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    Home > Medical News > Latest Medical News > Four key elements and development trend of ADC drug research and development

    Four key elements and development trend of ADC drug research and development

    • Last Update: 2020-06-19
    • Source: Internet
    • Author: User
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    ADCs (anti drug drugs) technology is to couple monoclonal antibody and drug molecules through linker, use the specificity of antibody to transport drug molecules to target tissues to play a role, reduce the systemic toxicity of drugs, improve drug treatment window and expand the potential of antibody treatment [1]After the ADC circulating in the blood is combined with the target antigen, the endocytosis mediated by the grid protein is internalized (Fig1) [2]The internalized complex then enters the endosome lysosome pathwayIn most cases, it is first transported to the early endosome and then to the lysosomeAcidic environment and proteolytic enzyme will lead to the degradation of lysosomes containing ADC, which will release cytotoxic drugs into the cytoplasmThe released cytotoxic drugs then flowed out to the cytoplasm and induced apoptosis by DNA insertion or inhibition of microtubule synthesisTherefore, the correct target, antibody, linker and cytoxic payloads are the four key factors that affect the ADCs< br / > Figure 1 the mechanism of action of ADC, which comes from the four key elements of reference 2 < br / > 1, < br / > ADC drugs < br / > 1.1 the selection of correct target < br / > the successful development of ADC depends on the specific binding of antibody to target antigenThe ideal target of ADC is high expression on the surface of tumor cells, low or no expression in normal tissues, or at least limited in specific tissues, such as CD138, 5T4, Mesothelin, leukemia and CD37The target expressed in normal tissue will ingest ADC drugs, which not only leads to the "off target" toxic effect, but also reduces the concentration of ADC in cancer tissue and the therapeutic window of ADC drugs< br / > effective ADC activity is related to the number of antigens on the cell surfaceIt has been proved that to achieve effective ADC activity, at least 104 antigens on the cell surface are needed to ensure that lethal doses of cytotoxic drugs are delivered to the cell interiorDue to the limited number of antigens on the surface of tumor cells (about 5000-106 antigens per cell surface on average), and the average Dar of ADC drugs in most clinical stages is 3.5-4, so ADC drugs are rarely delivered to tumor cellsThis is also considered as one of the main reasons for the clinical failure of ADC combined with conventional cytotoxic drugs such as methotrexate, paclitaxel and anthracycline antibiotics< br / > in addition to specificity and adequate expression, the best target antigen should also cause effective ADC internalizationThe combination of antibody and target cell surface antigen can trigger the internalization path of antibody antigen complex into cells, so as to achieve the intracellular delivery of drugs< br / > at present, leukocyte surface differentiation antigen is the first widely used ADC targetAt present, there are 10 targets (CD33, CD30, CD79b, CD22, CD19, CD56, CD138, CD74) of 20 kinds of ADC drugs in clinical development stageMany ADC drugs target leukocyte surface antigens to a large extent because of their high expression in tumor tissue, no expression in normal hematopoietic tissue, or very low expression level< br / > in addition, some solid tumor surface receptor molecules are gradually found to be suitable clinical ADC targets, such as PSMA for prostate cancer, EGFR for epidermal growth factor receptor, nectin 4 for ovarian cancer tissue and other ADC drugs have entered clinical phase IIKadcyla, which was approved by FDA in 2013, targets HER2Padcev, which was approved by FDA for marketing in 2019, is the second ADC drug target approved for marketing to treat solid tumorsThe selection of < br / > 1.2 antibody < br / > the high specificity of antibody molecule is the basic requirement to achieve the therapeutic effect of ADC, so that the cytotoxic agents are concentrated in the tumor siteDepending on high affinity specific antibodies, in addition to avoiding toxicity to healthy cells, antibodies lacking tumor specificity may be eliminated by the circulatory system, resulting in "depletion" of ADC drugs before reaching the tumor tissueTherefore, cytotoxic drugs are usually attached to the FC part or constant region of mAb to prevent the detection and binding of antigens< br / > because these ~ 150kda antibody molecules not only contain a number of natural sites for conjugation, but also can be modified for other reaction sites, at present, all ADC antibodies are IgG moleculesThe advantage of IgG molecule lies in its high affinity to target antigen and long half-life in blood, which leads to its accumulation in tumor siteCompared with other IgG molecules, IgG1 and IgG3 have much stronger antibody dependent cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), but IgG3 is not the ideal choice for ADC because of its short half-lifeIn addition, compared with IgG2 and IgG4, the hinge formed by IgG1 in the cell is easy to be reduced, so it is difficult to produce ADC drugs based on cysteineTherefore, because IgG1 has relatively strong ADCC and CDC, long half-life, easy to produce and other characteristics, most of the current ADC drugs are constructed with IgG1 scaffolds [3]The immunogenicity of < br / > ADC is one of the main determinants of the cycle half-lifeIn the early days, mouse monoclonal antibodies were used to induce strong and acute human immune response (HAMA) At present, most of the ADCs are humanized or fully humanized < br / > in general, the ideal mAb for ADC architecture should be humanized or fully humanized IgG1 molecules that can selectively bind tumor cells without cross reaction with healthy cells In addition, ADC internalization may be an important factor rather than an absolute factor for successful treatment < br / > 1.3 selection of toxin molecules < br / > toxin molecules are the key factors for the success of ADC drug research and development Only a small part of the antibody injected into the body is gathered in solid tumor tissue, so the first toxic molecule with nanomolar level (IC50 value in 0.01-0.1nm) is the appropriate payload In addition, the toxic molecules must have the