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Introduction to TNF Receptor Superfamily Member 10b

June 24, 2019

Author: chen shanshan

There are some antibodies: 1.Conatumumab TNF Receptor Superfamily Member 10b (TNFRSF10B) is a recombinant monoclonal antibody. Conatumumab (originally AMG 655) is a monoclonal antibody developed for the treatment of cancer. It is a fully human monoclonal agonist antibody directed against the extracellular domain of human TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptor 2 (TR-2, death receptor 5) with potential antineoplastic activity. Conatumumab mimics the activity of native TRAIL to bind to and activate TR-2, thereby activating caspase cascades and inducing tumor cell apoptosis. TR-2 is expressed by a variety of solid tumors and cancers of hematopoietic origin. Drozitumab Drozitumab is a human monoclonal antibody designed for the treatment of cancers. So, what is TNFRSF10B?   Figure 1. Apoptosis Apoptosis is a programmed cell death controlled by genes, which plays an important role in maintaining the stability of human internal environment. And it also plays an important role in eliminating potential dysplasia cells in the body. The imbalance of normal apoptotic mechanism is an important factor in the occurrence and development of tumors. There are many death receptors on the cell surface that can induce apoptosis. Receptors transmit death signals by recognizing the corresponding ligands, promptly activating the apoptotic mechanism and inducing apoptosis. Like other known receptors, such as CD95, TNFR1 and DR4, death receptor 5(TNFRSF10B) belongs to the tumor necrosis factor receptor (TNFR) superfamily, and they are highly homologous. CD95 and TNFR1 are classical receptors for inducing apoptosis, but TNFRSF10B has the advantage that it can quickly induce apoptosis of cancer cells when combined with corresponding ligands, but it has no toxicity to normal cells. TNFRSF10B is attracting more and more attention as a new potential breakthrough point in clinical cancer biotherapy. Great progress has been made in basic and clinical research. Structure and distribution of TNFRSF10B After cloning the full-length gene of DR4, the researchers found that there is another molecule on the surface of some cells. It is highly homologous to DR4 and is named TNFRSF10B. Sequence analysis shown that the full length of the coding frame is about 1.4 kb. DR 5 consists of 411 amino acids, of which 1-55 amino acids are signal peptides, 84-179 amino acids are extracellular domains (including two cysteine-rich repetitive functional domains), 184-206 amino acids are transmembrane domains, and 67 amino acids are intracellular domains and death domains (DD). The homology of the intracellular domain DD of DR 5 and DR4 is 64%, and the homology of DR 5 and TNFR1 DD is 25%. TNFRSF10B is widely expressed in many kinds of cancer tissues, such as liver cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, prostate cancer, etc. It is not expressed or less expressed in normal tissue cells. Ligand of TNFRSF10B The ligand of TNFRSF10B is tumor necrosis factor related apoptosis inducing ligand (TRAIL). The sequence of TRAIL contains 1769 bases, encoding 281 amino acids, and the gene is located on chromosome 3 3q26. It has no correlation with known TNF ligand family members. TRAIL is a type II transmembrane protein. The active site of TRAIL is 114-281 amino acids at the C-terminal. TRAIL mRNA is widely expressed in spleen, lung, prostate, peripheral lymphocyte, kidney, thymus, ovary, small intestine, colon, skeletal muscle, heart, placenta and other tissues, but it cannot be detected in brain, liver and testis. TRAIL acts as a trimer and can induce programmed cell apoptosis when combined with TNFRSF10B. However, TRAIL was found to be cytotoxic in the initial in vitro experiments. Later, it was found that recombinant TRAIL used in these experiments contained exogenous tags. Natural human TRAIL contains a unique cysteine residue (cys-230) at position 230. Crystal structure analysis has shown that the trimerization form of TRAIL is close to each other by three cys-230 and maintains trimerization stability by zinc ion chelation. On the contrary, polyhistidine-labeled recombinant TRAIL has low zinc content and different conformation, suggesting that the toxicity of TRAIL to normal cells may be related to the exogenous labeling in the recombinant. In order to prevent this cytotoxicity, TRAIL without exogenous label was used in subsequent experiments, which not only retained