AAPS Journal最新文献_第3页

Quantitative Characterization of Innate and Adaptive Pharmacology of Allogeneic anti-CD20 Chimeric Antigen Receptor (CAR) Vδ1 γδ T cells using Multiscale Mechanistic Modeling. 利用多尺度机制模型定量表征同种异体抗cd20嵌合抗原受体（CAR） Vδ1 γδ T细胞的先天和适应性药理学

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-18 DOI: 10.1208/s12248-026-01314-y

Devam A Desai, Omar Elashkar, Rodrigo Cristofoletti, Ganesh Mugundu, Aman P Singh

{"title":"Quantitative Characterization of Innate and Adaptive Pharmacology of Allogeneic anti-CD20 Chimeric Antigen Receptor (CAR) Vδ1 γδ T cells using Multiscale Mechanistic Modeling.","authors":"Devam A Desai, Omar Elashkar, Rodrigo Cristofoletti, Ganesh Mugundu, Aman P Singh","doi":"10.1208/s12248-026-01314-y","DOIUrl":"10.1208/s12248-026-01314-y","url":null,"abstract":"Gamma Delta (γδ) T Cells are currently being evaluated as a therapeutic alternative to traditional alpha-beta (αβ) T-cells due to their superior safety profile and enhanced tissue retention properties. The application of CAR technology to gamma delta (γδ) T cells presents a novel therapeutic avenue with the potential to overcome some limitations of conventional CAR T-cell therapies, such as targeting solid tumors and reducing on-target, off-tumor toxicities. The objective of this manuscript is development of a translational PK-PD framework to first characterize in vitro killing potential of un-transduced and CAR transduced anti- CD20 Vδ1 γδ T cells as well as development of an in vivo mechanistic CK-PD model designed to understand the complex dynamics of CAR γδ T cells and their interaction with IL-15 and tumor cells. All the preclinical and clinical datasets along with relevant information were digitized and obtained from the published work on Adicet Bio's AD-001. The developed model was able to estimate the in vitro killing potential of untransduced and CAR transduced anti- CD20 Vδ1 γδ T cells as well as expansion, tissue distribution, the impact of lymphodepletion and interleukin-15 (IL-15), and the tumor-killing potential of CAR-modified γδ T cells. These insights offer a deeper understanding of the potential therapeutic benefits and mechanisms of γδ T cells in immunotherapy, particularly in their application against various cancers. The development of this translational framework can be paramount in understanding the underlying dose-exposure-response relationship of CAR modified γδ T cell therapy and facilitate the discovery and development of these agents.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel Assay Platform for Targeted Protein Degradation Monitoring: Case Study of Antibody Free Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) for MALT1 Target Quantification. 靶向蛋白降解监测的新型检测平台：无抗体液相色谱串联质谱（LC-MS/MS）用于MALT1目标定量的案例研究

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-15 DOI: 10.1208/s12248-026-01287-y

Feng Jin, Craig Wallace, William Housley, Marlon Cowart, Lucia Eaton, John P Savaryn, David B Duignan, Christopher M Harris, Mario Richter, Gary J Jenkins, Qin C Ji