appropriate functional groups that can be coupled, strong cytotoxicity, hydrophobicity, and very stable under physiological conditions < br / > at present, the toxic molecules used for ADC drug development can be divided into two categories: microtubule inhibitors and DNA damage agents Other small molecules, such as α - amanitin (selective RNA polymerase II inhibitors), are also under study [12] The former is represented by MMAE and MMAF (free drug IC50: 10-11-10-9m) of Seattle's genetics and DM1 and DM4 (free drug IC50: 10-11-10-9m) developed by immunogen's company The latter is represented by the PBD (free drug IC50 < 10-9m) of calichemicin, duocamycins and spirogen's company These toxins have corresponding ADC drugs for exploration and development in clinical stage Many companies are also developing their own payloads, such as nervano Medical Sciences, mersana therapeutics and so on < br / > 1.4 linker selection < br / > although it is important to select specific antibodies and payloads according to the type of tumor cells, in terms of pharmacokinetics, pharmacology and treatment window, it is the key to successfully construct ADC to restrict antibodies and payloads by selecting appropriate linker, The ideal linker must meet the following conditions: (1) linker needs to be stable in the blood circulation system, and it can rapidly release the active payloads when it is located in or near the tumor cells The instability of linker will lead to the premature release of payloads, resulting in damage to normal tissue cells There is also a clinical study that showed that the ADC stability of uneden alkaloids is in the opposite relationship with adverse reactions Therefore, for the combination of antibody, tumor tissue and payloads, it is very important to determine the linker with the best stability (2) Once the ADC is internalized into the target tumor tissue, linker needs to have the ability to be rapidly cleaved and release toxic molecules (3) Hydrophobicity is also an important feature considered by linker Hydrophobic linkers and hydrophobic payloads usually promote the aggregation of small molecules of ADC, which leads to immunogenicity < br / > at present, linkers are divided into two categories according to whether they can be cut: one is acid labile linkers (disease cleavable linkers, disulfide linkers), the main type of ADC drugs; the other is non cutting linkers, the difference is whether they will be degraded in cells < br / > Table 1 Comparison of linker types and advantages and disadvantages [4] < br / > the cuttable linker is designed to take advantage of its environmental differences in the blood system and tumor cells For example, acid sensitive linker is usually very stable in the blood, but not stable in the lysosomes with low pH value, and it can rapidly degrade and release free active toxic molecules (Mylotarg (gemtuzumab ozogamicin)) Similarly, the protease sensitive protein cleavable linkers are stable in the blood, but in the lysosome rich in protease (which recognizes its specific protein sequence), they are rapidly cut to release the active toxic molecules, just as the Val CIT dipeptide cross-linked bond is rapidly hydrolyzed by the intracellular cathepsins enzyme (adcetris (brentuximab vedotin)) The designed linker uses the high level expression of intracellular reduced glutathione to release toxic molecules (imgn-901 (anti-cd56-maytanine)) < br / > Fig 2 cleavable linker, from reference 4 < br / > non cleavable linker is composed of stable bond of anti protease degradation, which is very stable in the blood It depends on ADC antibody composition to be completely degraded by cytoplasm and lysosomal protease, and finally releases the payload connected with amino acid residue derived from degradation antibody to kill cancer cells (such as ADO trastuzumab emtansine, t-dm1, or kadcyla) At the same time, the ADC drug of linker can not be released outside the cell, and can not kill nearby cancer cells by "bystander effect" < br / > Fig 3 can't split linker, which comes from reference 4 < br / > of course, which type of linker to choose is closely related to target selection Among the ADC drugs with cleavable linker, the target is B cell antigen (CD19, CD20, CD21, CD22, CD79b, cd180), which has been proved to be very effective in vivo In contrast, in ADC drugs with non cleavable linker, the targets confirmed to engulf and transport rapidly to lysosomes in vivo include CD22 and CD79b < br / > to ensure the specific release of free drugs in tumor cells is the ultimate goal of linker selection, as well as the control of drug toxicity Finally, through the case by case analysis, we will decide how to optimize the selection of linker, target and toxic molecules to balance the effectiveness and toxicity of ADC drugs The development of cancer drugs can be traced back to the middle of the 20th century It has been found that nitrogen mustard destroys bone marrow and lymphoid tissue by targeting rapidly dividing cancer cells Such drugs include folate and purine analogues (methotrexate and 6-mercaptopurine), microtubule polymerization inhibitors / accelerators (vinblastine alkaloids and taxanes) and DNA destructors (anthracyclines and nitrogen mustards) [2] Because early cancer drugs not only target cancer cells but also kill all the mitotic cells in the body, leading to serious side effects in patients, which greatly limits the dosage, the treatment index (maximum tolerance dose / minimum effective dose) of drugs is very low, and the treatment window is narrow ADC drugs may selectively deliver toxic compounds to specific cancer cells < br / > 2.1 the first generation of ADC drugs < br / > in the first generation of ADC drugs, mitomycin C, IDA bicin, anthracyclines, n-acetyl-mafan, adriamycin, vinblastine alkaloids and methotrexate and other anti-tumor drugs are mainly coupled with murine monoclonal antibody through the non cleavable linker (amide or succinimide) < br / > in 2000, gemtuzumab ozogamicin (trade name: Mylotarg, Wyeth, Pfizer subsidiary), the first antibody coupling drug approved by FDA of the United States, was targeted at CD33, Gemtuzumab ozogamicin consists of three parts: 1) recombinant human IgG4 kappa monoclonal antibody gemtuzumab; 2) n-acetyl-y-kazimycin with cytotoxicity; 3) acid splitting double antibody composed of 4 - (4-acetylphenoxy) - butanic acid (acbu) and 3-methyl-3-mercaptobutane hydrazide (dimethylhydrazide)
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