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    Home > Medical News > Latest Medical News > The characteristic difference and research status of PD-1/PD-L1 monoantial

    The characteristic difference and research status of PD-1/PD-L1 monoantial

    • Last Update: 2021-01-23
    • Source: Internet
    • Author: User
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    Since 2013, when the journal Science ranked oncology immunotherapy as one of the top ten scientific breakthroughs, immuno-checkpoint inhibitors have become the focus of research in the field of tumor immunotherapy.
    Existing studies have shown that the programmed death subject 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling path through which tumor-specific T-cell apoptosis can be induced by inhibiting T-cell activity, and lead to T-cell resistance, immune escape, immunosuppression, etc. in pathological conditions such as tumor and chronic inflammation.
    PD-1-PD-L1 path is a signaling path that suppresses the immune response.
    tumor cells express PD-L1, which binds to PD-1 on the surface of lymphocytes, thereby inhibiting lymphocytes from killing tumors and achieving "immune escape".
    PD-1 /PD-L1 monoantigen is acting on PD-L1 or PD-1 bits on tumor cells, respectively, preventing the two from binding to each other and activating immune cells to kill tumors.
    PD-1 and PD-L1 binding, through the occurrence of phosphatidyl inositol-3-kinase phosphorylation, further activation of protein kinase B, activation of stimulating T-cell signaling path, glucose metabolism and interferon secretion, resulting in T-cell activation of downstream signals blocked, and thus effectively inhibit the transcription of T-cells, and ultimately inhibit the immune function of T-cells, in the negative immune response.
    , blocking the PD-1/PD-L1 signaling path path can make T-cell activation upward, activating endogenic anti-tumor immune response, thus playing a therapeutic role in tumors.
    inhibitors targeted at PD-1/PD-L1 showed significant therapeutic effects in clinical applications, and many PD-1/PD-L1 inhibitors were listed, but different PD-1/PD-L1 inhibitors varied in terms of antibody source, type, stability, specificity, affinity, adaptive evidence, dosage, immunogenicity, pharmacodynamics, etc.
    currently, there are six FDA-approved anti-PD-1 mono-anti-drugs, namely Nivolumab, Pembrolizumab, Cemiplimab, Toripalimab, Cindilimab There are 3 anti-PD-L1 monoantigens, atezolizumab, Avelumab and Durvalumab, respectively, and a variety of anti-PD-1/PD-L1 monoantigens may be approved for the market in the future.
    the basic structure of the anti-PD-1 monoantial drug is IgG4, which has greater flexibility due to its short hinge area and unstable desulfur bonds.
    In vivo, IgG4 can exchange Fab segments with other IgG4 molecules, i.e. to form a "semi-molecular exchange": two single-specific IgG4 molecules exchange their own heavy chain and a light chain connected to the heavy chain, resulting in the production of new IgG4 molecules, which may result in dual-specificity.
    the core hinge sequence of 228 bits of serine is the key element required for "semi-molecular exchange", replacing serine with proline (S228P bits) with point mutations prevents the Fab segment exchange of IgG4.
    This is why anti-PD-1 monoantigens are modified by S228P to stabilize the inter-chain desulfur bond, prevent Fab segment exchange, and overcome the uncontroveability of efficacy and toxicity caused by the instability of IgG4.
    the basic structure of anti-PD-L1 monoanti-drug is IgG1, the core hinge base sequence of 228 bits of proline is relatively stable, there is no such "semi-molecular exchange" phenomenon.
    that PD-L1 single resistance may be combined with more stable or comprehensive, in-body functional analysis shows that PD-L1 single resistance blocking capacity is stronger.
    monoantigenic drugs can be divided into 4 generations according to their technical characteristics and degree of humanization, 1st generation mouse source antibodies, 2nd generation mouse chisel antibodies, 3rd generation source antibodies and 4th generation complete human antibodies.
    currently available anti-PD-1/PD-L1 monoantigens are humanized or fully human monoclonal antibodies.