{"title":"A Novel Assay Platform for Targeted Protein Degradation Monitoring: Case Study of Antibody Free Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) for MALT1 Target Quantification.","authors":"Feng Jin, Craig Wallace, William Housley, Marlon Cowart, Lucia Eaton, John P Savaryn, David B Duignan, Christopher M Harris, Mario Richter, Gary J Jenkins, Qin C Ji","doi":"10.1208/s12248-026-01287-y","DOIUrl":"10.1208/s12248-026-01287-y","url":null,"abstract":"The mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a central regulator of inflammatory signaling downstream of immunoreceptor tyrosine-based activation motif-containing receptors and G protein-coupled receptors (GPCRs). MALT1 has been investigated as a drug target in inflammation and cancer by inhibitors and targeted degradation. Accurate quantification of MALT1 protein is a critical unmet need for drug discovery. However, traditional ligand binding assays (LBAs), such as Enzyme-Linked Immunosorbent Assay (ELISA) or Meso Scale Discovery Assay (MSD), have been limited by the lack of suitable reagents. To address this limitation, we developed LC-MS/MS targeted MALT1 degradation monitoring assays which have enabled effective monitoring of target degradation in vivo and in vitro. A customized, reagent-independent one dimensional (1D)-LC-MS/MS assay was initially used to facilitate early-phase drug discovery screening. Furthermore, the continued progress of the discovery chemistry resulted in molecules with a higher percentage of MALT1 degradation, resulting in lower remaining MALT1 concentrations within sample matrices and the need for a highly sensitive quantitation. Consequently, a 2D-LC-MS/MS assay with a novel instrument configuration was developed. This assay has proven crucial for early drug optimization and dose selection in both in vitro and in vivo studies. The examples of assay application include the measurement of the DC50 of a lead compound across multiple species, with DC50 value of 5.2 nM in monkeys, 57.0 nM in rats, and 86.9 nM in dog splenocytes. This assay was also used to help select one of the best lead compounds with degradation showing 77.9% with in vivo treatment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Real-Time Single-Aggregate Analysis of Vaccine Antigen Stability via Stochastic Electrochemical Blocking. 随机电化学阻断法实时分析疫苗抗原稳定性

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-15 DOI: 10.1208/s12248-026-01293-0

Kathryn G Shields, Azaria A Wagner, Morgan F Rudesill, Weiyue Xin, Emory M Payne, Jeffrey E Dick

{"title":"Real-Time Single-Aggregate Analysis of Vaccine Antigen Stability via Stochastic Electrochemical Blocking.","authors":"Kathryn G Shields, Azaria A Wagner, Morgan F Rudesill, Weiyue Xin, Emory M Payne, Jeffrey E Dick","doi":"10.1208/s12248-026-01293-0","DOIUrl":"10.1208/s12248-026-01293-0","url":null,"abstract":"Protein aggregation remains a major challenge in vaccine stability, particularly for protein antigens that undergo structural perturbation during storage, reconstitution, and transport. Here, we apply stochastic electrochemical blocking to observe aggregation of the glycoprotein E (gE) antigen from the SHINGRIX™ vaccine under different formulation and temperature conditions. This orthogonal technique to more traditional light-based methods enables rapid, single-particle, qualitative measurements in solution without introducing shear forces or nonnative interfaces. We examined gE aggregates after reconstitution over a two-week period via additions of MilliQ water, the buffer matrix of the liposome-based adjuvant AS01B (sans the liposome itself), and the complete AS01B liposome adjuvant system. Day 0 measurements revealed formulation-dependent aggregation, with the AS01B Buffer addition promoting the largest aggregates, water addition producing intermediate aggregation, and AS01B itself minimizing aggregation. Time trial experiments showed that refrigeration (4 °C) consistently reduced aggregate size, whereas 37 °C accelerated aggregation until particles became too large to reach the electrode. Overall, stochastic electrochemical blocking provides a rapid, tangential method for monitoring protein aggregation in vaccine formulations and offers actionable insights into optimizing storage and reconstitution conditions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Commentary on "Reference Standard Calibration Challenges in the Case of Erythropoietin: Impact on Potency and Biosimilarity Determination". 对“促红细胞生成素的参考标准校准挑战：对效价和生物相似性测定的影响”的评论。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-11 DOI: 10.1208/s12248-026-01312-0

Ben Cowper, Peter Rigsby, Chris Burns

引用次数: 0

Four Decades of History & Evolution of Clinical Pharmacology at US Food and Drug Administration (FDA)-Part II: Dose Individualization and Approvability Evidence. 美国食品和药物管理局（FDA）临床药理学四十年的历史和演变-第二部分：剂量个体化和可批准性证据。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-11 DOI: 10.1208/s12248-026-01309-9

