The AAPS Journal[JOURNAL]
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200 papers
Updated Recommendations for the Bioanalysis of Antibody-Drug Conjugates (ADC) from the ADC working group of the AAPS Bioanalytical Community.
Shen JX, Dodge R, Oberstein S … +19 more , Cunliffe J, Ramani V, Mohana Sundaram S, Santos IC, Yu C, Dholakiya SL, Kumar S, Xu XS, Fraser S, Mokhtari Z, Yin F, Rizzo DG, Barnaby OS, Shen H, Warrino DE, Awasthi S, Burke K, Schaffer S, Rathi A
AAPS J · 2026 Jul · PMID 42387157 · Publisher ↗
Antibody-drug conjugates (ADCs) represent a rapidly evolving therapeutic modality, combining the selective targeting of monoclonal antibodies with highly potent small molecule payloads. Their inherent structural complexi...
Antibody-drug conjugates (ADCs) represent a rapidly evolving therapeutic modality, combining the selective targeting of monoclonal antibodies with highly potent small molecule payloads. Their inherent structural complexity demands a sophisticated and multi-faceted bioanalytical approach spanning preclinical discovery through late-stage clinical development. This white paper, developed by the ADC Working Group of the AAPS bioanalytical community, comprising over 100 members from industry, contract research organizations (CROs), and regulatory agencies, provides updated recommendations for ADC bioanalysis. Building upon the foundational 2013 AAPS position paper and recent publications governing regulatory frameworks on PK considerations, this work addresses advances in bioanalytical quantitation strategies for total antibody (tAb), conjugated ADC, free (unconjugated) payload, and drug-to antibody ratio (DAR); novel immunogenicity assessment considerations; soluble target interference; critical reagent lifecycle management; payload-specific stability requirements; cross-validation strategies; and regulatory considerations. The recommendations presented herein reflect over a decade of scientific progress and are designed to serve as a comprehensive, empirically validated, and industry aligned bioanalytical framework for contemporary ADC drug development.
In vivo Predictive Dissolution Test Using Biorelevant Bicarbonate Buffer for High-dose Free Acid Drug.
Tarumi Y, Sugano K
AAPS J · 2026 Jun · PMID 42380539 · Publisher ↗
The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen...
The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen were selected as model compounds exhibiting solubility-limited absorption at high doses. A biorelevant BCB solution (concentration: 10 mM, initial pH (pH) = 6.5, buffer capacity (β) = 4.4 mM/pH) (BCB), a phosphate buffer solution with the same pH and β (PPB), and a USP phosphate buffer solution (β = 27 mM/pH, modified to pH 6.5) were employed for dissolution tests. The dose-to-fluid volume ratio (Dose/FV) was set to reflect the clinical or compendial conditions. The fraction of a dose absorbed in humans (Fa) predicted using a simple theoretical framework was compared with the clinical Fa calculated from pharmacokinetic data in the literature. When using BCB or PPB with the same β and the clinical Dose/FV, the bulk-phase pH after 4 h (pH, ) was markedly lower than pH (< pH 6.0 for naproxen, < pH 5.0 for valsartan). Consequently, the dissolved drug concentration at 4 h (C) was markedly lower than the solubility at pH 6.5. Using C, the dose dependency of Fa was appropriately predicted. In contrast, when using USP or the compendial Dose/FV, the pH, and C were less reduced, leading to an overestimation of Fa. Overall, the use of BCB or PPB and a clinical Dose/FV improved the in vivo predictability for high-dose free acid drugs.
Whole-Body Pharmacokinetics of Ionizable Lipid, mRNA, and the Expressed Antibody following Intravenous Administration of mRNA-Loaded Lipid Nanoparticles.
Tiwari S, Kumar M, Wu S … +2 more , Kulkarni R, Shah DK
AAPS J · 2026 Jun · PMID 42373925 · Publisher ↗
Lipid nanoparticles (LNPs) containing mRNA that encodes therapeutic proteins have emerged as a promising therapeutic modality for a myriad of diseases. However, the pharmacokinetic (PK) relationships between the nanopart...