the ability to induce apoptosis of cancer cells, but also reduced the side effects of cytotoxicity. Mechanism of TNFRSF10B When ligand binds to TNFRSF10B, the DD conformation of TNFRSF10B changes, and then TNFRSF10B rapidly aggregates and activates, recruiting Fas-associated death domain (FADD) to induce apoptosis. FADD can bind caspase-8 precursor-caspase progenitor as a junction protein. Thus, a death-inducing signal complex composed of ligand-death receptor-adapter protein FADD-caspase was formed. Caspase-8 is formed by dimerization of two procaspases. Activated Caspase-8 initiates two apoptotic pathways: non-mitochondrial dependence and mitochondrial dependence. The application of TNFRSF10B in tumor therapy Recombinant human TRAIL (rhTRAIL) Although TRAIL has shown good clinical application prospects, the following problems are still urgently needed to be solved: (1) some types of tumors have obvious resistance to TRAIL-induced apoptosis, such as chronic lymphocytic leukemia, astrocytoma, meningioma and prostate cancer; (2) three kinds of decoy receptors of TRAIL can competently inhibit death receptor-induced apoptosis; (3) some of them can competently inhibit death receptor-induced apoptosis. RhTRAIL has cytotoxicity, especially hepatotoxicity. As mentioned above, rhTRAIL containing 141-281 amino acids of human TRAIL and without any exogenous labels has become the first choice in clinic. Although rhTRAIL with exogenous labels has a slightly higher biological activity, it has some immunogenicity problems. At present, rhTRAIL research has entered the clinical stage. Relevant clinical trials have suggested that rhTRAIL has a broad antitumor spectrum, can effectively induce apoptosis of cancer cells, and has no obvious toxicity to normal cells, but its shortcoming is its short half-life. Some cancer cells have obvious resistance to TRAIL. The combination of TRAIL with other drugs may be more reasonable than using it alone. Anti-TNFRSF10B monoclonal antibody Deception receptors can competitively inhibit the binding of TRAIL to death receptors. Therefore, the study on antibodies that specifically act on TNFRSF10B receptors and are not antagonized by decoy receptors can effectively improve the efficiency of inducing apoptosis of cancer cells. In 2011, a monoclonal antibody against human TNFRSF10B, TRA8, was prepared and found to induce apoptosis in most TRAIL-sensitive tumor cells in vitro and in vivo. With the development of monoclonal antibody preparation technology, more and more human anti-TNFRSF10B specific monoclonal antibodies are being applied in basic research and clinical experiments. A large number of studies have proved that specific monoclonal antibodies can enhance their anti-tumor activity when used in combination with other biochemical agents. Combination with chemotherapy and radiotherapy It has been found that the expression of death receptor in cancer cells could reflect the sensitivity of cells to TRAIL to some extent. Therefore, how to upregulate the expression of death receptor on the surface of cancer cells and enhance the sensitivity of cancer cells to TRAIL has become a research hotspot in recent years. Current studies have found that chemotherapy and radiotherapy can not only induce apoptosis, but also increase the expression of death receptor on the surface of tumor cells, amplify the apoptotic pathway of TRAIL, increase the sensitivity of tumor cells to TRAIL, and make TRAIL selectively killing cancer cells, which may provide a new method for cancer treatment. Many studies have shown that chemotherapeutic drugs can increase the expression of TNFRSF10B on the surface of various cancer cells and enhance the sensitivity of TRAIL to tumors. Prospects and significance of TNFRSF10B research In a word, DRS and its ligands are one of the hotspots of apoptotic research in recent years. They deepen people's understanding of death receptors and apoptosis in tumorigenesis, development and treatment, and provide a new way for cancer treatment. However, there are still some problems that need to be solved: the distribution of TNFRSF10B and its physiological role; the signal transduction pathway of DRS-induced apoptosis and its regulation mechanism; the influence of drug intervention on the apoptotic pathway and drug resistance mechanism of TRAIL; the lethal effect of the combination of TRAIL with chemotherapy and radiotherapy on normal human cells. We believe that further research will eventually help us solve these problems and will bring us new hope to fight cancer.

