such as monoclonal antibodies and their fragments, antibody mimetics, aptamers, and molecularly imprinted polymers. The methods of their obtaining as well as their main advantages and disadvantages are briefly described, with special attention focused on the molecular modeling methods used for their analysis and development.


Assuntos
Anticorpos Monoclonais , Anticorpos Monoclonais/química , Aptâmeros de Nucleotídeos/química , Modelos Moleculares , Humanos , Ligação Proteica , Polímeros Molecularmente Impressos/química
4.
PLoS One ; 19(9): e0310042, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39240995

RESUMO

Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 µg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.


Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Anti-HIV , HIV-1 , HIV-1/imunologia , HIV-1/efeitos dos fármacos , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Anticorpos Monoclonais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Testes de Neutralização/métodos
5.
Cancer Immunol Immunother ; 73(11): 220, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235609

RESUMO

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/genética , Adulto , Prognóstico
7.
Cancer Discov ; 14(9): 1577-1580, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39228298

RESUMO

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through N-linked glycosylation of CD79B and lower CD79B surface expression levels due to the activity of the KLHL6 E3 ligase. See related article by Corcoran et al., p. 1653 (6) See related article by Meriranta et al. (7).


Assuntos
Imunoconjugados , Humanos , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Antígenos CD79 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico
9.
Med Oncol ; 41(10): 239, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39230639

RESUMO

Immunotoxins (ITs) are specialized therapeutic agents designed for targeted treatment, particularly in cancer therapy. They consist of a monoclonal antibody or antibody fragment linked to a potent cytotoxic agent, such as bacterial- or plant-derived toxins like diphtheria toxin, ricin, or pseudomonas exotoxin. The monoclonal antibody component specifically binds to antigens expressed on the surface of target cells, facilitating the internalization of the IT. Once inside the cell, the cytotoxic agent is released, disrupting essential cellular processes and leading to cell death. This targeted approach minimizes damage to healthy tissues while effectively eliminating diseased cells. The production of ITs involves two primary methods: recombinant fusion and chemical conjugation. In recombinant fusion, genetic engineering is used to create a fusion protein that combines the antibody and toxin, ensuring precise control over their ratio and functionality. In chemical conjugation, pre-existing antibodies are chemically linked to toxins, allowing for greater flexibility in combining different antibodies and cytotoxic agents. Each method has its advantages and challenges, influencing the specificity, production complexity, and therapeutic potential of the resulting ITs. As research advances, ITs continue to show promise not only in oncology but also in treating other diseases, including inflammatory conditions and atherosclerosis. The precise targeting and potent effects of ITs make them a valuable tool in the development of new therapeutic strategies.


Assuntos
Imunotoxinas , Neoplasias , Imunotoxinas/uso terapêutico , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Anticorpos Monoclonais/uso terapêutico , Animais
10.
AAPS J ; 26(6): 104, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285067

RESUMO

Pre-existing anti-AAV antibodies can be detected using ligand binding-based assay formats. One such format is the MSD-based bridging assay, which uses sulfo-tag-labeled AAV vectors as detection reagents. However, no method has been developed to accurately measure the degree of sulfo-tag labeling on AAV vectors. To fill this gap, we developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to assess the degree of labeling (DoL) of sulfo-tag on AAV5 vectors, enabling the measurement of the DoL on AAV5 at six increasing levels of sulfo-tag challenge ratio. In addition, a Biacore-based assay was used to evaluate the binding affinity between an anti-AAV5 monoclonal antibody and various sulfo-tag labeled AAV5 vectors. The results indicated that increased DoL of sulfo-tag labeling on AAV5 did not compromise the binding affinity.Our study further employed the MSD-bridging assay to detect the binding Signal/Noise (S/N) ratios of four anti-AAV5 monoclonal antibodies (mAbs) to various sulfo-tag-labeled AAV5 vectors. The findings revealed a strong correlation between the degree of sulfo-tag labeling and both the S/N ratios and the sensitivity of MSD bridging assays. This result underscores the importance of optimizing the labeling of detection reagents to enhance assay sensitivity for detecting anti-AAV5 antibodies.