Lipid nanoparticles (LNPs) containing mRNA that encodes therapeutic proteins have emerged as a promising therapeutic modality for a myriad of diseases. However, the pharmacokinetic (PK) relationships between the nanoparticle carrier, its mRNA payload, and the expressed protein remain poorly understood. Here we have investigated whole-body PK of these components in mice following intravenous administration of an mRNA-LNP that expresses a non-cross-reactive monoclonal antibody. LNPs encapsulating mRNA were prepared via microfluidic mixing and characterized for physicochemical properties and encapsulation efficiency. Following a single intravenous administration of mRNA-LNP, blood, plasma, and tissues were collected for PK measurement over 2 weeks. Ionizable lipid (i.e., ALC-0315) concentrations were determined using LC-MS, mRNA concentrations were measured using qPCR, and the expressed antibody concentrations were determined using ELISA. It was found that each component exhibited a distinct PK profile. For example, lipid exposure was highest in liver and spleen, while mRNA accumulation peaked in spleen and heart. Strikingly, the expressed antibody demonstrated a distribution pattern that did not mirror mRNA exposure, with the lung showing the greatest antibody levels despite only modest mRNA delivery. Tissue-to-plasma ratios for the expressed antibody exceeded values reported for intravenously administered antibodies, suggesting localized production or enhanced retention following in situ translation. These findings highlight that functional protein exposure is governed by tissue-specific translational efficiency and protein properties, rather than just nanoparticle delivery. The comprehensive PK data presented here also provides a foundation for the development of systems-based PK models for antibody expressing mRNA-LNPs.
Simple Hydrodynamic Molecular Weight Model for Rapid Assessment of Therapeutic Protein Oligomerization States in Formulation.
Lu J, Chen K
AAPS J · 2026 Jun · PMID 42373916 · Publisher ↗
Therapeutic peptides and proteins form higher-order structures (HOS) including oligomeric forms in formulation, critical for drug efficacy, safety, and stability. To quickly assess protein oligomerization, dynamic light...
Therapeutic peptides and proteins form higher-order structures (HOS) including oligomeric forms in formulation, critical for drug efficacy, safety, and stability. To quickly assess protein oligomerization, dynamic light scattering (DLS) was applied to measure a series of protein standards with molecular weight (MW) range of 1.3-660 kDa, yielding translational diffusion coefficients (D), which were corrected to D using water diffusion data. A correlation between D and protein monomeric MW, representing their hydrodynamic MW (MW), was established as . This DLS/MW model was subsequently applied to therapeutic protein formulations with monomeric MW ranging from 3.8 to 149 kDa. The resulting MW values were several-fold greater than the corresponding monomeric MW of the glucagon-like peptide-1/2 (GLP-1/2) analogs, insulin analogs, and the monoclonal antibodies (mAbs) infliximab and bevacizumab, indicating varying degrees of oligomerization. The observed oligomerization states were largely consistent with those reported in literature. For insulin and mAb oligomers, pseudo-spherical diffusion coefficients (D) back calculated from the oligomer MW agreed within 6% of experimental D values, except for the insulin dimer. Incorporation of Perrin's anisotropic correction reduced insulin dimer discrepancy from 9 to 5%. Overall, the established MW model, incorporating a larger exponent of 0.428 that accounts for protein anisotropy, provides a rapid, non-invasive method to factually assess protein oligomerization in as-is formulations, aiding drug development and quality control. Minor discrepancies relative to size exclusion chromatograph (SEC) or prior biophysical studies may arise from experimental differences in protein concentration, oligomeric equilibrium, pH, excipients or modeling assumptions, warranting further investigation.
Guiding the Molnupiravir Tablet Formulation Using Physiologically Based Biopharmaceutics Modeling and Successfully Establishing Dissolution Safe Space.
Morrow T, Jarvi N, Halota M … +6 more , Sun C, Kafle P, King R, Okoh G, Patel S, Heimbach T
AAPS J · 2026 Jun · PMID 42260257 · Publisher ↗
Physiologically Based Biopharmaceutics Models (PBBMs) are evolving tools which can be used to aid in drug product quality specifications. PBBMs have gained increased regulatory interest and acceptance over the past 5 yea...