Mehul Mehta

{"title":"Four Decades of History & Evolution of Clinical Pharmacology at US Food and Drug Administration (FDA)-Part II: Dose Individualization and Approvability Evidence.","authors":"Mehul Mehta","doi":"10.1208/s12248-026-01309-9","DOIUrl":"10.1208/s12248-026-01309-9","url":null,"abstract":"The Office of Clinical Pharmacology (OCP) is a part of the Center for Drug Evaluation and Research (CDER) at the FDA. OCP is likely the largest group of scientists with expertise in the evaluation of all aspects of clinical pharmacology in new drug development, approval, and life cycle management. This article details the growth of this office over the last 40 years from one small Division of Biopharmaceutics (DB) in 1986, with staff of about 30 members carrying a large backlog of applications, to the current OCP of approximately 270 scientists with needed resources to carry out thousands of reviews and industry meetings in a timely manner. The growth of OCP is detailed with milestone developments in the areas of biopharmaceutics (BP) and CP science, which became a part of the review focus of new drug and biological applications over the last 40 years. Part I covered the organizational evolution of the OCP and the first segment of its scientific growth, i.e., bioanalysis, specific topics in the areas of bioavailability (BA) and bioequivalence (BE), biosimilars, and new drug applications (NDAs) on the basis of Sect. 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDC Act). Part II covers the areas of metabolism and drug‒drug interactions (DDI), including DDI-induced fatal terfenadine cardiotoxicity, special populations, pediatric efficacy extrapolation, pharmacogenomics, quantitative clinical pharmacology (QCP), and conclusions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering and Characterisation of 3D-Printed Timolol Maleate Implants for Long-Acting Glaucoma Treatment. 用于长效青光眼治疗的3d打印马来酸替马洛尔植入物的工程和特性。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-11 DOI: 10.1208/s12248-026-01300-4

Febri Annuryanti, Masoud Adhami, Eneko Larrañeta, Lalitkumar Vora, Thakur Raghu Raj Singh

{"title":"Engineering and Characterisation of 3D-Printed Timolol Maleate Implants for Long-Acting Glaucoma Treatment.","authors":"Febri Annuryanti, Masoud Adhami, Eneko Larrañeta, Lalitkumar Vora, Thakur Raghu Raj Singh","doi":"10.1208/s12248-026-01300-4","DOIUrl":"10.1208/s12248-026-01300-4","url":null,"abstract":"Timolol maleate (TM) is a nonselective β-blocker commonly used to treat ocular hypertension and glaucoma. Traditional formulations, such as eye drops and gel-forming solutions, often require frequent administration and may lead to systemic side effects and poor patient compliance. To address these challenges, this study investigated the fabrication and characterization of TM-loaded ocular implants via vat-polymerization 3D printing. The implants were fabricated using polyethylene glycol diacrylate (PEGDA) alone or in combination with polylactic acid/polyurethane acrylate (PLA/PUA) or poly(lactic-co-glycolic acid) (PLGA). The implants were characterized for their thermal properties, drug-release profiles, and biocompatibility. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of significant chemical interactions between the TM and the polymers. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) revealed the thermal stability of the TM-loaded implants, with drug loading influencing the thermal properties. In vitro release studies over 180 days showed that drug release was proportional to the surface area-to-volume (SA/V) ratio of the implant. The release kinetics followed a diffusion-controlled mechanism, as described by the Korsmeyer-Peppas model. The biocompatibility study showed no significant cytotoxicity, with fibroblast viability exceeding 80%. These findings suggest that TM-loaded implants could provide a more effective, sustained-release alternative for glaucoma treatment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Four decades of History & Evolution of Clinical Pharmacology at US Food and Drug Administration (FDA)- Part I: Product Quality. 美国食品和药物管理局（FDA）临床药理学四十年的历史和演变-第一部分：产品质量。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-11 DOI: 10.1208/s12248-026-01308-w

