Article
Chemistry, Analytical
Zhuoyu Liu, Yanjing Cao, Lei Zhang, Ya Xu, Zhongli Zhang
Summary: A novel MDLC-MS method was developed for charge variant characterization in therapeutic antibody development, aiming to discover potential risks on safety and efficacy. The method enabled detection of charged species at low abundance by implementing 96-well plate fractionation and on-column preconcentration. The charge variants of mAb-A were characterized, and post-translational modifications were identified and evaluated for their potential risks. The MDLC-MS detection demonstrated sample-economic, time-effective, and labor-saving features, providing a powerful and timely tool for charge variant characterization in antibody development.
ANALYTICAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Arthur J. J. van de Vyver, Antje-Christine Walz, Mariette S. S. Heins, Afsaneh Abdolzade-Bavil, Thomas E. E. Kraft, Inja Waldhauer, Michael B. B. Otteneder
Summary: Monoclonal antibodies play a vital role in the treatment of diseases, but their development for neurological disorders in the brain is challenging. This study investigated the pharmacokinetics of a bispecific monoclonal antibody in the brain of rats using different administration routes. The researchers developed a model to quantify the drug uptake and found that the blood-cerebrospinal fluid barrier impedes antibody transfer. The study suggests that intravenous administration may achieve higher local drug exposure compared to intracerebroventricular administration.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Hsueh-Yuan Chang, Shengjia Wu, Yinyi Li, Leiming Guo, Yuelin Li, Dhaval K. Shah
Summary: In this study, the impact of protein therapeutic size on brain pharmacokinetics (PK) following systemic administration in rats was investigated. The results showed that the exposure of protein therapeutics in different brain regions could be significantly different, and there could be optimal sizes of protein therapeutics to achieve maximum/selective exposure.
Article
Immunology
Ratchanont Viriyakitkosol, Asawin Wanitchang, Kanjana Srisutthisamphan, Janya Saenboonreung, Chatikorn Boonkrai, Trairak Pisitkun, Anan Jongkaewwattana
Summary: This study investigated the ability of two SARS-CoV-2 variants, BA.2 and BA.5, to evade neutralization by a human monoclonal antibody. The results showed that BA.2 had poor growth, while BA.5 regained robust growth with a significant increase in kinetics. A single mutation, A475V, in the spike protein of BA.5 substantially reduced the neutralizing activity of monoclonal antibodies and convalescent sera. The findings provide insights into the evolutionary development of SARS-CoV-2 variants under selection pressure from monoclonal antibodies and have implications for antibody therapies and vaccines against the virus.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Engineering, Chemical
Wenqian Chen, Xiaoyu Li, Mingxia Guo, Frederik J. Link, Siti S. Ramli, Jinbo Ouyang, Ian Rosbottom, Jerry Y. Y. Heng
Summary: The review discusses the advantages of mAb crystallisation as an alternative biopurification technology, highlighting its high product stability, purity, and scalability. Successful demonstrations of mAb crystallisation scale-ups are presented, with a focus on critical factors such as mixing and temperature control.
SEPARATION AND PURIFICATION TECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Terence L. Kirley, Andrew B. Norman, Kenneth D. Greis
Summary: Researchers have developed a high-affinity anti-cocaine antibody for the treatment of cocaine use disorders. They found that oxidation affects the binding of the antibody to cocaine, but excess methionine can protect the antibody from oxidation. Additionally, oxidation leads to a decrease in tryptophan fluorescence and the presence of oxidized forms of tryptophan.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Immunology
Taciana Manso, Anjana Kushwaha, Nika Abdollahi, Patrice Duroux, Veronique Giudicelli, Sofia Kossida
Summary: Cancer cells activate immune checkpoint pathways to evade immunosurveillance, and immunotherapies involving immune checkpoints have shown significant success in cancer treatment. The IMGT/mAb-DB database provides a standardized and comprehensive description of the mechanisms of action of monoclonal antibodies targeting immune checkpoints in cancer therapy.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Anna J. Boland, Anthony A. O'Kane, Richard Buick, Daniel B. Longley, Christopher J. Scott
Summary: This review examines the use of targeted monoclonal antibody therapy in treating pancreatic cancer, discussing the various molecules targeted and the potential therapeutic utility. While significant success has not yet been achieved with antibody therapy for pancreatic cancer, lessons learned from research thus far provide valuable insights for future directions.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Food Science & Technology
Zhi Li, Hua Xu, Bo Ma, Li Luo, Lei Guo, Pingping Zhang, Yong Zhao, Lili Wang, Jianwei Xie
Summary: Abrin is a highly toxic protein isolated from Abrus precatorious seeds, which has the potential to be used as a bioterrorism agent. Currently, there are no antidotes available for abrin poisoning, and neutralizing antibodies are the most effective therapy. In this study, a high-affinity neutralizing monoclonal antibody 10D8 was prepared and found to have a strong protective effect against abrin-induced toxicity.