Assuntos
Anticorpos Monoclonais , Dependovirus , Vetores Genéticos , Dependovirus/genética , Dependovirus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/química , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Afinidade de Anticorpos/imunologia , Animais
11.
Cancer Immunol Immunother ; 73(11): 231, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261363

RESUMO

CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.


Assuntos
Anticorpos Monoclonais , Carcinoma Hepatocelular , Proteína-1 Reguladora de Fusão , Neoplasias Hepáticas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia , Proteína-1 Reguladora de Fusão/metabolismo , Proteína-1 Reguladora de Fusão/imunologia , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/imunologia , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Cadeia Pesada da Proteína-1 Reguladora de Fusão
12.
Front Immunol ; 15: 1406643, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39263220

RESUMO

Introduction: Immunogenicity, the unwanted immune response triggered by therapeutic antibodies, poses significant challenges in biotherapeutic development. This response can lead to the production of anti-drug antibodies, potentially compromising the efficacy and safety of treatments. The internalization of therapeutic antibodies into dendritic cells (DCs) is a critical factor influencing immunogenicity. Using monoclonal antibodies, with differences in non-specific cellular uptake, as tools to explore the impact on the overall risk of immunogenicity, this study explores how internalization influences peptide presentation and subsequently T cell activation. Materials and methods: To investigate the impact of antibody internalization on immunogenicity, untargeted toolantibodies with engineered positive or negative charge patches were utilized. Immature monocyte-derived DCs (moDCs), known for their physiologically relevant high endocytic activity, were employed for internalization assays, while mature moDCs were used for MHC-II associated peptide proteomics (MAPPs) assays. In addition to the lysosomal accumulation and peptide presentation, subsequent CD4+ T cell activation has been assessed. Consequently, a known CD4+ T cell epitope from ovalbumin was inserted into the tool antibodies to evaluate T cell activation on a single, shared epitope. Results: Antibodies with positive charge patches exhibited higher rates of lysosomal accumulation and epitope presentation compared to those with negative charge patches or neutral surface charge. Furthermore, a direct correlation between internalization rate and presentation on MHC-II molecules could be established. To explore the link between internalization, peptide presentation and CD4+ T cell activation, tool antibodies containing the same OVA epitope were used. Previous observations were not altered by the insertion of the OVA epitope and ultimately, an enhanced CD4+ T cell response correlated with increased internalization in DCs and peptide presentation. Discussion: These findings demonstrate that the biophysical properties of therapeutic antibodies, particularly surface charge, play a crucial role in their internalization into DCs. Antibodies internalized faster and processed by DCs, are also more prone to be presented on their surface leading to a higher risk of triggering an immune response. These insights underscore the importance of considering antibody surface charge and other properties that enhance cellular accumulation during the preclinical development of biotherapeutics to mitigate immunogenicity risks.


Assuntos
Apresentação de Antígeno , Células Dendríticas , Ativação Linfocitária , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Apresentação de Antígeno/imunologia , Ativação Linfocitária/imunologia , Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Fatores de Risco , Endocitose/imunologia , Ovalbumina/imunologia
13.
Sci Rep ; 14(1): 21462, 2024 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271690

RESUMO

Potency assessment of monoclonal antibodies or corresponding biosimilars in cell-based assays is an essential prerequisite in biopharmaceutical research and development. However, cellular bioassays are still subject to limitations in sample throughput, speed, and often need costly reagents or labels as they are based on an indirect readout by luminescence or fluorescence. In contrast, whole-cell Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry (MS) has emerged as a direct, fast and label-free technology for functional drug screening being able to unravel the molecular complexity of cellular response to pharmaceutical reagents. However, this approach has not yet been used for cellular testing of biologicals. In this study, we have conceived, developed and benchmarked a label-free MALDI-MS based cell bioassay workflow for the functional assessment of complement-dependent cytotoxicity (CDC) of Rituximab antibody. By computational evaluation of response profiles followed by subsequent m/z feature annotation via fragmentation analysis and trapped ion mobility MS, we identified adenosine triphosphate and glutathione as readily MS-assessable metabolite markers for CDC and demonstrate that robust concentration-response characteristics can be obtained by MALDI-TOF MS. Statistical assay performance indicators suggest that whole-cell MALDI-TOF MS could complement the toolbox for functional cellular testing of biopharmaceuticals.