Mehul Mehta

{"title":"Four decades of History & Evolution of Clinical Pharmacology at US Food and Drug Administration (FDA)- Part I: Product Quality.","authors":"Mehul Mehta","doi":"10.1208/s12248-026-01308-w","DOIUrl":"10.1208/s12248-026-01308-w","url":null,"abstract":"The Office of Clinical Pharmacology (OCP) is a part of the Center for Drug Evaluation and Research (CDER) at the FDA. OCP probably comprises the largest group of scientists with expertise in, and involved with, the evaluation of all aspects of clinical pharmacology in new drug development, approval, and lifecycle management. Over a series of two parts, details are covered about the growth of this office over the last 40 years from one small Division of Biopharmaceutics (DB) in 1986, with staff of approximately 30 members carrying a large backlog of applications, to the current OCP of approximately 270 scientists with needed resources to carry out thousands of reviews and industry meetings in a timely manner. The growth of OCP is detailed with milestone developments in the areas of biopharmaceutics (BP) and clinical pharmacology (CP) science, which became a part of the review focus of new drug and biological applications over the last 40 years. Relevant regulations, guidances and some of the seminal articles/drug approvals highlighting critical contributions of the emerging components of OCP are also briefly covered. The parallel growth of CDER and enactment of new critical legislation requiring this growth are also summarized. In this first part, the organizational evolution of the OCP and the first segment of its scientific growth, i.e., bioanalysis, specific topics in the areas of bioavailability (BA) and bioequivalence (BE), biosimilars, and new drug applications (NDAs) based on Sect. 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDC Act), are covered. Part II covers the areas of metabolism and drug‒drug interactions (DDIs), including DDI-induced cardiotoxicity of terfenadine, special populations, pediatric efficacy extrapolation, pharmacogenomics, quantitative clinical pharmacology (QCP), and conclusions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Verification of a Physiologically-based Pharmacokinetic Model for Predicting CYP3A4-mediated Simvastatin and Simvastatin Acid Drug-drug Interactions. 预测cyp3a4介导的辛伐他汀和辛伐他汀酸-药物相互作用的基于生理的药代动力学模型的验证。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-09 DOI: 10.1208/s12248-026-01299-8

Bridget L Morse, Bing Han, Jeffrey J Alberts, Maria M Posada, Gemma L Dickinson, Stephen D Hall

{"title":"Verification of a Physiologically-based Pharmacokinetic Model for Predicting CYP3A4-mediated Simvastatin and Simvastatin Acid Drug-drug Interactions.","authors":"Bridget L Morse, Bing Han, Jeffrey J Alberts, Maria M Posada, Gemma L Dickinson, Stephen D Hall","doi":"10.1208/s12248-026-01299-8","DOIUrl":"10.1208/s12248-026-01299-8","url":null,"abstract":"Simvastatin is a commonly prescribed medication and a sensitive CYP3A4 substrate requiring dosage modification with CYP3A4 precipitants. Unlike other CYP3A4 substrates, grapefruit juice (GFJ) causes the largest increase in simvastatin exposure of any CYP3A4 inhibitor, leading to misunderstanding of simvastatin fraction escaping CYP3A4 metabolism in the gut (Fg, CYP3A4) and fraction metabolized by CYP3A4 in the liver (fm,CYP3A4). Simvastatin is a prodrug that is converted to the active simvastatin acid, though the mechanisms responsible for in vivo simvastatin acid formation are not well-understood. GFJ also decreases the simvastatin acid:simvastatin exposure ratio, suggesting inhibition of simvastatin acid formation. In the current work, we used a static approach to define simvastatin CYP3A4 parameters, using clinical data with index substrate midazolam; estimated simvastatin Fg,CYP3A4 and fm,CYP3A4 were ~ 0.4 and ~ 0.9, respectively. In vitro data assessing the stability of simvastatin and simvastatin acid demonstrated rapid conversion in gastric fluid that was highly pH-dependent. A simvastatin PBPK model was constructed incorporating these CYP3A4 parameters and simvastatin acid formation in stomach, intestine and plasma. The model reproduced the nonlinear pharmacokinetics of simvastatin and CYP3A4 precipitant effects, thus qualifying the model for prediction of CYP3A4-mediated interactions on both simvastatin and simvastatin acid. Simvastatin overall Fg was estimated as ~ 0.2, lower than the Fg,CYP3A4 due to additional intestinal esterase-mediated formation of simvastatin acid. The simvastatin-GFJ effect was explained by inhibition of this intestinal simvastatin acid formation, along with CYP3A4 inhibition. The unique effect of food on the simvastatin acid:simvastatin exposure ratio could also be replicated using this PBPK model.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dissolution Enhancement by Binding Agents: A Potential Shortcut to Improving Bioavailability? 结合剂增强溶出：提高生物利用度的潜在捷径？

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-09 DOI: 10.1208/s12248-026-01297-w