Review
Biochemistry & Molecular Biology
Anna J. Boland, Anthony A. O'Kane, Richard Buick, Daniel B. Longley, Christopher J. Scott
Summary: Although antibody therapy for pancreatic cancer has not yet achieved significant success, lessons learned from current research indicate potential future directions for overcoming observed hurdles to achieve clinically efficacious results.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Pharmacology & Pharmacy
Shengjia Wu, Florie Le Prieult, Colin J. Phipps, Mario Mezler, Dhaval K. Shah
Summary: This manuscript presents an improved physiologically-based pharmacokinetic (PBPK) model to characterize and predict the brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) in mice. The revised model was able to reasonably describe the PK of antibodies in the brain, cerebrospinal fluid (CSF), and interstitial fluid (ISF) with a three-fold error. However, it underestimated the ISF PK in the initial phase. A local sensitivity analysis suggested that minor changes in brain-related parameters, particularly an increase in convective flow across the blood-brain barrier (BBB), could resolve this discrepancy. The presence of this pathway requires further validation. This model can be a valuable quantitative tool for the discovery, preclinical evaluation, and translation of novel antibodies for central nervous system (CNS) disorders.
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
(2022)
Article
Medicine, Research & Experimental
Be-Sheng Kuo, Chao-Hung Li, Jiun-Bo Chen, Yu-Yu Shiung, Chia-Yu Chu, Chih-Hung Lee, Yaw-Jen Liu, Je-Hung Kuo, Cindy Hsu, Hsiao-Wen Su, Ywan-Feng Li, Annie Lai, Yueh-Feng Ho, Yi-Ning Cheng, Hong-Xuan Huang, Meng-Chung Lung, Ming-Syue Wu, Fu-Hong Yang, Chen-Han Lin, William Tseng, Jasper Yang, Chia-Yin Lin, Pei-Hua Tsai, Heng-Kwei Chang, Yi-Jen Wang, Techeng Chen, Shugene Lynn, Mei-June Liao, Chang Yi Wang
Summary: Over the past 20 years, only omalizumab has been approved as an anti-IgE antibody for treating asthma and chronic spontaneous urticaria (CSU). This report introduces UB-221, a newer class of anti-IgE antibody with different characteristics compared to omalizumab and ligelizumab. UB-221 demonstrates superior efficacy in CD23-mediated downregulation of IgE production and exhibits strong IgE-neutralizing activity.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Immunology
Gordana Simeunovic, James Polega, Subhan Toor, Nicholas J. Andersen
Summary: Strategies to combat COVID-19 include vaccines and Monoclonal Antibody Therapy. While vaccines aim to prevent symptoms, Monoclonal Antibody Therapy prevents progression to severe disease. A retrospective study compared outcomes and risks for disease progression between vaccinated and unvaccinated COVID-19 patients treated with Monoclonal Antibody Therapy and found that unvaccinated patients were more likely to seek help in the Emergency Department, be hospitalized, and progress to severe disease.
Article
Mathematics
Sandra A. Obiri, Bernard T. Agyeman, Sarupa Debnath, Siyu Liu, Jinfeng Liu
Summary: This paper provides guidelines for sensor selection in the upstream production process of mAbs and applies a variable selection technique to improve estimation accuracy. The proposed approach is demonstrated through different case studies and evaluated using RMSE as the evaluation criterion.
Article
Pharmacology & Pharmacy
E. Carlier, S. Marquette, C. Peerboom, K. Amighi, J. Goole
Summary: This study investigates the feasibility of printing monoclonal antibody (mAb)-loaded implantable systems using fused-deposition modelling (FDM), achieving stable, affinity retention, and sustained-release profiles through the development and optimization of various steps. The results show promising potential for FDM to produce mAb-loaded devices with good stability and sustained-release characteristics.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Pharmacology & Pharmacy
Sharad Sharma, Zhe Li, David Bussing, Dhaval K. Shah
DRUG METABOLISM AND DISPOSITION
(2020)
Article
Pharmacology & Pharmacy
David Bussing, Dhaval K. Shah
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
(2020)
Article
Medicine, General & Internal
Hsuan Ping Chang, Yuen Kiu Cheung, Dhaval K. Shah
Summary: MMAE is rapidly cleared from plasma but extensively distributed in tissues, blood cells, and tumors. A PBPK model was developed to characterize its whole-body pharmacokinetics, facilitating preclinical-to-clinical translation and clinical dose optimization of ADCs containing MMAE.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Pharmacology & Pharmacy
Hsuan Ping Chang, Valentina Shakhnovich, Adam Frymoyer, Ryan Sol Funk, Mara L. Becker, K. T. Park, Dhaval K. Shah
Summary: A population-based physiological-based PK model was developed to characterize antibody PK in paediatric patients, demonstrating that only 50% of children reached desired trough concentrations with the FDA-labelled dosing regimen for infliximab. Higher doses and/or more frequent dosing may be needed to achieve target trough concentrations of this antibody.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Zhe Li, Yingyi Li, Hsuan Ping Chang, Xiaoying Yu, Dhaval K. Shah
Summary: The two-pore PBPK model proposed by the lab for protein therapeutics of different sizes was validated using plasma PK data and tissue distribution data of different-size antibodies. The model showed relatively accurate predictions for plasma, tissues, and tumor exposure of studied molecules, proving its potential as a platform for developing a generic PBPK model for protein therapeutics in the future.