Assuntos
Rituximab , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Humanos , Rituximab/farmacologia , Proteínas do Sistema Complemento/metabolismo , Bioensaio/métodos , Anticorpos Monoclonais , Glutationa/metabolismo , Trifosfato de Adenosina/metabolismo
14.
MAbs ; 16(1): 2402701, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39279104

RESUMO

Elimination of the binding of immunoglobulin Fc to Fc gamma receptors is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been used in the clinic, but they have not been systematically compared. We have now produced a matched set of anti-CD20 antibodies with different Fc subclasses and variants and compared their activity for binding to C1q, Fc-gamma receptors and in cell-based assays. Most of the variants still have significant levels of activity in one or more of these assays and many of them have impaired temperature stability compared with the corresponding wild-type antibody.


Assuntos
Fragmentos Fc das Imunoglobulinas , Receptores de IgG , Receptores de IgG/genética , Receptores de IgG/metabolismo , Receptores de IgG/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/metabolismo , Mutação , Ligação Proteica , Antígenos CD20/imunologia , Antígenos CD20/genética , Antígenos CD20/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/genética
15.
MAbs ; 16(1): 2402713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39279181

RESUMO

Subcutaneous (SC) administration is transforming the delivery of biopharmaceuticals, facilitating care in a variety of healthcare settings, including home self-treatment. Large-volume single SC doses have gained attention for their potential to expand therapeutic applications and improve long-term, patient-centric dosing regimens, often at a reduced SC injection frequency. However, a systematic understanding of dose volumes and frequencies for large-volume (>2.0 mL) SC biopharmaceuticals (LVSCs) is lacking. Accordingly, this study systematically reviewed clinical-stage and approved intravenous (IV) and SC biopharmaceuticals, identifying 182 LVSCs - predominantly monoclonal or bispecific antibodies - which correspond to approximately 15% of all IV and SC biopharmaceuticals. These LVSCs are designed to target cancer and a range of non-cancer chronic disease states, including autoimmune, neurological, and cardiovascular diseases. Results show that anti-cancer LVSCs (n = 75) typically require 5.0 to 20.0 mL doses every three weeks and are administered by healthcare professionals. In contrast, non-cancer LVSCs (n = 107), which are typically self-administered monthly, show more significant dosing variability, with < 5.0 mL being the predominant volume range. Furthermore, the study identified a substantial clinical pipeline of potential LVSCs, many of which are being injected at increasingly lower dosing frequencies, suggesting significant future growth in this area. Most non-cancer LVSCs are currently undergoing clinical trials via the SC route, whereas the majority of the cancer LVSCs are being administered IV and require transition to the SC route. These findings highlight the importance of developing large-volume drug delivery systems and novel formulations to reduce injection volumes. The analysis provides valuable guidance for new product development, as well as for marketing and commercialization strategies in the rapidly evolving LVSC landscape.