Physiologically Based Biopharmaceutics Models (PBBMs) are evolving tools which can be used to aid in drug product quality specifications. PBBMs have gained increased regulatory interest and acceptance over the past 5 years. For molnupiravir, PBBM has been used for: a) calculation of a bioequivalence safe space for capsule formulation and tablets, b) informing of the definitive bioequivalence study (P011) with a target tablet formulation selection designed to be bioequivalent to the capsule formulation, c) selection of a deliberately slower release tablet formulation (beyond f similarity criteria) designed to widen the dissolution knowledge space, d) help select the clinically relevant specification and the dissolution bioequivalence safe space. PBBM data inputs, model development, validation, and application using data from several independent clinical studies are described. Predictive errors for Cmax and AUC were < 25%. The z-factor for dissolution data modeling is described for QC (Quality Control) method(s). The molnupiravir bioequivalence safe space or knowledge space widening is described. The value of the wider dissolution space includes increased potential flexibility with scale-up and post approval changes (SUPAC), including adding or changing a site for a high-volume drug product such as molnupiravir. PBBM is not only important in the development of drug products aiding formulation selection, but can also be a key component toward regulatory flexibility and approval of clinically relevant specifications, such as when the clinical knowledge space has been widened through inclusion of a slow-release variant, as was done for the relative bioavailability study for molnupiravir.
Correction: Nanotechnology-enhanced Natural Products for Cancer Chemoprevention: Molecular Mechanisms and Clinical Translation.
Nath R, Kityania S, Nath D … +5 more , Patra JK, Habibi E, Sarker SD, Talukdar AD, Nahar L
AAPS J · 2026 Jun · PMID 42260059 · Publisher ↗
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Quantitative Estimation of Clinical Intrasubject Variability of a Pharmacokinetic Parameter.
Hsu HJ, Casteel K, Yang S … +3 more , Purohit V, Le V, Sagawa K
AAPS J · 2026 Jun · PMID 42249247 · Publisher ↗
The virtual bioequivalence (VBE) approach, which employs physiologically based pharmacokinetic (PBPK) modeling in lieu of clinical bioequivalence (BE) studies, provides a valuable alternative for the pharmaceutical indus...
The virtual bioequivalence (VBE) approach, which employs physiologically based pharmacokinetic (PBPK) modeling in lieu of clinical bioequivalence (BE) studies, provides a valuable alternative for the pharmaceutical industry. The VBE has the potential to substantially reduce both the time and costs associated with traditional clinical BE studies. Furthermore, this approach supports ethical principles by eliminating the need to expose healthy volunteers to investigational compounds without medical benefit. Intrasubject variability (intrasubject coefficient of variation, ICV) is a main factor for balanced cross-over design BE studies in calculating the confidence intervals for the geometric mean ratio of AUC and C, which determines if bioequivalence criteria are met. Thus, it is essential to employ realistic and accurate ICV values for BE assessment through PBPK modeling. Published literature indicates that the drug properties that affect oral bioavailability exhibit a good correlation with ICV. The aim of this research is to expand drug databases to reevaluate the correlation between drug properties and clinically observed ICV for C (ICV). The results demonstrated that the dose number (dose to solubility ratio), permeability and elimination half-life are three main factors influencing ICV. Permeability becomes a dominating factor when the value is relatively low (P < 0.8 × 10 cm/sec). In addition, PBPK modeling tools, Gastroplus and Simcyp were evaluated for their ability to predict ICV based on drug properties and their built-in physiological variations. Both simulation tools estimated intersubject variability and ICV similarly and underestimated ICV compared with clinically observed ICV.
Targeting Pyruvate Kinase M2: Signal Transduction Pathways and Exploration of Cancer Therapeutic Strategies.
Wang J, Zhang W, Shen N … +7 more , Li P, Xie W, Wang S, Cheng Y, Zhao L, Yang Y, Zhao H
AAPS J · 2026 Jun · PMID 42230450 · Publisher ↗
The pathogenesis of cancer represents a multifaceted, progressive process driven by an intricate interplay of physical, chemical, biological, and other etiological factors. Recent advancements in clinical oncology, inclu...
The pathogenesis of cancer represents a multifaceted, progressive process driven by an intricate interplay of physical, chemical, biological, and other etiological factors. Recent advancements in clinical oncology, including targeted therapy, surgical resection, radiation therapy, chemotherapy, and immunotherapy, have substantially improved patient outcomes. Targeted therapy has emerged as a promising approach due to its precision and minimal adverse effects. Pyruvate kinase M2 (PKM2) is a metabolic enzyme with protein kinase function that has been extensively studied for its critical role in inflammation and metabolic diseases. By interacting with key oncogenic signaling pathways, PKM2 exerts a critical influence on cancer progression, thereby establishing its status as a potential therapeutic target for cancer. Notably, the role of PKM2 in cancer is not determined solely by expression level but also depends on post-translational modifications, conformational plasticity, nuclear localization, and tumor microenvironment. Extensive preclinical studies have demonstrated that various natural products and compounds exert antitumor effects by modulating PKM2 activity and expression, conformation, or nuclear localization. However, these strategies have not yet entered the clinical trial phase, and the path to clinical application remains fraught with challenges, including the biological complexity of PKM2, tumor resistance, and drug specificity. In summary, this article summarizes the regulatory network between PKM2 and oncogenic signaling pathways, highlights the importance of PKM2 in current clinical strategies for cancer treatment, and discusses the challenges facing therapies targeting PKM2 as well as future research directions.