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
(2021)
Article
Pharmacology & Pharmacy
Lyndsey F. Meyer, Pooja M. Rajadhyaksha, Dhaval K. Shah
Summary: The study found that DNP has limited distribution in mice and exhibits significant nonlinear pharmacokinetics, possibly due to nonlinear protein binding and distribution. By enhancing our understanding of the pharmacokinetic-pharmacodynamic relationship, we can develop new weight loss strategies.
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
(2022)
Article
Pharmacology & Pharmacy
Hsueh-Yuan Chang, Shengjia Wu, Ekram Ahmed Chowdhury, Dhaval K. Shah
Summary: In this manuscript, a translational PBPK model was presented to characterize the receptor-mediated transcytosis of anti-TfR mAbs in the CNS. The model takes into account the brain's anatomy and physiology and fixed physiological parameters based on different species. By estimating several parameters associated with TfR concentration, turnover, and internalization rate, the model characterizes the PK of unbound and bound anti-TfR mAbs in plasma, whole brain, interstitial fluid, and cerebrospinal fluid in mice, rats, and monkeys. The model was validated using external PK data in mice and monkeys with different affinities and doses. The simulation reasonably predicted the PK properties of anti-TfR mAbs in plasma and brain and revealed a relationship between brain ISF/plasma AUC ratio and K-D value.
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
(2022)
Article
Chemistry, Multidisciplinary
Hsuan-Ping Chang, Zhe Li, Dhaval K. Shah
Summary: This study aimed to quantitate and mathematically characterize the whole-body pharmacokinetics of different ADC analytes following administration of an MMAE-conjugated ADC. The results showed that conjugation of MMAE did not significantly affect the PK of the antibody, but ADC may demonstrate higher deconjugation in certain tissues. Additionally, the conjugation of MMAE to antibody altered its tissue distribution profile.
PHARMACEUTICAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Pooja M. Rajadhyaksha, Divyesh H. Shastri, Dhaval K. Shah
Summary: This study aims to develop sustained release formulations using injectable, thermosensitive hydrogels made from natural polymers. The hydrogel systems demonstrated controlled release of the protein therapeutic and maintained detectable concentrations for at least 14 days. These findings suggest that subcutaneous injection of thermosensitive in situ hydrogels may provide a solution for sustained exposure of protein therapeutics with short half-lives.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Chemistry, Medicinal
David Bussing, Yingyi Li, Leiming Guo, Ashwni Verma, Jack M. Sullivan, Dhaval K. Shah
Summary: Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. This study investigated the PK of 4 different size non-binding protein therapeutics in various ocular tissues of mice following IVT administration. The findings provide valuable insights for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Hsuan-Ping Chang, Huyen Khanh Le, Dhaval K. K. Shah
Summary: We hypothesized that different routes of administration may have an impact on the PK/PD behavior of ADCs and help improve their therapeutic index. To test this hypothesis, we evaluated the PK/PD of an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Our findings showed that IT administration significantly increased tumor exposure and anti-tumor activity of the ADC. The PK/PD model suggested that the IT route could provide similar efficacy as the IV route at a reduced dose level and increased dosing interval, while SC administration led to local toxicity and reduced efficacy.
Article
Pharmacology & Pharmacy
Autumn M. Spyhalsky, Se Jin Kim, Calvin J. Meaney, Nicholas M. Smith, Dhaval K. Shah, Amanda B. Hassinger, Nicholas M. Fusco
Summary: This study compared the use of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) in critically ill children exposed to vancomycin. The results showed that concentrations of uNGAL and uKIM-1 significantly increased in children with acute kidney injury (AKI) compared to those without AKI during the first 48-72 hours of vancomycin exposure, suggesting that they may serve as prospective biomarkers for AKI.
Article
Medicine, Research & Experimental
Shufang Liu, Ashwni Verma, Hubert Kettenberger, Wolfgang F. Richter, Dhaval K. Shah
Summary: Research has shown the significant impact of molecular charge on antibody PK, with engineered complementarity-determining regions (CDRs) of trastuzumab leading to variants with increased positive charge accumulation in tissues. Whole-body PK experiments revealed a bell-shaped relationship between systemic exposure and Fv charge, and positive charge variants exhibited superior accumulation in well-perfused organs.
Article
Medicine, Research & Experimental
Hsueh-Yuan Chang, Shengjia Wu, Yingyi Li, Wanying Zhang, Matthew Burrell, Carl I. Webster, Dhaval K. Shah
Summary: Receptor-mediated transcytosis (RMT) is used to enhance the delivery of monoclonal antibodies (mAb) into the central nervous system (CNS). The binding affinity of mAbs has a complex relationship with pharmacokinetics (PK) in the brain, with optimal dissociation constant (K-D) values resulting in the highest brain exposure of mAbs in the brain interstitial fluid (bISF). This study highlights the importance of accurately measuring the PK of CNS-targeted antibodies using microdialysis in the brain.
