Pub Date : 2024-05-10DOI: 10.1208/s12248-024-00930-w
Jacob Felderman, Lila Ramaiah, Maria-Dolores Vazquez-Abad, Dean Messing, Ying Chen
Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.
与静脉注射(IV)给药途径(RoA)相比,皮下注射(SC)给药被认为具有更高的免疫原性风险。然而,目前还缺乏支持这种说法的系统性临床数据评估。本荟萃分析旨在比较同一种治疗性蛋白质通过静脉注射和体外给药的免疫原性。分析了 48 个治疗组中通过静脉注射和皮下注射两种途径给药的 7 种治疗蛋白的抗药抗体 (ADA) 数据和控制变量。RoA是主要的自变量,而治疗蛋白、患者人群、调整剂量和ADA样本数量则是控制变量。方差分析用于比较静脉注射和静脉注射 RoA 的 ADA 发生率,同时考虑控制变量和潜在的相互作用。随后,在上述 7 种治疗蛋白的基础上,又增加了 10 种已公布了静脉注射和皮下注射 ADA 数据的治疗蛋白,并对其 ADA 发生率进行了评估。对于最初的 7 种治疗蛋白数据集,RoA 对 ADA 发生率没有统计学意义上的显著影响(p = 0.55)。唯一对 ADA 发生率有明显影响的变量是治疗蛋白。其他控制变量(包括与 RoA 的交互作用)均不显著。将 17 种治疗蛋白的所有数据汇总后发现,RoA 对 ADA 发病率的影响在统计学上并不显著(p = 0.81)。总之,根据对 17 种治疗蛋白的临床 ADA 数据的分析,静脉注射和静脉注射 RoA 之间的 ADA 发生率没有明显差异。
{"title":"Anti-Drug Antibody Incidence Comparison of Therapeutic Proteins Administered Via Subcutaneous vs. Intravenous Route.","authors":"Jacob Felderman, Lila Ramaiah, Maria-Dolores Vazquez-Abad, Dean Messing, Ying Chen","doi":"10.1208/s12248-024-00930-w","DOIUrl":"10.1208/s12248-024-00930-w","url":null,"abstract":"<p><p>Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904921","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}
Pub Date : 2024-05-09DOI: 10.1208/s12248-024-00929-3
Tan Zhang, Elisa A M Calvier, Elke H J Krekels, Catherijne A J Knibbe
Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m2, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.
{"title":"Impact of Obesity on Hepatic Drug Clearance: What are the Influential Variables?","authors":"Tan Zhang, Elisa A M Calvier, Elke H J Krekels, Catherijne A J Knibbe","doi":"10.1208/s12248-024-00929-3","DOIUrl":"10.1208/s12248-024-00929-3","url":null,"abstract":"<p><p>Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m<sup>2</sup>, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899978","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}
Pub Date : 2024-05-06DOI: 10.1208/s12248-024-00927-5
Helmut Schütz, Divan A Burger, Erik Cobo, David D Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy
{"title":"Correction: Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies.","authors":"Helmut Schütz, Divan A Burger, Erik Cobo, David D Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy","doi":"10.1208/s12248-024-00927-5","DOIUrl":"10.1208/s12248-024-00927-5","url":null,"abstract":"","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872420","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}
Pub Date : 2024-04-23DOI: 10.1208/s12248-024-00905-x
Mélanie Guhl, Julie Bertrand, Lucie Fayette, François Mercier, Emmanuelle Comets
The standard errors (SE) of the maximum likelihood estimates (MLE) of the population parameter vector in nonlinear mixed effect models (NLMEM) are usually estimated using the inverse of the Fisher information matrix (FIM). However, at a finite distance, i.e. far from the asymptotic, the FIM can underestimate the SE of NLMEM parameters. Alternatively, the standard deviation of the posterior distribution, obtained in Stan via the Hamiltonian Monte Carlo algorithm, has been shown to be a proxy for the SE, since, under some regularity conditions on the prior, the limiting distributions of the MLE and of the maximum a posterior estimator in a Bayesian framework are equivalent. In this work, we develop a similar method using the Metropolis-Hastings (MH) algorithm in parallel to the stochastic approximation expectation maximisation (SAEM) algorithm, implemented in the saemix R package. We assess this method on different simulation scenarios and data from a real case study, comparing it to other SE computation methods. The simulation study shows that our method improves the results obtained with frequentist methods at finite distance. However, it performed poorly in a scenario with the high variability and correlations observed in the real case study, stressing the need for calibration.
