A "Dual" Cell-Level Systems PK-PD Model to Characterize the Bystander Effect of ADC

Journal of Pharmaceutical Sciences
Aman P Singh, Dhaval K Shah

Abstract

Here, we have developed a cell-level systems PK-PD model to characterize the bystander effect of antibody-drug conjugates (ADCs). Cytotoxicity data generated following incubation of Trastuzumab-vc-MMAE in cocultures of high HER2-expressing N87 and low HER2-expressing GFP-MCF7 cells were used to build the model. Single-cell PK model for ADC was used to characterize the PK of trastuzumab-vc-MMAE and released MMAE in N87 and GFP-MCF7 cells. The 2 cell-level PK models were mechanistically integrated to mimic the coculture condition. MMAE-induced intracellular occupancy of tubulin was used to drive the efficacy of ADC, and improvement in the tubulin occupancy of GFP-MCF7 cells in the presence of N87 cells was used to drive the bystander effect of trastuzumab-vc-MMAE. The "dual" cell-level PK-PD model was able to capture the observed data reasonably well. It was found that similar and high occupancy of tubulin by MMAE was required to achieve the cytotoxic effect in each cell line. In addition, estimated model parameters suggested that ∼60% improvement in the tubulin occupancy was required to attain half of the maximum bystander killing effect by the ADC. The presented model provides foundation for in vivo systems PK-PD model to chara...Continue Reading

References

Mar 15, 1977·FEBS Letters·B Bhattacharyya, J Wolff
Jan 15, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Anthony W TolcherEric K Rowinsky
Apr 14, 2009·Nature·Sabrina L SpencerPeter K Sorger
Mar 6, 2012·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Hyesil SeolSo Yeon Park
Mar 23, 2012·Nature Reviews. Cancer·Matthew Vanneman, Glenn Dranoff
Nov 20, 2013·Biomarkers in Cancer·Muaiad KittanehStefan Glück
Sep 8, 2015·Journal of Pharmaceutical Sciences·Katie F MaassKarl Dane Wittrup
Apr 6, 2016·Expert Opinion on Biological Therapy·Serengulam V GovindanDavid M Goldenberg
Sep 28, 2016·Journal of Pharmacokinetics and Pharmacodynamics·Aman P SinghDhaval K Shah
Dec 19, 2016·Drug Discovery Today·Eric ValeurMalin Lemurell
Apr 1, 2017·Advances in Therapy·John M Lambert, Charles Q Morris
Aug 20, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aman P Singh, Dhaval K Shah
Sep 19, 2017·Journal of Clinical Pharmacology·Heather E VezinaManish Gupta
Oct 14, 2017·Investigational New Drugs·Joanna C MastersMichael Amantea
Oct 25, 2017·British Journal of Cancer·Alexander H Staudacher, Michael P Brown
Feb 8, 2018·Annual Review of Medicine·John M Lambert, Anna Berkenblit
Feb 10, 2018·Journal of Pharmacokinetics and Pharmacodynamics·Dhaval K ShahAlison Betts

❮ Previous
Next ❯

Citations

Apr 1, 2020·American Society of Clinical Oncology Educational Book·Anthony W Tolcher

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.