Assuntos
Neoplasias , Humanos , Injeções Subcutâneas , Neoplasias/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Biespecíficos/administração & dosagem
16.
Acta Pharm ; 74(3): 479-493, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39279529

RESUMO

The formulation of biopharmaceutical drugs is designed to eliminate chemical instabilities, increase conformational and colloidal stability of proteins, and optimize interfacial stability. Among the various excipients involved, buffer composition plays a pivotal role. However, conventional buffers like histidine and phosphate buffers may not always be the optimal choice for all monoclonal antibodies (mAbs). In this study, we investigated the effects of several alternative buffer systems on seven different mAbs, exploring various combinations of ionic strengths, concentrations of the main buffer component, mAb concentrations, and stress conditions. Protein stability was assessed by analyzing soluble aggregate formation through size exclusion chromatography. At low protein concentrations, protein instability after temperature stress was exclusively observed in the bis-TRIS/ glucuronate buffer. Conversely, freeze-thaw stress led to a significant increase in aggregate formation in tested formulations, highlighting the efficacy of several alternative buffers, particularly arginine/ citrate, in preserving protein stability. Under temperature stress, the introduction of arginine to histidine buffer systems provided additional stabilization, while the addition of lysine resulted in protein destabilization. Similarly, the incorporation of arginine into histi-dine/HCl buffer further enhanced protein stability during freeze--thaw cycles. At high protein concentrations, the histidine/citrate buffer emerged as one of the most optimal choices for addressing temperature and light-induced stress. The efficacy of histidine buffers in combating light stress might be attributed to the light-absorbing properties of histidine molecules. Our findings demonstrate that the development of biopharmaceutical formulations should not be confined to conventional buffer systems, as numerous alternative options exhibit comparable or even superior performance.


Assuntos
Anticorpos Monoclonais , Excipientes , Estabilidade Proteica , Soluções Tampão , Anticorpos Monoclonais/química , Excipientes/química , Concentração Osmolar , Composição de Medicamentos/métodos , Temperatura , Estabilidade de Medicamentos , Histidina/química , Congelamento , Química Farmacêutica/métodos , Arginina/química , Agregados Proteicos
17.
Front Immunol ; 15: 1434463, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39281668

RESUMO

Functionally bivalent non-covalent Fab dimers (Bi-Fabs) specific for the TCR/CD3 complex promote CD3 signaling on T cells. While comparing functional responses to stimulation with Bi-Fab, F(ab')2 or mAb specific for the same CD3 epitope, we observed fratricide requiring anti-CD3 bridging of adjacent T cells. Surprisingly, anti-CD3 Bi-Fab ranked first in fratricide potency, followed by anti-CD3 F(ab')2 and anti-CD3 mAb. Low resolution structural studies revealed anti-CD3 Bi-Fabs and F(ab')2 adopt similar global shapes with CD3-binding sites oriented outward. However, under molecular dynamic simulations, anti-CD3 Bi-Fabs crosslinked CD3 more rigidly than F(ab')2. Furthermore, molecular modelling of Bi-Fab and F(ab')2 binding to CD3 predicted crosslinking of T cell antigen receptors located in opposing plasma membrane domains, a feature fitting with T cell fratricide observed. Thus, increasing rigidity of Fab-CD3 crosslinking between opposing effector-target pairs may result in stronger T cell effector function. These findings could guide improving clinical performance of bi-specific anti-CD3 drugs.


Assuntos
Complexo CD3 , Fragmentos Fab das Imunoglobulinas , Ativação Linfocitária , Linfócitos T , Complexo CD3/imunologia , Complexo CD3/metabolismo , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/metabolismo , Fragmentos Fab das Imunoglobulinas/química , Ativação Linfocitária/imunologia , Animais , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Ligação Proteica , Simulação de Dinâmica Molecular , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Camundongos , Anticorpos Monoclonais/imunologia , Transdução de Sinais , Sítios de Ligação
18.
Front Immunol ; 15: 1397692, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39234238