    Paboli pearl monoanti, simipuri monoanti, Terriple monoanti, Karelli single resistance and Atju monotonic antibody humanized monoclonal antibody, Navuliyu monoclonal antibody, xindili monoanti, Avilu monoanti and dovru monoantigen antibody for complete human monoclonal antibody.
    of antibody sources will affect anti-PD-1/PD-L1 monoantigen anti-tumor activity or sensitivity.
    the differences in target, antibody source, antibody type, binding area, binding area, affinity of each PD-1/PD-L1 inhibitor resulting in different adaptation certificates for the currently approved anti-PD-1/PD-L1 monoantigen.
    e.g. Navuliyu monoantitor and Pabliju monoantigen are widely used for melanoma, non-small cell lung cancer, Hodgkin's lymphoma, urethra skin cancer, etc., while Xindili monoanti and Karelli pearl monoantigen are currently only approved for the treatment of recurring/refractic Hodgkin's lymphoma.
    In addition, the dosage of each monoantror drug is different, from substance-quality-based administration to fixed-dose administration options, depending largely on the characteristics of the drug, clinical data analysis, and research and development strategies.
    anti-PD-1/PD-L1 monoanti-drug is a large molecular drug, compared with small molecule drugs, has different physical and chemical properties and pharmacodynamic characteristics, its pharmacodynamic characteristics and net charge, isoelectre, FcR, glycosyl modification, spatial structure and other factors are related.
    net charge changes in monoantigen drugs are usually associated with acid/alkaline changes caused by deamination, isomerization, or post-translation modification.
    studies have shown that the pH thresholds for different subtypes of IgG monoantigens are small to large: IgG1< sugar-free IgG1 anti-PD-1/PD-L1 monoantial relative molecular mass of about 140 to 150 kDa, with high hydro hydropyriability, poor ability to pass through the cell membrane, easy to be degraded in the gastrointestinal tract, etc. , so generally need to be administered through intravenous infusion.
    most of the anti-PD-1/PD-L1 is distributed in blood vessels and cell gaps, except for a slightly higher steady-state distribution volume (approximately 13.3 L) of the Ripley monoantigen, the steady-state distribution volume of the other drugs is lower.
    anti-PD-1/PD-L1 monoantigenic half-life and reach a stable state time is longer, Navuliyu monoanti and Pabliju monoanti-resistance half-life can be as long as 26 d or so, and the degree of valu monoanti and Pabli-pearl monoantigen can reach a steady state time of 16 to 18 weeks.
    metabolic elimination of monoantigens includes nonse specific elimination (e.g. protein hydrolytic action) and target-mediated elimination (including target binding, protein hydrolyzing, and internalization).
    Anti-PD-1/PD-L1 monoantid drugs are metabolized without cytochrome P450 enzymes and other drug metabolases, metabolic and metabolic changes include deamide, oxidation, isomerization, protein hydrolysis and glycolysis hydrolysis, and disulfluation bond fracture, so there is less drug interaction.
    Approved anti-PD-1/PD-L1 monoantigens vary in stability, affinity, Fc segment characteristics, dosage, certificate of adaptation, immunogenicity, etc., all of which may have a significant impact on the pharmacology or pharmacodynamics of PD-1/PD-L1 monoantigens, which may affect the adaptive, efficacy and safety of such drugs.
    medical personnel through the antibody source, subtype, Fab segment and Fc domain and adaptive evidence of in-depth understanding, will help the rational use of anti-PD-1/PD-L1 monoantigen drugs, reduce adverse reactions, achieve individualized treatment.
    In addition, anti-PD-1/PD-L1 monoantigens also have inevitable defects, such as long half-life, itself has immunogenicity easily lead to drug-based immune-related adverse events, coupled with difficult production, high treatment costs, transportation inconvenience and other shortcomings, these characteristics seriously limit the clinical application of anti-PD-1/PD-L1 monoantigens.
    , Yang Lin, Xie Ruixiang. Overview of the characteristics of 9 approved anti-PD-1/PD-L1 monoantigens, China Pharmacy, 2020, 18:2294-2299. [2] PD-1 monoantigen and PD-L1 monoantigen are immunologic drugs, but there are four major differences. Oncology Clinical and Rehabilitation in China, 2020, 03:362.
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