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    Home > Medical News > Medical World News > Bioanalysis Column . . . Pharmacokinetics and bioanalysis of monoclonal antibody drugs.

    Bioanalysis Column . . . Pharmacokinetics and bioanalysis of monoclonal antibody drugs.

    • Last Update: 2020-08-03
    • Source: Internet
    • Author: User
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    Text . . . The rise of the Sunde-American biotech drug began in 1982, when the FDA approved the first gene recombinant drug Humulin (recombinant human insulin) to market.
    This is the first year of the development of biotechnology drugs, is the drug acquisition means from chemical synthesis or chinese medicine extraction to obtain by biotechnology means of the landmark event.
    1986, the first therapeutic monoclonal antibody drug Orthoclone OKT3 was approved for sale, beginning the development of monoclonal antibody drug.
    subsequently, from the emergence of the chimeric antibody melohua in 1997, to 2002 to achieve the full humanized Xiu Meile was approved for listing, and in the next less than 20 years, ADC, bispecific antibodies, monodomain antibodies, etc. have been approved, many new treatment strategies from the scientific concept gradually to clinical.
    currently, the U.S. FDA has approved 94 mono-drug drugs (as of July 14, 2020), accounting for almost half of biotech drugs.
    different from small molecule chemicals, monoantidrugs are based on disease-related targets and their signaling pathways.
    can produce drug effects or/and side effects through the irreversible, high affinity of the target through non-covalent action, which causes blocking or activation effects and thus regulates downstream biological effects.
    Compared with small molecule drugs, monotophosis has the characteristics of high target selectivity, strong specificity and accurate clinical efficacy, and the indications involve tumors, immune system-related diseases, nervous system-related diseases, ophthalmology diseases, rare diseases, etc.
    in the development process of mono-anti-drugs, to understand the pharmacokinetic characteristics of singic target-mediated, to obtain the level of invivifying targets and drug concentrations, for a deep understanding of the effects of drug-target interaction on PD indicators or/and clinical endpoints, evaluation of potential biomarkers, elaboration of quantitative relationships, exploration of PK/PD correlations and other significant significance.
    this paper will elaborate on the type of target, the pharmacodynamic characteristics of monoantiapid, the influence factors of the monoantiapid generation and the biological analysis of mono-resistance.
    , target type biological target sacs are biomolecules that can bind to drug molecules and produce pharmacological effects.
    these targets are present in the cell membrane of the target organ of the body or in the body fluids, mainly receptors, ligands, enzymes, ion channels and nucleic acids.
    receptors are mostly glycoproteins and generally consist of at least two functional regions, i.e. the regions bound to the ligand and the regions that produce effects.
    receptors are activated by identifying and selectively binding ligands (signal molecules) to alter the conformation, initiating a series of processes, which are ultimately characterized by biological effects.
    receptors are cell membrane receptors such as ion channel coupling receptors, G-protein conjugate receptors, intracellular receptors such as cell plasma receptors and cell nucleoreceptors.
    ligands are bioactive molecules that can produce specific bindings to receptors, including bioactive substances (such as hormones, neurotransmitters, cytokines, information molecules) and exogenous bioactive substances such as drugs. the distribution and regulation of
    targets is related to the accuracy and efficacy of treatment.
    many ligands and receptors are involved in the growth and proliferation of cells, and target expression changes in a physiological site or disease state, so the drug can achieve therapeutic purposes by selectively binding to the receptor, acting to activate or block the activity of the receptor.
    monotonic binding to targets causes changes in downstream signaling pathways and/or mediated antibody-dependent cytotoxic (ADCC) effects and complement-dependent cell toxicity (CDC) effectfunctions.
    whether monoanti-drugs can play a role and the type of target, if the receptor expression in the solid tumor, the drug will be affected by a number of factors, such as the permeability of the endothelial to the tissue, circulation time, endothelial permeability, hydrostatic pressure, expression of targets on endothelial cells, etc. ;
    understanding the types and characteristics of targets helps us to understand more intuitively how targets interact with drugs, as well as a deep understanding of the drug disposition characteristics of the target.
    can be divided into membrane-bound targets and soluble targets (Solution ligand) depending on where the target sits, as shown in Figure 1, which is described below.