Introduction to Epithelial Cell Adhesion Molecule

June 21, 2019

Author: chen shanshan

Here are two antibodies: Anti-EpCAM Immunocytokine, IgG (huKS)-IL2 This antibody-cytokine fusion protein was achieved by conjugating/fusing the Anti-EpCAM IgG to IL2. It was expressed in CHO and purified with affinity chromatography. The immunocytokine retains the ability to bind the EpCAM as well as the biological activity of IL2. Mutation of the lysine at the C-terminus of certain Fc regions to an alanine can improve the pharmacokinetic properties of a fusion protein that already has improved pharmacokinetics as a result of reduced Fc receptor binding. This immunocytokine was designed for treating solid tumor based on the following non-limiting example “Deduction of immunogenic reactive epitopes of huKS-IL2 immunocytokme”. Anti-EpCAM Therapeutic Antibody   Recombinant monoclonal antibody to Endosialin. OCAb9-1 is a mouse monoclonal antibody intended for the prophylaxis and treatment of related diseases. This antibody is able to specifically recognize EpCAM expression in different human cancer tissues, including oral, breast, colon, ovary, pancreas, and uterus.   These are EpCAM antibodies, so what is EpCAM?   Epithelial cell adhesion molecule (EpCAM) is also known as TACSTD1 (tumor-associated calcium signal transducer1). EPCAM is a 40 kDa transmembrane glycoprotein encoded by GA-733-2 gene. As a calcium-independent homophilic intercellular adhesion molecule, EPCAM plays a role in the process of epithelial carcinogenesis. Through participating in nuclear signal transduction and through mediating cell migration, proliferation and differentiation, it plays an important role in tumorigenesis and distant metastasis. In recent years, anti-EpCAM targeted drugs have been used to treat malignant peritoneal effusion, especially for advanced patients unsuitable for surgery and chemotherapy. Structure of EpCAM Human EpCAM gene is located on chromosome 2p21 and is highly conserved in evolution. The full-length of RNA is 1500 bp. It encodes 314 amino acid residues of type I transmembrane glycoprotein. Its relative molecular weight is 39 000 and 42 000. The N-terminal extracellular domain of the protein folds into an epidermal growth factor-like domain and a thyroglobulin-like repeat sequence. The repeating sequence of two adjacent cells twists into tetramers to make it fine. The cells form tight junctions. There are at least four distinct antigenic epitopes in the extracellular domain, and the dominant epitopes are between 27 and 59 amino acids. The intracellular domain is a 26-amino acid domain. Biological function Regulation of intercellular adhesion and migration and cell morphology: EpCAM mainly mediates adhesion between non-calcium-dependent homologous cells, which is looser than E-cadherin. Under physiological conditions, EpCAM can regulate cell movement by rearranging actin skeleton, which may promote cell migration. In addition, EpCAM is also involved in the occurrence, development and tumorigenesis of epithelial tissues through the regulation of cell morphology. Regulating cell cycle and cell proliferation: EpCAM has effects on cell cycle and cell proliferation. When full-length EpCAM gene was transfected into EpCAM-negative HEK293 cells, EpCAM was expressed in HEK293 cells. Cyclin A/E and its protein and c-mye genes were up-regulated rapidly to promote cell metabolism and proliferation. EpCAM also participates in cell proliferation through Wnt signaling pathway.In addition, EpCAM can directly affect cell cycle by regulating the expression of cyclin D1 at transcriptional level and by its ability to interact with FHL2 (four and half LIM domains-2). EpCAM signal transduction pathway Regulated intramembrane proteolysis: The oligomerization of EpCAM is the promoter of signal