Context-of-use-Guided Development and Validation of a Transthyretin Immunoassay: A Framework for Biomarker Assay Design.
Watanabe T, Canfield J, Anderson E … +4 more , Tayefeh L, Allinson JL, Viney NJ, Mathews JA
AAPS J · 2026 Jun · PMID 42228252 · Publisher ↗
Transthyretin (TTR) is a circulating protein biomarker central to the evaluation of therapies for transthyretin amyloidosis. Clinical trials with Eplontersen, a TTR-targeting antisense oligonucleotide, required an assay...
Transthyretin (TTR) is a circulating protein biomarker central to the evaluation of therapies for transthyretin amyloidosis. Clinical trials with Eplontersen, a TTR-targeting antisense oligonucleotide, required an assay with a context of use differing from existing assay, requiring a more sensitive method. This study describes the development, optimization, and validation of a quantitative immunoassay for TTR, guided by a context-of-use framework. Method development focused on calibration curve modeling, weighting, parallelism, and determination of the minimal required dilution. Antibody selection and calibrator characterization followed established best practices. Pre-validation experiments optimized antibody concentrations and curve-fitting (five-parameter logistic with 1/y weighting). Assay performance was then evaluated through validation, including assessments of accuracy, precision, parallelism, specificity, stability, interference of endogenous binding partners, and comparison against other commercially available assays. The assay demonstrated a functional lower limit of quantitation of approximately 0.07 mg/dL, which would enable measurement of > 95% reductions in TTR after treatment. Parallelism improved at higher dilutions. The assay showed robust performance across endogenous samples, recombinant TTR variants and in the presence of potential interferents. Total analytical variability was shown to be 29.4%. Comparisons with commercial assays showed strong correlation, though absolute values varied by platform. This work establishes a robust, context-driven assay for quantifying TTR in clinical studies. The development process highlights generalizable principles in biomarker assay design, including matrix considerations, variability analysis, and curve optimization. These insights provide a transferable framework for biomarker method development in regulated environments.
New Frontiers of Drug Development Through the Use of New Approach Methodologies.
Martinez MN, Mochel JP, Allenspach K … +3 more , Zdyrski C, Krishna S, Rusyn I
AAPS J · 2026 May · PMID 42215821 · Publisher ↗
On November 2025, AAPS PharmSci 360 convened a symposium that included experts in the application of various types of New Approach Methodologies (NAMs). They shared their experiences and insights on topics that included...
On November 2025, AAPS PharmSci 360 convened a symposium that included experts in the application of various types of New Approach Methodologies (NAMs). They shared their experiences and insights on topics that included microphysiological systems (MPS), the use of 3D organoids, and in silico tools. MPS systems were explored from the perspective of their testing and qualification through an academia-industry-government tissue chip testing consortium whose mission is to perform context-of-use-based testing of MPS and conduct comparative evaluations to support the use of MPS systems in safety assessments. 3D organoids were described and insights shared on how and when they may provide an appropriate tool for evaluating drug safety and effectiveness, and their use in supporting personalized medicine. Regarding in silico tools, examples were provided to describe their growing utility in predicting drug toxicity, population variability, and its potential benefits over traditional evidence-based toxicology. These tools include in silico models (e.g., physiologically based pharmacokinetic models), Artificial Intelligence (AI), and Machine Learning (ML) which, unlike other aspects of model informed drug development, reduce reliance on predefined models and allows for the integration of diverse sources of data. Computationally, these tools can generate predictions in hours where it would otherwise have taken weeks or months (and extensive experimentation). Within this meeting report, we highlight the key issues discussed during that symposium and share additional aspects to consider when developing a NAMs-based roadmap for specific contexts of use.
Correction to: Considerations in Kp,uu,brain-based Strategy for Selecting CNS-targeted Drug Candidates with Sufficient Target Coverage and Substantial Pharmacodynamic Effect.
