A5058739959- Monoclonal and Polyclonal Antibodies Research
- Protein purification and stability
- Innovative Microfluidic and Catalytic Techniques Innovation
- HIV Research and Treatment
- Glycosylation and Glycoproteins Research
- HIV/AIDS Research and Interventions
- HIV/AIDS drug development and treatment
- Biosimilars and Bioanalytical Methods
- Histone Deacetylase Inhibitors Research
- 3D Printing in Biomedical Research
- Viral Infectious Diseases and Gene Expression in Insects
- HIV-related health complications and treatments
- HER2/EGFR in Cancer Research
- Mosquito-borne diseases and control
- Hormonal and reproductive studies
- Biochemical and Molecular Research
- Cellular Mechanics and Interactions
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Genetics and Neurodevelopmental Disorders
- Microtubule and mitosis dynamics
- Hormonal Regulation and Hypertension
- Epigenetics and DNA Methylation
- Metabolism, Diabetes, and Cancer
- Pharmacogenetics and Drug Metabolism
Sanofi (United States)
2019-2024
AVEO Oncology (United States)
2024
Pfizer (United States)
2016-2018
Johns Hopkins Medicine
2010-2015
Johns Hopkins University
2010-2015
Despite combination antiretroviral therapies (cARTs), a significant proportion of HIV-infected patients develop HIV-associated neurocognitive disorders (HAND). Ongoing viral replication in the central nervous system (CNS) caused by poor brain penetration cART may contribute to HAND. However, it has also been proposed that toxic effects long-term A better understanding neurotoxic potential is critically needed light use CNS-penetrating cARTs contend with virus reservoir brain. The efavirenz...
Implementation of in vitro assays that correlate with vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection therapeutic monoclonal antibody (mAb) candidates minimal non-target-related PK risk. Use these minimizes likelihood mAbs unfavorable be advanced into costly and clinical development. In total, 42 varying isotype soluble versus membrane targets were tested studies. MAb physicochemical properties assessed by measuring non-specific interactions...
Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential pharmacokinetic (PK) model project PK of monoclonal (mAbs). Using panel 27 mAbs broad range, we sought characterize and establish utility this animal provide guidance its application development mAbs. This set was administered both hemizygous homozygous hFcRn transgenic...
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) can contribute to gene silencing. This study describes the design synthesis analogues a monoamine oxidase antidepressant, phenelzine, their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing phenyl-butyrylamide appendage was shown be potent inhibitor in vitro selective versus oxidases A/B homologue,...
The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge these parameters across species could used avoid unnecessary in vivo PK studies and enable early predictions pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was determine single set 'typical' popPK describing the mAbs human, cynomolgus monkey transgenic mice...
A large body of data exists demonstrating that neonatal Fc receptor (FcRn) binding an IgG via its CH2-CH3 interface trends with the pharmacokinetics (PK) IgG. We have observed PK molecules vary widely, even when they share identical domains. This led us to hypothesize domains distal from could contribute FcRn and affect PK. In this study, we explored role these in altering affinity between FcRn. Using a surface plasmon resonance-based assay developed examine steady-state (KD) FcRn, dissected...
Significance Despite the integral role of cell mechanics, efforts to target mechanics for drug development have lagged. Here, we present an approach identifying small molecules capable modulating mechanics. We characterize 4-hydroxyacetophenone (4-HAP), isolated as a breakdown product hit from our pilot screen over 22,000 compounds. show that 4-HAP specifically alters localization mechanoenzyme myosin II, increasing stiffness cells. The effect on whose specificity defined, occurs across...
Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of epilepsy. Here we demonstrate that VPA novel activator AMP-activated protein kinase (AMPK), key regulator cellular metabolism, using primary mouse and human hepatocytes. Incubation hepatocytes with resulted in increased levels phosphorylated AMPK acetyl-CoA carboxylase (ACC). This finding was recapitulated Pretreatment small-molecule inhibitor AMPK, Compound C...