非线性混合效应模型(NLMEM)中人口参数向量的最大似然估计值(MLE)的标准误差(SE)通常使用费雪信息矩阵(FIM)的逆矩阵来估计。然而,在有限距离内,即远离渐近线时,FIM 可能会低估 NLMEM 参数的 SE。另外,在 Stan 中通过汉密尔顿蒙特卡洛算法获得的后验分布的标准偏差已被证明是 SE 的替代值,因为在先验的某些规则性条件下,MLE 的极限分布和贝叶斯框架中最大后验估计器的极限分布是等价的。在这项工作中,我们开发了一种类似的方法,使用 Metropolis-Hastings (MH) 算法与随机逼近期望最大化 (SAEM) 算法并行,在 saemix R 软件包中实现。我们在不同的模拟场景和实际案例研究数据中对该方法进行了评估,并将其与其他 SE 计算方法进行了比较。模拟研究表明,我们的方法改进了频繁法在有限距离下获得的结果。然而,在实际案例研究中观察到的高变异性和高相关性情况下,该方法表现不佳,强调了校准的必要性。
{"title":"Uncertainty Computation at Finite Distance in Nonlinear Mixed Effects Models-a New Method Based on Metropolis-Hastings Algorithm.","authors":"Mélanie Guhl, Julie Bertrand, Lucie Fayette, François Mercier, Emmanuelle Comets","doi":"10.1208/s12248-024-00905-x","DOIUrl":"10.1208/s12248-024-00905-x","url":null,"abstract":"<p><p>The standard errors (SE) of the maximum likelihood estimates (MLE) of the population parameter vector in nonlinear mixed effect models (NLMEM) are usually estimated using the inverse of the Fisher information matrix (FIM). However, at a finite distance, i.e. far from the asymptotic, the FIM can underestimate the SE of NLMEM parameters. Alternatively, the standard deviation of the posterior distribution, obtained in Stan via the Hamiltonian Monte Carlo algorithm, has been shown to be a proxy for the SE, since, under some regularity conditions on the prior, the limiting distributions of the MLE and of the maximum a posterior estimator in a Bayesian framework are equivalent. In this work, we develop a similar method using the Metropolis-Hastings (MH) algorithm in parallel to the stochastic approximation expectation maximisation (SAEM) algorithm, implemented in the saemix R package. We assess this method on different simulation scenarios and data from a real case study, comparing it to other SE computation methods. The simulation study shows that our method improves the results obtained with frequentist methods at finite distance. However, it performed poorly in a scenario with the high variability and correlations observed in the real case study, stressing the need for calibration.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900123","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}
Pub Date : 2024-03-28DOI: 10.1208/s12248-024-00907-9
Sam Zhang, Christine C Orozco, Lloyd Wei Tat Tang, Jillian Racich, Anthony A Carlo, George Chang, David Tess, Christopher Keefer, Li Di
Hepatocytes are one of the most physiologically relevant in vitro liver systems for human translation of clearance and drug-drug interactions (DDI). However, the cell membranes of hepatocytes can limit the entry of certain compounds into the cells for metabolism and DDI. Passive permeability through hepatocytes can be different in vitro and in vivo, which complicates the human translation. Permeabilized hepatocytes offer a useful tool to probe mechanistic understanding of permeability-limited metabolism and DDI. Incubation with saponin of 0.01% at 0.5 million cells/mL and 0.05% at 5 million cells/mL for 5 min at 37°C completely permeabilized the plasma membrane of hepatocytes, while leaving the membranes of subcellular organelles intact. Permeabilized hepatocytes maintained similar enzymatic activity as intact unpermeabilized hepatocytes and can be stored at -80°C for at least 7 months. This approach reduces costs by preserving leftover hepatocytes. The relatively low levels of saponin in permeabilized hepatocytes had no significant impact on the enzymatic activity. As the cytosolic contents leak out from permeabilized hepatocytes, cofactors need to be added to enable metabolic reactions. Cytosolic enzymes will no longer be present if the media are removed after cells are permeabilized. Hence permeabilized hepatocytes with and without media removal may potentially enable reaction phenotyping of cytosolic enzymes. Although permeabilized hepatocytes work similarly as human liver microsomes and S9 fractions experimentally requiring addition of cofactors, they behave more like hepatocytes maintaining enzymatic activities for over 4 h. Permeabilized hepatocytes are a great addition to the drug metabolism toolbox to provide mechanistic insights.