Zou L, Chien HC, Pade D … +6 more , Li Y, Nguyen M, Bhamidipati RK, Wang Z, Enogieru OJ, Wahlstrom J
AAPS J · 2026 May · PMID 42209871 · Publisher ↗
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Development and Implementation of a Hinderance-based In Vitro Model for Porous Membranes.
Paterson DA, Coleman L, Dancik Y … +5 more , Thakur K, Zhang Y, Tabosa AM, Polak S, Clarke JF
AAPS J · 2026 May · PMID 42204028 · Publisher ↗
In vitro release testing (IVRT) is an inexpensive and routine step in dermal formulation development where an inert membrane separates the donor formulation from a receptor solution. Experimental IVRT data provides insig...
In vitro release testing (IVRT) is an inexpensive and routine step in dermal formulation development where an inert membrane separates the donor formulation from a receptor solution. Experimental IVRT data provides insights into formulation behaviour in the absence of skin permeation complexities. This source of formulation data has the potential to be incorporated into a modelling workflow to aid parameterisation of a mechanistic dermal physiologically based pharmacokinetic (PBPK) model. Therefore, a hinderance-based IVRT model was developed within the Simcyp in vitro permeation testing (IVPT) module framework, using membrane characteristics to inform drug movement through inert, non-silicone, membranes. Modelling as a cylindrical pore system, the membranes key characteristics (pore size, porosity, tortuosity and membrane thickness) are utilised to parameterise a 2-step model where drug enters the membrane pores, diffuses across and partitions into the receptor solution. A description of the model's equations and setup are provided in addition to an ibuprofen in vitro case study using a range of membranes for model performance validation. Comparison of simulated IVRT to experimental data using membranes of microfiltration (pore diameters > 0.1 µm) resulted in acceptable performance, while simulation of nanofiltration membranes (pore diameters < 0.01 µm) require optimisation steps.
Exploration of Colonic Mucus as A Dissolution Compartment for Orally Administered Drugs.
Wu M, Karlsson EM, Bergström CAS
AAPS J · 2026 May · PMID 42174323 · Publisher ↗
Colonic mucus has gained interest as a dissolution compartment in the large intestine due to the large fraction of bound water. Notably, the mucus layer contains more water than what is freely mobile within the colonic l...
Colonic mucus has gained interest as a dissolution compartment in the large intestine due to the large fraction of bound water. Notably, the mucus layer contains more water than what is freely mobile within the colonic lumen. Here, we studied solubility of a series of structurally and physicochemically diverse orally administered drugs. In total, 15 compounds were measured for their solubility in an artificial colonic mucus solution. Equilibrium solubility was measured using the traditional shake-flask method at 37°C in several important media for dissolution studies in the colon: the mucus solution, fed-state simulated colonic fluid (FeSSCoF) and the corresponding buffers. Molecular descriptors were generated by RDKit to identify the molecular features that might benefit from solubilization in the mucus solution. Of the studied compounds, 93% presented their highest solubility in the colonic mucus solution. Molecules with high lipophilicity were more likely to benefit from the solubilization potential of the mucus, herein identified to be a result of interactions with BSA and lipids in the system. To summarize, the large dataset investigated in this study clearly shows that the colonic mucus holds great potential as a dissolution compartment facilitating the drug absorption. Hence, the colonic mucus may drive absorption for poorly water-soluble compounds and should not only be viewed as a potential diffusion barrier for drug molecules and particles.
A Mechanistic Framework Integrating Renal QSP-PK-PD and Machine Learning for Baseline-Informed Stratification of Diuretic Resistance.
Zhou J, Lou V, Zhao Y … +7 more , Tang L, Hu Z, Sun J, Chen J, Cheng P, Cheng Y, He H
AAPS J · 2026 May · PMID 42174295 · Publisher ↗
Diuretic resistance represents a major source of heterogeneity in loop diuretic response and remains a key barrier to effective decongestion in heart failure. A key clinical challenge is the early identification of patie...