Monoclonal antibody ( mA b) pharmacokinetics PK ) have largely been predicted via allometric scaling with little consideration for cross‐species differences in neonatal Fc receptor (FcRn) affinity or clearance/distribution mechanisms. To address this, we developed a b physiologically‐based model that describes the intracellular trafficking and FcRn recycling of bs human transgenic homozygous mouse human. This uses b‐specific vitro data together species‐specific tissue expression, volume,...
Abstract Development of antibodies often begins with the assessment and optimization their physicochemical properties, efficient engagement target interest. Decisions at early stage are critical for success drug candidate but constrained due to limited knowledge antibody pharmacology. In present work, we propose a machine learning-based pharmacology framework that utilizes minimal physiologically based pharmacokinetic (mPBPK) modeling learning (ML) infer optimal properties targets. We use...
Objective: Protein therapeutics have revolutionized the treatment of a wide range diseases. While they distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, relationship between properties PK is still largely unknown. In this work, we present minimal physiologically-based pharmacokinetic (mPBPK) model incorporates multivariate quantitative relation therapeutic's parameters its corresponding ADME PK. Method: The...
HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS by modulating inflammatory signaling limiting viral replication.To establish whether initiating inhibition during early infection altered progression, outcomes were compared simian immunodeficiency virus...
Abstract Protein therapeutics have revolutionized the treatment of a wide range diseases. While they distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, relationship between properties PK is still largely unknown. In this work we present minimal physiologically-based pharmacokinetic (mPBPK) model incorporates multivariate quantitative relation therapeutic’s parameters its corresponding ADME properties. The...
In vitro assessments for the prediction of pharmacokinetic (PK) behavior biotherapeutics can help identify corresponding liabilities significantly earlier in discovery timeline. This minimize need extensive early vivo PK characterization, thereby reducing animal usage and optimizing resources. this study, we recommend bolstering classical developability workflows with measures correlated PK. agreement current literature, assessing nonspecific interactions, self-interaction, FcRn interaction...
Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in treatment human immunodeficiency virus (HIV) infection. EFV extensively metabolized by cytochrome P450 to a number oxygenated products; however, pharmacologic activity and distribution these metabolites anatomic compartments have yet be explored. The systemic oxidative was examined blood plasma, seminal cerebrospinal fluid from subjects on an EFV-based regimen. 8-hydroxy metabolite detected fluid, with median...
The neonatal Fc receptor (FcRn) is a homeostatic responsible for prolonging immunoglobulin G (IgG) half-life by protecting it from lysosomal degradation and recycling to systemic circulation. Tissue-specific FcRn expression critical parameter in physiologically-based pharmacokinetic (PBPK) modeling translational pharmacokinetics of Fc-containing biotherapeutics. Using online peptide immuno-affinity chromatography coupled with high resolution mass spectrometry, we established quantitative...
Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used to treat HIV-1. In the present study, pathways responsible for biotransformation of rilpivirine were defined. Using human liver microsomes, formation two mono- and dioxygenated metabolites detected via ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Mass spectral analysis products suggested that these resulted from oxygenation 2,6-dimethylphenyl ring methyl groups rilpivirine. Chemical...
The objective of this study was to develop an in vitro pharmacodynamic (PD) system test the impact protein binding on antiretroviral (ARV) drug effect and intracellular ARV distribution. CD4(+) T cells were isolated from peripheral blood mononuclear (PBMCs) exposed varying physiologically relevant concentrations human serum albumin (HSA) drugs efavirenz (EFV), raltegravir (RAL), etravirine (ETR), enfuvirtide (ENF). extracellular concentration distribution EFV, RAL, ETR assessed using...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...
The PBPK model of FcRn-mediated recycling large molecules was developed and studied by \cite{de2023mechanistic} to characterize predict Immunoglobulin G (IgG) disposition in plasma tissues. This study investigated the large-molecule PK-Sim its applicability with FcRn binding affinity plasma. Subsequently, extended ensure a more mechanistic description internalization FcRn-drug complex. has applications autoimmune disorders such as primary immune thrombocytopenia which is mediated partly...