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Blog entry by Gemini Smith

Investigation of Pharmacokinetics/pharmacodynamics (PK/PD) of Antibody Drug

Investigation of Pharmacokinetics/pharmacodynamics (PK/PD) of Antibody Drug

In the past few decades, both
pharmaceutical companies and academia have spent much financial resources and
energy to improve the practicability and accuracy of in vitro screening
technology that can test the biological activity and physicochemical properties
of compounds. However, the study of potential drug candidates in animal models
remains disposable.

 

FDA, NMPA, and other regulatory agencies
require that before the drug enters the clinic, its effectiveness and safety
must be assessed in animals. An animal, whether a rat, a dog, a monkey, or even
a human, is a complex biological system. At present, there is no in vitro
screening method or combined method that can mimic and reflect the complexity
of the entire organism. Therefore, it is indispensable to use animal models to
evaluate the effects of candidate drugs on humans and diseases.

 

Classification of tumor animal models 

Mouse xenograft tumor model

Among the tumor disease models, the mostly
used is the mouse xenograft tumor model that utilizes specific mice, such as
SCID, NSG, B-NDG mice, and other conventional immunodeficiency or severe
immunodeficiency mice, which cannot produce immune attacks on foreign cells.

 

* CDX (Cell-line-derived Xenograft) model: Standardized
cancer cell lines are used for modeling. The cells are easy to obtain but have
drawbacks that they cannot represent the original clinical tumor.

* PDX
(Patient-derived Xenograft) model
: Tumor tissue or cells obtained from
tumor patients with the characteristics of clinical tumors.

 

Most antibody drugs kill tumors by
mediating the immune system, so to evaluate their effectiveness, it is
necessary to reconstitute an animal model of the human immune system (including
DC, B, T, and NK).

 

Mouse allograft tumor model

The disadvantage of the xenotransplantation
model is that the use of immunodeficient mice for modeling may result in the
rejection of the immune system caused by cross-species transplantation. The
allograft tumor model allows researchers to use a mouse model with a sound
immune system but requires the mouse tumor cell lines for modeling studies. The
fully functional immune system makes the allograft model better than the
xenograft model to simulate the real situation of cancer.

 

* Wild mouse allotransplantation model:
mainly used in the pharmacological and pharmacological study of Surrogate
antibody.

* Genetically modified/humanized
mouse model
: for the study of humanized antibodies.

 

Research on the Biomarkers of Antibody
Drugs Using Genetically Humanized Mice

The core of PD/PK evaluation is the
determination of suitable biomarkers.

1. Target biomarkers

2. Mechanism biomarker: detection of the tumor
microenvironment (biomarker profiling)

* Changes in the number, location, and
status (e.g., activation, dysfunction) of immune cells in the tumor

* Changes in the number of tumor cells and
status

3. Toxicity biomarkers

The study of metabolism of antibody drug using
genetically humanized mice is different from that of small molecule drugs. The
factors that affect antibody pharmacokinetics are:

* Fcγ receptor

* FcRn cycle

* Absorption and metabolism

* Immunogenicity

* TMDD (target-mediated drug disposal)


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