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Modeling of antibody-drug conjugate pharmacokinetics

Published on June 30, 2019   49 min

Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms

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0:00
The topic of this presentation is "Modeling of Antibody-Drug Conjugate Pharmacokinetics". My name is Dhaval K.Shah, I'm an Associate Professor in the Department of Pharmaceutical Sciences at the State University of New York at Buffalo.
0:14
Here's the outline for today's talk. I'll mainly go over the basic tenets of antibody-drug conjugate pharmacokinetics. How the profiles typically look like, and then we will go over several examples of mathematical modeling, the pharmacokinetics of ADCs at the cellular level, at the tumor level, and at the whole-body level.
0:35
So, as the name suggests, antibody-drug conjugates are basically conjugates of antibodies with potent small molecule drugs. As shown on the left, over here, an antibody is basically a molecule with 150 Kilodaltons in size; the ability of an antibody to specifically bind to a target is really what makes them attractive for targeting certain tissues within the body. However, small molecules which can be very potent some times don't have the selectivity. So, what is done, basically these drugs are attached to antibodies and this conjugate is now able to bring the drugs to the desired location with the help of the antibody. What is shown here is a cartoon of antibody-drug conjugates. It consists of three different components: your own antibody, you have a chemical linker, and you have a drug. On average, the amount of drug on an antibody can range from 2 to 12 and this ratio is known as the Drug-Antibody Ratio or DAR. What is shown in the middle is a typical mechanism of action of ADCs. When the ADCs are administered in the systemic circulation, it circulates in the system and goes outside the cell which expresses the target that the antibody portion of the ADC binds. Then the target internalizes the ADC and within the cell, depending on the nature of the linker, the small molecule drug is released and then the small molecule drug can supposedly diffuse it in the cytosol and go to the desired location, such as if the small molecule is a tubulin binder, then it will go to tubulins and bind there. Or, if it is a DNA damaging agent, it will go to the nucleus and that will lead to the pharmacology and most of the time this pharmacology is the killing of a cell. While the antibody-drug conjugate platform can be used to treat any disease per se, cancer as a disease has the most potential and there are four FDA approved ADCs out there- all approved for cancer. So, for today's talk, we'll be mainly focusing on oncology usage of the antibodies-drug conjugate.

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