{"title":"Characterization and Applications of Permeabilized Hepatocytes in Drug Discovery.","authors":"Sam Zhang, Christine C Orozco, Lloyd Wei Tat Tang, Jillian Racich, Anthony A Carlo, George Chang, David Tess, Christopher Keefer, Li Di","doi":"10.1208/s12248-024-00907-9","DOIUrl":"10.1208/s12248-024-00907-9","url":null,"abstract":"<p><p>Hepatocytes are one of the most physiologically relevant in vitro liver systems for human translation of clearance and drug-drug interactions (DDI). However, the cell membranes of hepatocytes can limit the entry of certain compounds into the cells for metabolism and DDI. Passive permeability through hepatocytes can be different in vitro and in vivo, which complicates the human translation. Permeabilized hepatocytes offer a useful tool to probe mechanistic understanding of permeability-limited metabolism and DDI. Incubation with saponin of 0.01% at 0.5 million cells/mL and 0.05% at 5 million cells/mL for 5 min at 37°C completely permeabilized the plasma membrane of hepatocytes, while leaving the membranes of subcellular organelles intact. Permeabilized hepatocytes maintained similar enzymatic activity as intact unpermeabilized hepatocytes and can be stored at -80°C for at least 7 months. This approach reduces costs by preserving leftover hepatocytes. The relatively low levels of saponin in permeabilized hepatocytes had no significant impact on the enzymatic activity. As the cytosolic contents leak out from permeabilized hepatocytes, cofactors need to be added to enable metabolic reactions. Cytosolic enzymes will no longer be present if the media are removed after cells are permeabilized. Hence permeabilized hepatocytes with and without media removal may potentially enable reaction phenotyping of cytosolic enzymes. Although permeabilized hepatocytes work similarly as human liver microsomes and S9 fractions experimentally requiring addition of cofactors, they behave more like hepatocytes maintaining enzymatic activities for over 4 h. Permeabilized hepatocytes are a great addition to the drug metabolism toolbox to provide mechanistic insights.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319786","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}
Pub Date : 2024-03-28DOI: 10.1208/s12248-024-00908-8
Jianhua Liu, Daria Vernikovskaya, Gary Bora, Anthony Carlo, Woodrow Burchett, Samantha Jordan, Lloyd Wei Tat Tang, Joy Yang, Ye Che, George Chang, Matthew D Troutman, Li Di
Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format. Four 384-well assay plates can be run at the same time to maximize throughput. This is the first multiplexed HTS assay for drug-metabolizing enzymes reported. The HTS assay is technologically enabled with state-of-the-art robotic systems and highly sensitive modern LC-MS/MS instrumentation. Virtual screening is utilized to identify inhibitors for HTS based on known inhibitors and enzyme structures. Screening of ~4600 compounds generated many hits for many drug-metabolizing enzymes including the two time-dependent and selective aldehyde oxidase inhibitors, erlotinib and dibenzothiophene. The hit rate is much higher than that for the traditional HTS for biological targets due to the promiscuous nature of the drug-metabolizing enzymes and the biased compound selection process. Future efforts will focus on using this method to identify selective inhibitors for enzymes that do not currently have quality hits and thoroughly characterizing the newly identified selective inhibitors from our screen. We encourage colleagues from other organizations to explore their proprietary libraries using a similar approach to identify better inhibitors that can be used across the industry.