transduction, which makes EpCAM hydrolyzed by protease and releases its intracellular domain. Recent studies have confirmed that there are several other cleavage sites in the extracellular domain of EpCAM, suggesting that EpCAM signaling is regulated by different protein hydrolysis pathways, which may be involved with controlling various functions of EpCAM. EpCAM and Wnt signaling pathway: Wnt signaling pathway is a classical cancer signal transduction pathway. Studies have shown that EpCAM is a direct transcriptional target of Wnt pathway. Interference of EpCAM expression or inhibition of beta-catenin expression by RNA can lead to the death of EpCAM-positive hepatocellular carcinoma cells. Activation of Wnt signaling pathway increased the number of EpCAM-positive hepatocellular carcinoma cells. EpCAM and PIK pathways:In 2007, researchers studied breast epithelial cells HBL100 and found that 3-phosphatidylinositol 3-kinase (PIK) regulated the shuttle of P85 subunits between EpCAM and N-cadherin. EpCAM/p85 complex has kinase activity, and the activation of PIK can promote cells to enter the DNA synthesis phase and change the characteristics of precancerous transformation. The activation of PIK is also necessary to induce cell proliferation and intercellular adhesion. These results suggest that EpCAM may partially regulate cell proliferation through PIK pathway. EpCAM and tumor expression EpCAM is expressed in almost all epithelial tissues and epithelial-derived tumor cells under physiological conditions, but not in tissues and cells with certain autoimmunity such as stratified squamous epithelium, liver cells, bone marrow-derived cells, blood vessels, lymph nodes, spleen and brain. However, EpCAM is widely expressed in various human tumors, including lung cancer, esophageal cancer, gastric cancer, breast cancer, colorectal cancer and hepatocellular carcinoma, while it is absent or rarely expressed in stromal tumors. The expression of EpCAM in breast cancer depends on its histological subtypes, in which lobular cancer usually has no or weak expression. Metastatic tumors with positive EpCAM expression often reflect the phenotype of primary tumors. EpCAM and targeted therapy EpCAM has a long history as a targeted antigen for cancer treatment. Various mouse-derived, chimeric and fully humanized anti-EpCAM monoclonal antibodies have been successfully tested in various clinical trials. At present, many anti-EpCAM monoclonal antibodies have been introduced into clinical trials of human tumors. Through the study of these monoclonal antibodies, it is found that the advantages and disadvantages of EpCAM monoclonal antibodies are not only related to their affinity to tumors, but also to their types and binding epitopes. A thorough understanding of the differences in the characteristics of anti-EpCAM monoclonal antibodies is helpful to optimize the clinical application of EpCAM monoclonal antibodies. There are bispecific antibodies in Europe, which can specifically recognize CD3 T cells and EpCAM positive tumor cells, form a complex of three kinds of cells: tumor cells, T cells and ADCC effector cells, and trigger a variety of immune mechanisms to induce apoptosis of cancer cells. Clinical trials have shown that anti-EpCAM targeted drugs have definite efficacy in the treatment of epithelial tumors. So far, this molecule has been effectively transformed in oncology and is expected to be applied in clinical monitoring of lung cancer. In the future, we should further clarify the mechanism of EpCAM and tumorigenesis and migration, the relationship between EpCAM signaling pathway and other biological signaling pathways, explore the best combination therapy of anti-EpCAM targeting drugs and other anti-cancer drugs, and standardize and guide the clinical use of drugs.