    Figure 1 Type of Monoanti-Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Metab. Toxicol, 2012,1 Membrane target, i.e. receptors on the cell surface, are present on the cell membrane surface and bind to ligand-specificity to produce biological effects such as EGFR, HER2, PD-1, PDL-1 and CTLA-4.
    receptors (membrane receptors) on the cell membrane surface change depending on the cell's functional state to maintain the dynamic balance of the receptor.
    membrane receptors are continuously internalized through circulation or degradation. The internalization of
    receptor refers to the process by which the receptor protein enters the cytoplasm through the recess of the plasmid membrane, the receptor inactivates after internalization, the signal transduction process may be interrupted, and the downstream effector may be further regulated.
    some drugs can lower receptors on the cell surface and increase efficacy by reducing the effects of receptors.
    continuous administration may reduce the net number of targets on the cell surface, which can affect efficacy.
    if the drug's mechanism of action is ADCC or CDC, it is hoped that the endoscosis complex of antigens is weak either to maximize the recruitment of immune-effect cells or complements to play a role. The extracellular domain (ECD) of the
    membrane-binding protein falls off and enters the circulatory system, which is a shedable target.
    targets that exist in the body in both membrane binding and solubility are CD20, CD25, CD52, EGFR, HER2 and CTLA4.
    can be observed in some tumors and inflammatory diseases to increase the level of shedding receptors, and can be affected by the administration of drugs and other factors.
    increase in the level of falling targets in the cycle is closely related to disease processes such as HER2.
    at the same time, the receptor position of the membrane target (Receptor occupancy, RO) is also affected by the level of the drop-off target. Receptors that fall off
    may reduce the drug's efficacy by occupying the binding site of the drug, making it less likely that the drug will bind to the membrane target.
    some receptors secrete related functions that regulate cells that do not express the receptor, such as IL-6 and soluble IL6-R alpha complexes that bind to beta-receptor gp130 to stimulate cells that do not express IL6-R alpha through signal transduction mechanisms.
    generally, soluble targets and shedable targets are not biomarkers raised as direct targets and, in some cases, are used to predict disease.
    by detecting receptor levels in the circulatory system helps us understand the manifestations of disease and its development. In addition, different human cell membrane shedding targets vary
    .
    2 Soluble target soluble ligands can function by binding to drugs in the circulatory system.
    normally, the soluble target in the cycle or the dropable target content is very low, from pg/mL to ng/mL.
    soluble targets maintain a lower baseline level in the body through rapid updates, including: rapid removal, rapid generation. the expression level of
    soluble target is closely related to disease.
    the total target level will be raised in the state of disease, and after administration, the removal rate will be reduced due to combination with the drug, which will also increase the target level.
    common soluble ligands such as TNF alpha (also in membrane binding form), VEGF, BLyS, IL-1 beta, IL-12/IL-23, RANKL, IgE, IL-6 (also in membrane binding form).
    , monoantithetic characteristics monoclonal antibody drugs are composed of antigen binding domain (Fab) and crystalline region (Fc).
    Fab segment consists of light chains and partial heavy chains, which mainly specifically identify related antigens, which regulate downstream signaling pathways, while fc segments are composed of the remaining heavy chain components that identify and combine immune cells expressing Fc receptors (e.g. natural killer cells, macrophages and neutrophils) and complements to activate the corresponding immune response, mediated antibody-dependent cell toxicaction (ADCCCC), antibody-dependent cells (AD) and other antibody-dependent cells (AD)
    Figure 2 The structural characteristics of the Mono-Reactor (Protn and Cell, 2018) are mainly IgG subtypes, each chain of IgG contains a constant zone (Constant region, Area C) and a variable zone (Variable region, V zone).
    constant region is a relatively constant structural domain of amino acid sequences near the C-side, and variable regions are the domain smaller than the amino acid sequences of light and heavy chains near the N-end, and the variable region determines the antigen specificity of the antibody.