{"title":"Novel Multiplexed High Throughput Screening of Selective Inhibitors for Drug-Metabolizing Enzymes Using Human Hepatocytes.","authors":"Jianhua Liu, Daria Vernikovskaya, Gary Bora, Anthony Carlo, Woodrow Burchett, Samantha Jordan, Lloyd Wei Tat Tang, Joy Yang, Ye Che, George Chang, Matthew D Troutman, Li Di","doi":"10.1208/s12248-024-00908-8","DOIUrl":"10.1208/s12248-024-00908-8","url":null,"abstract":"<p><p>Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format. Four 384-well assay plates can be run at the same time to maximize throughput. This is the first multiplexed HTS assay for drug-metabolizing enzymes reported. The HTS assay is technologically enabled with state-of-the-art robotic systems and highly sensitive modern LC-MS/MS instrumentation. Virtual screening is utilized to identify inhibitors for HTS based on known inhibitors and enzyme structures. Screening of ~4600 compounds generated many hits for many drug-metabolizing enzymes including the two time-dependent and selective aldehyde oxidase inhibitors, erlotinib and dibenzothiophene. The hit rate is much higher than that for the traditional HTS for biological targets due to the promiscuous nature of the drug-metabolizing enzymes and the biased compound selection process. Future efforts will focus on using this method to identify selective inhibitors for enzymes that do not currently have quality hits and thoroughly characterizing the newly identified selective inhibitors from our screen. We encourage colleagues from other organizations to explore their proprietary libraries using a similar approach to identify better inhibitors that can be used across the industry.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319788","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}
The utilization of antibody-drug conjugates (ADCs) has gained considerable attention in the field of targeted cancer therapy due to their ability to synergistically combine the specificity of monoclonal antibodies (mAbs) and the potency of small molecular drugs. However, the immunogenic nature of the antibody component within ADCs warrants the need for robust immunogenicity testing, including a neutralizing antibody (NAb) assay. Since the mechanism of action (MOA) of the ADC is to first bind to the target cells and then release the payload intracellularly to kill the cells, the most relevant NAb assay format would be a cell-based killing assay. However, in this paper, we present a case where a cell-based killing assay could not be developed after multiple cell lines and NAb-positive controls (PC) had been tested. Surprisingly, contrary to our expectations, all NAb PCs tested exhibited an increased killing effect on the target cells, instead of the expected protective response. This unexpected phenomenon most likely is due to the non-specific internalization of drug/NAb complexes via FcγRs, as an excessive amount of human IgG1 and mouse IgG2a, but not mouse IgG1, greatly inhibited drug or drug/NAb complexes induced cell death. To overcome this obstacle, we implemented a novel cell-based binding assay utilizing the Meso Scale Discovery (MSD) platform. We also propose that an in vitro cell killing NAb assay is limited to at best monitoring the target binding and internalization induced cell death, but not by-stander killing induced by prematurely released or dead-cell released payload, hence cannot really mimic the in vivo MOA of ADC.