RESUMO

Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that has been approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma (UC). This study presents a comprehensive pharmacovigilance analysis of the post-marketing safety profile of EV in the real-world based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Adverse event (AE) reports regarding EV between January 2020 and December 2023 were obtained from the FAERS database. The standardized MedDRA query (SMQ) narrow search AEs on the preferred term (PT) level were used. Disproportionality analysis was performed to identify the AE signals for EV with the reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). Results: A total of 2,216 reports regarding EV were included in the present study. SMQ analysis results indicated that a stronger strength signal was found in severe cutaneous adverse reactions, retroperitoneal fibrosis, and peripheral neuropathy. A total of 116 significant disproportionality PTs referring to 14 system organ classes (SOCs) were retained by disproportionality analysis, with 49 PTs not listed on the EV drug label. Frequently reported EV-related AEs included rash, peripheral neuropathy, decreased appetite, alopecia, and pruritus. The time to onset of the majority of EV-related AEs was within 30 days (66.05%), with only 0.73% events occurring after 1 year. Conclusion: The disproportionality analysis highlights that dermatologic toxicity and peripheral neuropathy were the major AEs induced by EV. The potential AEs not listed on the drug label were mainly related to gastrointestinal, hepatic, and pulmonary events. Further research is needed to confirm and explore the EV-related AEs in clinical practice.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Bases de Dados Factuais , Farmacovigilância , Vigilância de Produtos Comercializados , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Adulto , Estados Unidos/epidemiologia , Imunoconjugados/efeitos adversos , Adulto Jovem , Anticorpos Monoclonais/efeitos adversos , Adolescente , Idoso de 80 Anos ou mais , United States Food and Drug Administration , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia
19.
Front Immunol ; 15: 1408892, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39234256

RESUMO

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.


Assuntos
Análise Custo-Benefício , Imunoterapia Adotiva , Lenalidomida , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/economia , Talidomida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Masculino , Feminino , Bortezomib/uso terapêutico , Bortezomib/administração & dosagem , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento , Idoso , Resistencia a Medicamentos Antineoplásicos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/economia
20.
Appl Microbiol Biotechnol ; 108(1): 456, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39222096

RESUMO

The diagnosis of mycobacterial infections, including both the Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM), poses a significant global medical challenge. This study proposes a novel approach using immunochromatographic (IC) strip tests for the simultaneous detection of MTBC and NTM. Traditional methods for identifying mycobacteria, such as culture techniques, are hindered by delays in distinguishing between MTBC and NTM, which can affect patient care and disease control. Molecular methods, while sensitive, are resource-intensive and unable to differentiate between live and dead bacteria. In this research, we developed unique monoclonal antibodies (mAbs) against Ag85B, a mycobacterial secretory protein, and successfully implemented IC strip tests named 8B and 9B. These strips demonstrated high concordance rates with conventional methods for detecting MTBC, with positivity rates of 93.9% and 85.9%, respectively. For NTM detection, the IC strip tests achieved a 63.2% detection rate compared to culture methods, considering variations in growth rates among different NTM species. Furthermore, this study highlights a significant finding regarding the potential of MPT64 and Ag85B proteins as markers for MTBC detection. In conclusion, our breakthrough method enables rapid and accurate detection of both MTBC and NTM bacteria within the BACTEC MGIT system. This approach represents a valuable tool in clinical settings for distinguishing between MTBC and NTM infections, thereby enhancing the management and control of mycobacterial diseases. KEY POINTS: • Panel of mAbs for differentiating MTB versus NTM • IC strips for diagnosing MTBC and NTM after the BACTEC MGIT • Combined detection of MTP64 and Ag85B enhances diagnostic accuracy.


Assuntos
Anticorpos Monoclonais , Antígenos de Bactérias , Proteínas de Bactérias , Mycobacterium tuberculosis , Micobactérias não Tuberculosas , Tuberculose , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/genética , Anticorpos Monoclonais/imunologia , Humanos , Micobactérias não Tuberculosas/isolamento & purificação , Micobactérias não Tuberculosas/classificação , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Antígenos de Bactérias/análise , Antígenos de Bactérias/imunologia , Tuberculose/diagnóstico , Tuberculose/microbiologia , Proteínas de Bactérias/genética , Cromatografia de Afinidade/métodos , Sensibilidade e Especificidade , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Aciltransferases , Anticorpos Antibacterianos/imunologia
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