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Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates.

Kamath AV, Iyer S - Pharm. Res. (2014)

Bottom Line: The structure of an ADC is very complex with multiple components and considerable efforts are ongoing to determine the attributes necessary for clinical success.Understanding the pharmacokinetics of an ADC and how it impacts efficacy and toxicity is a critical part of optimizing ADC design and delivery i.e., dose and schedule.This review discusses the pharmacokinetic considerations for an ADC and tools and strategies that can be used to evaluate molecules at the preclinical stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc, 1 DNA Way (Mailstop 463A), South San Francisco, CA, 94080, USA. kamath.amrita@gene.com.

ABSTRACT
Antibody drug conjugates (ADCs) are an emerging new class of targeted therapeutics for cancer that use antibodies to deliver cytotoxic drugs to cancer cells. There are two FDA approved ADCs on the market and over 30 ADCs in the clinical pipeline against a number of different cancer types. The structure of an ADC is very complex with multiple components and considerable efforts are ongoing to determine the attributes necessary for clinical success. Understanding the pharmacokinetics of an ADC and how it impacts efficacy and toxicity is a critical part of optimizing ADC design and delivery i.e., dose and schedule. This review discusses the pharmacokinetic considerations for an ADC and tools and strategies that can be used to evaluate molecules at the preclinical stage.

No MeSH data available.


Related in: MedlinePlus

Proposed disposition of an ADC.
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Fig3: Proposed disposition of an ADC.

Mentions: The primary mechanism of action of an ADC is binding to its specific antigen target on tumor cells and internalization via receptor mediated endocytosis followed by trafficking from endosomes to the lysosomes where the cytoxic drug is released into the cell causing cell death (1). The ADC however can also be taken up into cells (with or without target expression) non-specifically via pinocytosis, which could lead to unwanted drug release in non-target cells. Such non-specific uptake and release of potent drug could contribute to toxicity. The theoretical ADC elimination pathways based on nonclinical and clinical data are shown in Fig. 3 and include deconjugation and degradation or catabolism through nonspecific or target-mediated proteolysis (9). These processes could take place to varying extents in circulation and/or intracellularly depending on the characteristics of the ADC components (5,17,18). Deconjugation of the ADC leads to the formation of unconjugated antibody and unconjugated drug, while catabolism of the ADC leads to the formation of antibody fragments or drug containing catabolites. The unconjugated antibody or antibody fragments can further undergo proteolysis to generate/release amino acids. The cytotoxic drug and drug related catabolites can undergo metabolism via CYP or non-CYP enzymes or be transported by transporters like P-gycoprotein and get excreted via the biliary or renal route.Fig. 3


Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates.

Kamath AV, Iyer S - Pharm. Res. (2014)

Proposed disposition of an ADC.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4596897&req=5

Fig3: Proposed disposition of an ADC.
Mentions: The primary mechanism of action of an ADC is binding to its specific antigen target on tumor cells and internalization via receptor mediated endocytosis followed by trafficking from endosomes to the lysosomes where the cytoxic drug is released into the cell causing cell death (1). The ADC however can also be taken up into cells (with or without target expression) non-specifically via pinocytosis, which could lead to unwanted drug release in non-target cells. Such non-specific uptake and release of potent drug could contribute to toxicity. The theoretical ADC elimination pathways based on nonclinical and clinical data are shown in Fig. 3 and include deconjugation and degradation or catabolism through nonspecific or target-mediated proteolysis (9). These processes could take place to varying extents in circulation and/or intracellularly depending on the characteristics of the ADC components (5,17,18). Deconjugation of the ADC leads to the formation of unconjugated antibody and unconjugated drug, while catabolism of the ADC leads to the formation of antibody fragments or drug containing catabolites. The unconjugated antibody or antibody fragments can further undergo proteolysis to generate/release amino acids. The cytotoxic drug and drug related catabolites can undergo metabolism via CYP or non-CYP enzymes or be transported by transporters like P-gycoprotein and get excreted via the biliary or renal route.Fig. 3

Bottom Line: The structure of an ADC is very complex with multiple components and considerable efforts are ongoing to determine the attributes necessary for clinical success.Understanding the pharmacokinetics of an ADC and how it impacts efficacy and toxicity is a critical part of optimizing ADC design and delivery i.e., dose and schedule.This review discusses the pharmacokinetic considerations for an ADC and tools and strategies that can be used to evaluate molecules at the preclinical stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc, 1 DNA Way (Mailstop 463A), South San Francisco, CA, 94080, USA. kamath.amrita@gene.com.

ABSTRACT
Antibody drug conjugates (ADCs) are an emerging new class of targeted therapeutics for cancer that use antibodies to deliver cytotoxic drugs to cancer cells. There are two FDA approved ADCs on the market and over 30 ADCs in the clinical pipeline against a number of different cancer types. The structure of an ADC is very complex with multiple components and considerable efforts are ongoing to determine the attributes necessary for clinical success. Understanding the pharmacokinetics of an ADC and how it impacts efficacy and toxicity is a critical part of optimizing ADC design and delivery i.e., dose and schedule. This review discusses the pharmacokinetic considerations for an ADC and tools and strategies that can be used to evaluate molecules at the preclinical stage.

No MeSH data available.


Related in: MedlinePlus