{"title":"Development and Validation of a Cell-Based Binding Neutralizing Antibody Assay for an Antibody-Drug Conjugate.","authors":"Weifeng Xu, Nazneen Bano, Olguitza Guzman-Valdes, Jessica Amberman, Elisha Bandlamudi, Pooja Khanna, Rebecca Carmean, Roy Helmy","doi":"10.1208/s12248-024-00909-7","DOIUrl":"10.1208/s12248-024-00909-7","url":null,"abstract":"<p><p>The utilization of antibody-drug conjugates (ADCs) has gained considerable attention in the field of targeted cancer therapy due to their ability to synergistically combine the specificity of monoclonal antibodies (mAbs) and the potency of small molecular drugs. However, the immunogenic nature of the antibody component within ADCs warrants the need for robust immunogenicity testing, including a neutralizing antibody (NAb) assay. Since the mechanism of action (MOA) of the ADC is to first bind to the target cells and then release the payload intracellularly to kill the cells, the most relevant NAb assay format would be a cell-based killing assay. However, in this paper, we present a case where a cell-based killing assay could not be developed after multiple cell lines and NAb-positive controls (PC) had been tested. Surprisingly, contrary to our expectations, all NAb PCs tested exhibited an increased killing effect on the target cells, instead of the expected protective response. This unexpected phenomenon most likely is due to the non-specific internalization of drug/NAb complexes via FcγRs, as an excessive amount of human IgG1 and mouse IgG2a, but not mouse IgG1, greatly inhibited drug or drug/NAb complexes induced cell death. To overcome this obstacle, we implemented a novel cell-based binding assay utilizing the Meso Scale Discovery (MSD) platform. We also propose that an in vitro cell killing NAb assay is limited to at best monitoring the target binding and internalization induced cell death, but not by-stander killing induced by prematurely released or dead-cell released payload, hence cannot really mimic the in vivo MOA of ADC.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140319787","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}
Pub Date : 2024-03-21DOI: 10.1208/s12248-024-00906-w
Joshua Yu, Nirnoy Dan, Seyyed Majid Eslami, Xiuling Lu
Over the past few years, nanoparticles have drawn particular attention in designing and developing drug delivery systems due to their distinctive advantages like improved pharmacokinetics, reduced toxicity, and specificity. Along with other successful nanosystems, silica nanoparticles (SNPs) have shown promising effects for therapeutic and diagnostic purposes. These nanoparticles are of great significance owing to their modifiable surface with various ligands, tunable particle size, and large surface area. The rate and extent of degradation and clearance of SNPs depend on factors such as size, shape, porosity, and surface modification, which directly lead to varying toxic mechanisms. Despite SNPs' enormous potential for clinical and pharmaceutical applications, safety concerns have hindered their translation into the clinic. This review discusses the biodistribution, toxicity, and clearance of SNPs and the formulation-related factors that ultimately influence clinical efficacy and safety for treatment. A holistic view of SNP safety will be beneficial for developing an enabling SNP-based drug product.
在过去的几年里,纳米颗粒因其独特的优势,如改善药代动力学、降低毒性和特异性,在设计和开发给药系统方面引起了特别的关注。与其他成功的纳米系统一样,二氧化硅纳米粒子(SNPs)在治疗和诊断方面也显示出了良好的效果。这些纳米颗粒具有重要意义,因为它们的表面可使用各种配体进行修饰,粒度可调,表面积大。SNP 的降解和清除速度和程度取决于尺寸、形状、孔隙率和表面修饰等因素,这些因素直接导致了不同的毒性机制。尽管 SNP 在临床和制药应用方面潜力巨大,但安全性问题一直阻碍着 SNP 的临床应用。本综述将讨论 SNP 的生物分布、毒性和清除率,以及最终影响临床疗效和治疗安全性的制剂相关因素。对 SNP 安全性的全面认识将有助于开发基于 SNP 的药物产品。
{"title":"State of the Art of Silica Nanoparticles: An Overview on Biodistribution and Preclinical Toxicity Studies.","authors":"Joshua Yu, Nirnoy Dan, Seyyed Majid Eslami, Xiuling Lu","doi":"10.1208/s12248-024-00906-w","DOIUrl":"10.1208/s12248-024-00906-w","url":null,"abstract":"<p><p>Over the past few years, nanoparticles have drawn particular attention in designing and developing drug delivery systems due to their distinctive advantages like improved pharmacokinetics, reduced toxicity, and specificity. Along with other successful nanosystems, silica nanoparticles (SNPs) have shown promising effects for therapeutic and diagnostic purposes. These nanoparticles are of great significance owing to their modifiable surface with various ligands, tunable particle size, and large surface area. The rate and extent of degradation and clearance of SNPs depend on factors such as size, shape, porosity, and surface modification, which directly lead to varying toxic mechanisms. Despite SNPs' enormous potential for clinical and pharmaceutical applications, safety concerns have hindered their translation into the clinic. This review discusses the biodistribution, toxicity, and clearance of SNPs and the formulation-related factors that ultimately influence clinical efficacy and safety for treatment. A holistic view of SNP safety will be beneficial for developing an enabling SNP-based drug product.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140186210","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}
Pub Date : 2024-03-14DOI: 10.1208/s12248-024-00903-z
Lori McCaig, Steven Nowak, Alexander Abbott, Jenny Carhart, Megan E McMahon, Elke Debie, Hanlin Li, Francis Maina, Andrea J Ji, Mingkun Fu, Yan Wu, Andrew Lennard, Tony Mazzeo, Chad Wolfe, Robert Timpano, Yelizaveta Babayan, Lars Gruenig
ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.