A Guide for Selection of Delivery Vectors for Cancer Vaccine (p

June 20, 2019

Author: chen shanshan

Vaccines were originally developed as a prophylactic agent, administered to healthy individuals to induce long-term immunity against a pathogen and to prevent the outbreak of viral diseases. Therapeutic vaccines aim at inducing strong antigen-specific T cell responses. In contrast to prophylactic vaccines, they are used in patients who already have a growing, established tumor. In the field of cancer immunotherapy, prophylactic vaccination only applies to the few virally induced malignancies, such as the vaccine against hepatitis B virus that can cause liver cancer, or the nowadays widespread human papilloma virus (HPV) vaccination of teenagers, which aims to prevent genital cancers induced by high-risk HPV strains. Unfortunately, however, most cancers are of nonvital origin, instead resulting from a succession of inherited and somatic DNA mutations leading to malignant cell transformation. Most of the time when the cancer is diagnosed, it is already well established and has largely evaded the control of the immune system. In this context, therapeutic cancer vaccines have been developed to stimulate or boost the immune system of the patient against established tumors. The main components of cancer vaccines are tumor antigens, immunological adjuvants, and vehicles or carriers. Viral Vectors     There are two main types of viral vaccines in tumor vaccines: one type is that the target tumors are those with high correlation with viral infection, another type called recombinant, which uses virus as a vector to transfer the gene of interest into a virus. Available viral vectors include adenovirus, adeno-associated virus, retrovirus, etc. Adenovirus is widely used for its safety and high titer. 1.1. Adenovirus Adenovirus is a non-enveloped double-stranded DNA virus. The 36 kbp genome accepts cDNA sequences up to 7.5 kbp. Replication of the genome occurs in the nucleus but remains extrachromosomal, minimizing the risk of insertional mutagenesis with this vector. Adenovirus can infect proliferating and resting cells and express transgenes with high efficacy. The majority of adenoviral vectors are replication-incompetent, following deletion of E1 and E3 viral genes. This limits their pathogenicity, while still allowing for the generation of a humoral and cellular response to transgenes. Adenoviral vectors are stable and easily propagated in laboratory settings, which allow researchers to easily modify the vector; this includes retargeting the virus’s tropism to enhance infection of DCs and target cells lacking the common Ad receptor, which is critical for infection. Adenovirus induces neutralizing antibodies in infected hosts, thus limiting the number of vaccinations. Adenoviruses have proven promising for vaccine vector development because they are capable of eliciting T and B cell responses to both self-antigens. The rationale underlying cancer vaccines is that they should enable the immune system to recognize cancer cells and influence their growth or lead to their eradication. One approach is immunization against tumor-specific antigens, which can be achieved via adenovirus-mediated delivery of tumor-associated antigens (TAAs) or immunomodulatory molecules. Adenoviruses as vaccine vectors are potentially as safe, or safer than live attenuated vaccines because the theoretical risk of reversion to virulence of the attenuated pathogen is extremely low, if not absent. Also appealing is that adenoviruses offer the possibility of targeting any antigen of interest. There are several ways to create space for inserting foreign DNA (i.e., the antigen of interest) into adenoviruses. Most of the currently investigated recombinant adenovirus-based vaccine vectors are vectors of first and second generation where foreign DNA can be inserted into at least three regions of the adenoviral genome: the E1, E3, and the short region between E4 and right ITR. Recombinant adenovirus vectors transduce both quiescent and actively dividing cells, can be produced at very high titers, have relatively high capacity for transgene insertion, and allow high expression of the recombinant protein. After entering the nucleus, adenoviruses do not integrate into the host genome, avoiding the risk of insertional mutagenesis and increasing the safety of these vectors. First-generation adenovirus vectors provide only transient transgene expression, and while this is of limited benefit for gene therapy, it is nonetheless adequate for cancer treatment and vaccination. 1.1.1 Adenovirus-mediated cytokine or immune-assisted molecular vaccine It has been reported in the literature that recombinant adenoviruses IL-2, IL-6, IFN-γ and TNF-α can significantly reduce tumor volume and have significant anti-tumor effects. Although recombinant adenovirus IL-12 enhances CTL responses in tumors, activates NK activity, and disrupts angiogenesis, it has unacceptable dose-related toxicity and even death. 1.1.2 Adenovirus-mediated tumor suppressor gene vaccine Recombinant adenovirus cancer gene p53 (AdVsp53) is widely used for gene therapy of cancer. Infection of human prostate cancer cells with AdVsp53 in vitro caused significant tumor suppression and apoptosis; tumor-bearing mice immunized with prostate cancer with AdVsp53 in vivo not only inhibited tumor growth, but also reduced tumor metastasis. The AdVsp53 vaccine has a corresponding effect in breast cancer and brain tumors. 1.1.3 Adenovirus-mediated chemical gene vaccine Phase I clinical trial of recombinant adenovirus HSK-TK vaccine in the treatment of recurrent ovarian cancer, 14 patients enrolled, 13 were evaluated, 5 stable (SD), 8 disease progression, 2 days after injection HSK-TK can occur in the body, so the vaccine can be used to treat metastatic ovarian cancer. 1.1.4 Adenovirus-mediated other genetic vaccine The range of currently used adenovirus-mediated gene vaccines is also expanding, such as recombinant adenovirus telomerase reverse transcriptase (Ad-TERT), recombinant adenovirus VE-cadherin (Ad-VE-cad) in animal tumor models. Both show significant anti-tumor effects and inhibit lung cancer metastasis. …to be continued in part two. Reference [1] Parkin D M, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55: 74–108 [2] Wong H H, Lemoine N R. Biological approaches to therapy of pancreatic cancer. Pancreatology, 2008, 8: 431–461 [3] Avogadri F.,Martinoli C.,Petrovska a/.Cancer immunther- apy based on killing of Salmonella-infected tumor cells.Can— cer Res,2005.65(9):3920--3927. [4] Sato E,Bfiones a1.In vivo antigen delivery by a Salmonella typhimurium type 111 secretion system for therapeutic cancer vaccines.J Clin Invest,2006。116:1946—1954.

What are the characteristics of a successful ADC company?