Diuretic resistance represents a major source of heterogeneity in loop diuretic response and remains a key barrier to effective decongestion in heart failure. A key clinical challenge is the early identification of patients at high risk of an inadequate response to standard-dose furosemide in order to inform timely treatment intensification or alternative decongestive strategies. However, current approaches remain reactive and rely on post-treatment response, limiting prospective risk stratification and treatment decision-making. To address this problem, we integrated a mechanistic renal quantitative systems pharmacology (QSP) model with furosemide pharmacokinetics and pharmacodynamics to enable baseline-informed risk stratification of diuretic resistance. The model was calibrated using published clinical pharmacokinetic and renal response data and applied to generate a physiologically constrained virtual patient population capturing heterogeneity in renal function, tubular sodium handling, and neurohormonal activation. Machine learning methods were incorporated as complementary analytical tools to identify and validate baseline physiological determinants that define risk categories of diuretic response within the mechanistic simulation framework. Model-based analyses indicated that diuretic resistance arises from the combined effects of reduced filtration capacity, enhanced tubular sodium avidity, diminished pharmacodynamic sensitivity and sustained neurohormonal activation. Across analytical approaches, baseline fractional excretion of sodium and glomerular filtration rate emerged as integrative biomarkers that stratify patients into distinct risk categories of diuretic response, reflecting a mechanism-informed reduction of underlying physiological variability. These findings provide a mechanistically grounded framework for baseline-informed risk stratification and may inform earlier identification of patients at risk of inadequate response, supporting model-informed evaluation of treatment intensification or alternative decongestive strategies.
HLA Class II Alleles DRB1*11:01 and DQB1*03:01 Unmask Immunogenetic Susceptibility to Anti-Nivolumab Antibodies in Combination with Ipilimumab.
Rajendran S, Gutierrez AH, Chien MS … +6 more , Tang T, Gokemeijer J, Forman D, De Groot AS, Jawa V, Hamuro L
AAPS J · 2026 May · PMID 42162441 · Publisher ↗
Biologic combinations that modulate immune responses are increasingly used in oncology, enhancing anti-tumor immunity but also raising the risk of anti-drug antibody (ADA) development. Nivolumab administered in combinati...
Biologic combinations that modulate immune responses are increasingly used in oncology, enhancing anti-tumor immunity but also raising the risk of anti-drug antibody (ADA) development. Nivolumab administered in combination with ipilimumab results in significantly higher nivolumab ADA incidence (44%) compared to nivolumab monotherapy (12%). While previous analyses showed no clinical impact of nivolumab ADA on safety and efficacy for the combination, it provided a unique dataset to evaluate genetic predispositions to nivolumab ADA development and impact of co-administered ipilimumab. HLA Class II alleles were evaluated for associations with nivolumab ADA. Logistic regression analyses were performed on HLA-DRB1, DQB1, and DQA1 alleles from melanoma subjects treated with nivolumab plus ipilimumab and nivolumab alone. Univariate screening identified candidate alleles that were associated with immunogenicity. This was followed by multivariable modeling to assess independent and combined effects after accounting for sex, age and region. Multivariable analyses indicated that DRB1*11:01 (Odds Ratio (OR) = 2.5, p-value (p) = 0.011) and DQB1*03:01 (OR = 3.2, p = 0.0002) were each significantly associated with nivolumab ADA positivity in combination therapy. The combined presence of both alleles conferred an even stronger association (OR = 4.1, p = 0.0017). No significant associations were observed for nivolumab monotherapy. In silico predictions and MHC-associated peptide proteomics (MAPPs) confirmed high-affinity binding of a nivolumab framework peptide (a known Treg epitope) to DRB1*11:01. DRB1*11:01 and DQB1*03:01 may predict anti-nivolumab antibody development in the context of combination therapy. These findings underscore the role of host genetics and immune modulation by ipilimumab in shaping immunogenicity.
Immunogenicity Assessment for siRNA Therapeutics: A Risk-Based Proposal for Event-Driven Testing.
Zhao A, Bond S, Clausen V … +5 more , Chen M, Lai CH, Zylstra J, Grimaldi C, Partridge MA
AAPS J · 2026 May · PMID 42156611 · Publisher ↗
Oligonucleotide therapeutics (ONTs) have emerged as a transformative treatment modality with numerous products approved globally for addressing a variety of diseases. Within this class, siRNAs therapeutics have achieved...