ICH Q12 规定,以科学和风险为基础的方法适用于支持化学、生产和控制 (CMC) 批准后变更 (PAC) 的稳定性研究,以便更及时地实施;但是,没有提供指导或具体示例来说明如何通过对产品的事先了解来为拟议变更的风险评估提供信息。本手稿介绍了十个不同的案例研究,以展示如何利用基于科学和风险的稳定性策略来支持药物和产品的 CMC PAC 和生命周期管理活动。已上市产品的原始生产商积累了大量稳定性知识,这些知识库中的不同元素被用于评估拟议变更的风险和影响,以便进行有把握的变更管理。本文介绍了如何利用以科学和风险为基础的稳定性策略,将其作为批准后变更管理风险缓解策略的一部分,从而减少稳定性数据承诺和/或减少变更实施的报告类别。
{"title":"Science- and Risk-Based Stability Strategies to Support Product Lifecycle Changes.","authors":"Lori McCaig, Steven Nowak, Alexander Abbott, Jenny Carhart, Megan E McMahon, Elke Debie, Hanlin Li, Francis Maina, Andrea J Ji, Mingkun Fu, Yan Wu, Andrew Lennard, Tony Mazzeo, Chad Wolfe, Robert Timpano, Yelizaveta Babayan, Lars Gruenig","doi":"10.1208/s12248-024-00903-z","DOIUrl":"10.1208/s12248-024-00903-z","url":null,"abstract":"<p><p>ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133150","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}
Pub Date : 2024-03-08DOI: 10.1208/s12248-024-00902-0
Carlo Giannelli, Francesca Necchi, Elena Palmieri, Davide Oldrini, Beatrice Ricchetti, Maria M Papathanasiou, Zoltan Kis, Cleo Kontoravdi, Cristiana Campa, Francesca Micoli
In recent years, Generalized Modules for Membrane Antigens (GMMA) have received increased attention as an innovative vaccine platform against bacterial pathogens, particularly attractive for low- and middle-income countries because of manufacturing simplicity. The assessment of critical quality attributes (CQAs), product-process interactions, identification of appropriate in process analytical methods, and process modeling is part of a robust quality by design (QbD) framework to support further development and control of manufacturing processes. QbD implementation in the context of the GMMA platform will ensure robust manufacturing of batches with desired characteristics, facilitating technical transfer to local manufacturers, regulatory approval, and commercialization of vaccines based on this technology. Here, we summarize the methodology suggested, applied to a first step of GMMA manufacturing process.
{"title":"Quality by Design Framework Applied to GMMA Purification.","authors":"Carlo Giannelli, Francesca Necchi, Elena Palmieri, Davide Oldrini, Beatrice Ricchetti, Maria M Papathanasiou, Zoltan Kis, Cleo Kontoravdi, Cristiana Campa, Francesca Micoli","doi":"10.1208/s12248-024-00902-0","DOIUrl":"10.1208/s12248-024-00902-0","url":null,"abstract":"<p><p>In recent years, Generalized Modules for Membrane Antigens (GMMA) have received increased attention as an innovative vaccine platform against bacterial pathogens, particularly attractive for low- and middle-income countries because of manufacturing simplicity. The assessment of critical quality attributes (CQAs), product-process interactions, identification of appropriate in process analytical methods, and process modeling is part of a robust quality by design (QbD) framework to support further development and control of manufacturing processes. QbD implementation in the context of the GMMA platform will ensure robust manufacturing of batches with desired characteristics, facilitating technical transfer to local manufacturers, regulatory approval, and commercialization of vaccines based on this technology. Here, we summarize the methodology suggested, applied to a first step of GMMA manufacturing process.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140066104","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}