Maja Chronowska, Jennifer Dressman

{"title":"Dissolution Enhancement by Binding Agents: A Potential Shortcut to Improving Bioavailability?","authors":"Maja Chronowska, Jennifer Dressman","doi":"10.1208/s12248-026-01297-w","DOIUrl":"10.1208/s12248-026-01297-w","url":null,"abstract":"The poor water solubility of many drugs and drug candidates is a limiting factor to their bioavailability after oral administration. Although dissolution enhancing approaches, e.g. amorphous solid dispersions, are often used to make enabling formulations, these are usually associated with high development and manufacturing costs. This study focuses on the potential of using pharmaceutical excipients (binders) in simple tablet formulations to improve drug release and thus bioavailability. Loperamide hydrochloride, fenofibrate, compound c0 (a drug candidate) and carvedilol were chosen for this study as poorly water-soluble model compounds. Their solubility in the absence and presence of three polymeric binders, polyvinylpyrrolidone (PVP) K90, hydroxypropyl methylcellulose (HPMC) E4M and E15, and methylcellulose (MC) was tested in FaSSIF-V1 buffer and biorelevant media. Additionally, after wet granulation using PVP K90 or HPMC E15 as binders and tablet compression, the dissolution of the model compounds was tested in FaSSIF-V1 buffer and biorelevant media. Although solubilities and dissolution profiles of the model compounds were mostly improved by the binders, correlation between solubility in buffers and dissolution from the tablets in biorelevant FaSSIF-V1 was poor, indicating that dissolution experiments may be a better screening tool than solubility experiments. An important conclusion of these studies is that it is possible to increase the rate, and in some cases, the extent of dissolution of four poorly soluble drugs using wet granulation with polymeric binders, followed by tablet compression - a simple and cost-effective approach to improving drug performance.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunogenicity Assays Used in Support of Marketing Applications of Oligonucleotide Therapeutics. 免疫原性试验用于支持寡核苷酸疗法的市场应用。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-09 DOI: 10.1208/s12248-026-01275-2

Cecilia Arfvidsson, Lin-Zhi Chen, Susovan Mohapatra, Kamalika Mukherjee, Pallab Pradhan, Gnana Oli Rajaraman, Arkadeep Sinha, Christopher C Stebbins, An Zhao, Zhandong Don Zhong, Robert J Kubiak

{"title":"Immunogenicity Assays Used in Support of Marketing Applications of Oligonucleotide Therapeutics.","authors":"Cecilia Arfvidsson, Lin-Zhi Chen, Susovan Mohapatra, Kamalika Mukherjee, Pallab Pradhan, Gnana Oli Rajaraman, Arkadeep Sinha, Christopher C Stebbins, An Zhao, Zhandong Don Zhong, Robert J Kubiak","doi":"10.1208/s12248-026-01275-2","DOIUrl":"10.1208/s12248-026-01275-2","url":null,"abstract":"Oligonucleotide therapeutics (ONT) continue to emerge as a versatile new class of medicines. While relatively small in terms of molecular weight, ONT may trigger formation of anti-drug antibodies (ADA), which in turn may impact pharmacokinetics, pharmacodynamics, efficacy, and safety. Bioanalytical methodology for detection of ADA against protein-based therapeutics is well established, however, detection of ADA against ONT presents its own unique challenges. In this manuscript, the Immunogenicity Sub-team of AAPS Bioanalytical Community Oligonucleotide Discussion Group, reviewed bioanalytical assays used to detect and characterize ADA as reported in documents supporting marketing applications of oligonucleotide therapeutics. Based on the available data and the Authors' own experience, a direct ELISA is by far the most common format used for detection of ADA against ONT. Characterization of ADA neutralizing activity is not performed. No issues with insufficient drug tolerance have been reported and postmarketing requirements to improve assay sensitivity are rare. Data generated in the Authors' laboratories indicate that difficulties with low sensitivity of immunogenicity assays for ONT appear to stem from difficulties in raising and purifying high affinity positive control antibodies. Given the inherently low immunogenic potential of ONTs, generation of positive controls with sufficient affinity and titer may necessitate multiple immunizations with immunogens incorporating repetitive sequence motifs, together with alternation of carrier proteins across immunization cycles.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0