Oligonucleotide therapeutics (ONTs) have emerged as a transformative treatment modality with numerous products approved globally for addressing a variety of diseases. Within this class, siRNAs therapeutics have achieved remarkable success, with eight approvals to date. siRNA therapeutics are short double-stranded RNAs designed to hybridize with complementary mRNA sequences and regulate disease-related protein expression through endogenous RNA interference (RNAi) mechanism. This manuscript outlines a framework of immunogenicity risk assessment for siRNA therapeutics, discusses the challenges associated with anti-drug antibody (ADA) assay development, and reviews available immunogenicity data from both approved and investigational GalNAc-siRNA therapeutics. Across clinical development programs, GalNAc- conjugated siRNA therapeutics have demonstrated a low immunogenicity risk profile, supported by comprehensive immunogenicity risk assessment and accumulated clinical data. Reported treatment-emergent ADA response has been generally low (≤ 6%), with no observed impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and/or safety. Given the favorable immunogenicity profile observed to date, routine prospective ADA assessments throughout clinical development may not be scientifically warranted for all siRNA therapeutics. Instead, the manuscript advocates adopting a risk-based immunogenicity assessment strategy. This approach emphasizes immunogenicity risk assessment early in the program development, for low-risk molecules, such as GalNAc- or lipid-conjugated siRNA, ADA samples can be collected and banked during early phase studies for retrospective testing if evidence emerges of altered PK, PD, or immune-mediated adverse events. This risk-based immunogenicity assessment strategy ensures patient safety and therapeutic efficacy while streamlining development process for siRNA therapeutics.
Nanotechnology-enhanced Natural Products for Cancer Chemoprevention: Molecular Mechanisms and Clinical Translation.
Nath R, Kityania S, Nath D … +5 more , Patra JK, Habibi E, Sarker SD, Talukdar AD, Nahar L
AAPS J · 2026 May · PMID 42128977 · Publisher ↗
Cancer remains a major global health challenge. Natural compounds, such as curcumin, resveratrol, genistein, thymoquinone, and paclitaxel, show chemopreventive activity by modulating signaling pathways, including PI3K/Ak...
Cancer remains a major global health challenge. Natural compounds, such as curcumin, resveratrol, genistein, thymoquinone, and paclitaxel, show chemopreventive activity by modulating signaling pathways, including PI3K/Akt, NF-κB, and p53. These agents also promote apoptosis, autophagy, and DNA repair. However, their clinical use is restricted by poor solubility, instability, and low bioavailability. Nanotechnology offers solutions by improving stability, enhancing pharmacokinetics, and enabling targeted delivery. Liposomes, polymeric nanoparticles, dendrimers, and albumin-bound systems amplify the anticancer effects of natural compounds. Preclinical studies confirm improved efficacy, while early clinical trials reveal both promise and barriers. The key translational challenges include immune clearance, large-scale reproducibility, and regulatory approval. This review highlights the synergy between nanotechnology and natural compounds in cancer chemoprevention and outlines opportunities for future research.
Applications of Thermoresponsive Hydrogels for Sustained Drug Release in Ocular and Intravitreal Formulations Treating Visual Impairments.
Alshahrouri B, Blass BE, Dürig T … +1 more , Fassihi R
AAPS J · 2026 May · PMID 42115584 · Publisher ↗
Vision loss is one of the most debilitating eye impairments, with the leading causes such as cataracts, glaucoma, injuries to the surface of the eye and age-related macular degeneration, significantly affecting a person'...
Vision loss is one of the most debilitating eye impairments, with the leading causes such as cataracts, glaucoma, injuries to the surface of the eye and age-related macular degeneration, significantly affecting a person's quality of life and placing a substantial burden on healthcare systems. Effective treatment of these conditions remains challenging due to the complex anatomical and physiological barriers of the eye, which limit the penetration and retention of topically and intravitreally administered drugs. As a result, conventional ocular therapies often exhibit poor therapeutic efficacy, low bioavailability, necessitating frequent administration, reducing patient compliance, and increasing the risk of treatment-related complications. Thermoresponsive hydrogels have emerged as a promising class of in situ-forming drug delivery systems that utilize physiological temperature as a trigger to transition from a sol to a gel state upon administration. This sol-gel transition enhances precorneal or intraocular residence time, improves mucoadhesion, and facilitates sustained drug release. These characteristics make thermoresponsive hydrogels particularly suitable for ocular and intravitreal formulations targeting both anterior and posterior-segment diseases. Thermoresponsive polymers may exhibit lower critical solution temperature (LCST), upper critical solution temperature (UCST), or combined LCST-UCST phase behavior depending on polymer composition, enabling tunable gelation properties to control rate of drug release profiles. This review provides an overview of recent developments in thermoresponsive hydrogels for ophthalmic drug delivery, including emerging dual-responsive systems, with emphasis on gelation mechanisms, drug-release kinetics, and therapeutic applications in anterior and posterior-segment diseases. Key translational considerations, including formulation stability, sterilization, scalability, and regulatory challenges, are also discussed. In addition, the article highlights future research directions to support the continued application and clinical translation of thermoresponsive hydrogel-based ocular drug delivery systems.