    VH and VL each have three highly variable amino acid compositions and highly variable sequences, known as hypervariate zones (Hypervariable region, HVR), which form spatial construdal structures that complement the antigen epitope, are called complementary determining regions (Complementary ing region, CDR), and the CDR sequence is more variable than the rest of the variable region.
    pharmacokinetics plays an extremely critical role in the development of small molecule drugs, singogenic resistance due to its large molecular mass (up to 150 kDa), has hydrophiliability, variable solubility, poor membrane permeability and other physical and chemical characteristics, so that it presents a unique drug characteristics different from small molecule drugs, such as: oral absorption difference, subcutaneous /muscle injection lymphatic transport, limited renal excretion, Fc
    the absorption, distribution, elimination, and pharmacokinetic models of monoantigens are described below.
    1 Absorbs monoanti-molecular weight, has strong polarity, has a low distribution coefficient and diffusion performance, makes it not easy to be lipophilic biofilm ingestion, so it is difficult to absorb through the gastrointestinal tract.
    at the same time, a large number of enzymes present in the gastrointestinal tract can degrade the drug.
    the barrier effects of low permeability and high enzyme activity of the gastrointestinal mucosa make it very biologically available (less than 1%-2%), and the vast majority of oral cannot produce sufficient efficacy.
    , therefore, monotonica is usually administered intravenously, subcutaneously or intramuscularly.
    subcutaneous or intramuscular drug administration is more biologically available, generally in the 52%-80% range.
    , the molecular weight of 16 kDa is usually through capillaries into the body circulation system, whereas it is now thought that the amount of molecules in subcutaneous or intramuscular injections is largemonort, mainly in the lymphatic system by convection transport (as shown in Figure 3), and rarely partially through neonatal receptors (the neonatal receptor, FcRn).
    lymphatic system is porous, the intercepting molecular weight of the channel is 100 times the amount of monoanti-molecular, so that the monoantigen with relatively large molecular mass can be transported and absorbed under the action of intercellular fluid convection.
    in the lymphatic system, monotophosis can be transported one way to the venous system.
    normal physiological conditions, the lymphatic flow rate is slow (15 mL/day), so that subcutaneous injection stake takes up to several hours or even several days to be absorbed, mAb peak time is 1.7-13.5 d, mostly 6-8 d reached peak concentration. many factors
    affect the absorption process of monoantithetics during subcutaneous injection, such as injection site, drug factors such as charge, molecular size, glycosylation, formulation type and dose of administration, etc.;
    Figure 3 Monoantine transport through the lymphatic system of the distribution of the "Aging, 2019"2 distribution of traditional small molecule drugs, in order to identify the accumulation of possible toxic metabolites in the tissue, the study of the distribution of drugs throughout the body is essential.
    however, for monoanti-drugs, the product of decomposition metabolism is amino acids, which can be recycled in endogenous amino acid libraries, therefore, the distribution of monoantinos is mainly used to evaluate the drug's targeted effect on specific tissues, and to identify the main elimination organs. the distribution of
    monoantigens depends on the permeability of the tissue and the distribution of tissue gaps, the level of binding of receptors on the cell surface, and the ability to remove from the tissue, including intracellular ingestion and degradation.
    monogenic osmosis (extravasation) is mainly through three processes: passive diffusion, convection transport, and the cell swallowing of epithelial cells.
    the affinity constant of the target and the drug is about 1 nM, while the general monoanti-heeder concentration exceeds 10 nM.
    are mainly limited by the physical and chemical properties and molecular size of monoantiresist, which makes it difficult to spread into the tissue.
    monotomoids are less likely to cross the cell membrane through passive diffusion, but mainly through cell bypass transport or trans-cell transport to peripheral tissues.
    convection transport is driven by a blood-tissue hydrostatic gradient, where the drug enters the tissue gap through a gap between the endothelial cells of an blood vessel or through the lymphatic system from the interstitial gap to the blood.
    convection is a cellular bypass pathway and is considered to be the main way of transshipment of monotoantisis from blood to tissue, determined by the flow of bodily fluids from blood vessels to tissues.
    transcellular transport path is mainly achieved through cell swallowing.
    cytoswallowing includes receptor-mediated endogenous action (e.g. Fc-based receptors, FcRn) and non-receptor-mediated phagocytosis and cytodrinking.
    the cell swallowing of blood vessel epithelial cells, mediated by Fc receptors, may be another important transport route for monotophobic.
    especially in organizations, this approach is particularly important when the transmembrane of flow is limited.
    many studies have shown that the pathway has bidirectional transport properties, such as antibodies into endothelial cells under the action of FcRn.
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