In-depth Characterization of Photo-Stressed Antibody-Drug Conjugates by Mass Spectrometry.
Pan X, Zhao Y, Luo S … +12 more , Bulos J, Zhong J, Yan Y, Wu Z, Su Y, Zhang S, Wang S, Xiao H, Wang W, Liu D, Li N, Qiu H
AAPS J · 2026 May · PMID 42115538 · Publisher ↗
Camptothecin (CPT)-based antibody-drug conjugates (ADCs) have become popular oncology biotherapeutics that integrate the targeted specificity of monoclonal antibodies (mAbs) with camptothecin and its derivatives. Because...
Camptothecin (CPT)-based antibody-drug conjugates (ADCs) have become popular oncology biotherapeutics that integrate the targeted specificity of monoclonal antibodies (mAbs) with camptothecin and its derivatives. Because mAbs are vulnerable to photodegradation and the light-absorbing characteristics of camptothecin, understanding the effects of light exposure on CPT-based ADCs is critical to ensure product quality, efficacy, and safety. Herein, we harnessed the capabilities of advanced liquid chromatography-mass spectrometry (LC-MS) to perform in-depth molecular-level characterization of photo-stressed antibodies conjugated with a camptothecin derivative payload, deruxtecan (DXd). Peptide mapping via LC-MS/MS revealed significant oxidative modifications in methionine, tryptophan, and histidine residues, and degradation of the linker payload in the photo-stressed ADC molecules. Native SEC-MS with post-column denaturation was conducted to further characterize the covalent nature of high molecular weight species formed under photo stress and provide insights into aggregation mechanisms. Additionally, coupling LC to high-resolution MS enabled the identification and quantitation of degradants from excipients and the linker payload, thus providing a comprehensive understanding of light exposure effects on DXd ADCs. Application of these LC-MS based assays to evaluate the effects of various formulations on photostability revealed that histidine and methionine act as oxidative scavengers that protect ADC molecules against light-induced degradation. This study highlights the utility of LC-MS methods in the comprehensive characterization of photo-stressed CPT-based ADCs, and provides valuable insights for process optimization, formulation development, and storage condition recommendations.
Estimating Intragastric Disintegration Times of Immediate Release Dose Units Administered After a High-Calorie, High-Fat Meal Using Standardized, Commercially Available Equipment and Materials.
Vertzoni M, Androulaki E, Dietrich S … +6 more , Gereoudaki M, Karpasiti P, Margiori Z, Papazoglou I, Stavrinoudi I, Reppas C
AAPS J · 2026 May · PMID 42098433 · Publisher ↗
Intragastric disintegration times of immediate release (IR) dose units after high-calorie, high-fat meal would be useful in the assessment of drug absorption process and when considering waivers of bioequivalence assessm...
Intragastric disintegration times of immediate release (IR) dose units after high-calorie, high-fat meal would be useful in the assessment of drug absorption process and when considering waivers of bioequivalence assessment of non-high risk IR products in the fed state. We investigated the usefulness of standardized, commercially available equipment and materials in estimating intragastric disintegration times of IR dose units after high-calorie, high-fat meal. Disintegration times were estimated from the cumulative % drug in the medium vs. time data sets. When using 330 mL Level III FeSSGF-V3 and the compendial Apparatus II (60 rpm) with apex vessel without sinkers, the complete disintegration times of Panadol Actifast® tablets were close to previously estimated mean intragastric complete disintegration time (14 min), and the initial disintegration times of hard gelatine capsules were close to previously estimated mean intragastric initial disintegration time (11 min). Also, initial intragastric disintegration times of hard hypromellose capsules without gelling agents were predicted to be in line with intragastric initial disintegration times in the fasted state whereas disintegration of hard hypromellose capsules prepared with gelling agents was dramatically extended, in line with intragastric data after high-calorie, high-fat meal. Level III FeSSGF-V3 and the compendial Apparatus II (60 rpm) with apex vessel could be useful in estimating average intragastric disintegration times, in supporting justification for waiving in vivo bioequivalence studies, or in detecting non-IR characteristics of dose units after a high-calorie, high-fat meal.
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