June 19, 2019

Author: chen shanshan

What is an ADC? The antibody-conjugated drug (ADC) is a chemotherapeutic drug with strong cytotoxicity formed by the coupling of a linker with a monoclonal antibody. It combines the strong killing power of small molecule drugs with the high targeting of pure monoclonal antibodies, thus becoming a tumor target treatment research and development hotspots.A significant increase in efficacy is achieved by regulating the uniformity and stability of the drug. Nowadays, the two mature coupling technologies focus on homogeneity and stability, and some new coupling techniques can improve simultaneously in two aspects. 1.For therapeutic uses ADC drugs are used in the treatment of cancer, which is determined by the target to which the antibody is directed, and is capable of performing targeted DNA destruction or inhibiting microtubules on tumor cells that express the target at high levels. Because of its high degree of targeting, it can use highly toxic drugs that cannot be used in chemotherapy or that cannot be increased in dosage.  Compared to chemotherapeutic drugs, the therapeutic potential of ADC drugs will be larger and safer. Basic principles The targeting of the ADC comes from the antibody part, the toxicity is mostly from the small molecule drug poison part, and the antibody part can also be toxic (ADCC and CDC). The antibody moiety and the drug moiety are interconnected by a linker. After the antibody moiety binds to a targeted antigen on the surface of the tumor cell, the tumor cell will endocytize the ADC. After that, the ADC drug will decompose in the lysosome, releasing the active chemical poison, destroying the DNA or preventing the tumor cells from dividing, and killing the cells. The idealized linker should remain stable so that it does not cause off-target toxicity and efficiently releases poisons within the cell. Compared with other treatment methods, ADC has the following five characteristics: strong therapeutic effect; high tumor cell specificity, small killing rate; weak immunogenicity, not easy to produce drug resistance; long circulating time in serum (shorter than monoclonal antibody); Non-target cytotoxicity is weak. The figure below shows the molecular formulas of all three ADC drugs, Mylotarg, Kadcyla and Adcetris, which have been marketed. Among them, the black part is an antibody, the blue part is a linker, and the red part is a toxin.   2.1 Antibody part (1) Target selection: The targets selected by the ADC are all tumor-associated and will be associated with more blood tumors. The criteria for selecting targets are similar to those of other monoclonal antibodies, requiring clear biological mechanisms and unmet medical needs. According to the survey, the seven targets of CD22, CD30, CD33, HER2, Mesothelin, PSMA and TROP2 are currently progressing faster or more popular. The risk of research is relatively small, but there is also a risk of competition in the current gradual liberalization of policies.   (2) Antibody selection: ADC drugs have the following three requirements for the antibody moiety: receptors that are highly expressed (or mutated) to tumor cells; retain their own properties after coupling; minimal non-corresponding target linkages. Antibodies are classified into human antibodies, humanized antibodies, and compatible antibodies. Human antibodies require transgenic mice or phage and are costly to develop. The affinity of the compatible antibody is low, which affects immunogenicity and causes side effects. Relatively speaking, humanized antibodies are more advantageous. In ADCs, antibodies retain their properties as a monoclonal antibody after ligation, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent toxicity, etc., leading to increased toxicity of ADC drugs, enhancedtumor localization accuracy, and tumors of ADCs. The monoclonal antibody developed in the past can be used in the development of ADC. The benefits are that it can reduce the risk of research and development. (3) Antibody modification: For some ADC companies, antibodies are also modified to enhance the effect. The modification techniques of antibodies in ADC are divided into two categories. One is to modify the linkable sites, and the general antibody is modified to THIOMAB to make the number of toxins connected to the ADC product more uniform, which significantly reduces the proportion of defective products in the product. It can solve the core problems in ADC production. The second is glycosylation modification, divided into the following categories. Among them, defucosylation is a very effective new technology with the following characteristics: low density static culture, increased galactosylation, enhanced CDC; enhanced affinity with Fc-gamma-RIIIa, enhanced ADCC; reduced terminal saliva Acidification, enhance ADCC; increase terminal acetylglucosamine and enhance ADCC; treatment of CHO cells with mannosidase inhibitor can increase mannosylation, significantly increase ADCC, and slightly reduce CDC. (4) Antibody endocytosis: Not every target can be endocytosed, and the endocytosis efficiency of each antibody-antigen pairing is different. Part of the target can directly lead to endocytosis of the antibody, and other targets can cause endocytosis by interaction between the antibody and the target by selection of the antibody. There are several types of receptors that can directly cause endocytosis: 1. Absorbing substances. 2. from the cell surface to the nuclear transmission of signals, which in the transmission of signals need to synthesize a special signal complexe hormones. There is also endocytosis efficiency when the antibody is endocytosed, which is a percentage of the extracellular concentration, which determines how many doses will eventually produce an effect. Endocytosis is primarily determined by the target, but antibodies also have some effect. 2.2 Connector section The connector can be roughly divided into two parts, the Linker and the Attachment site. The characteristics of Linker are: (1). degradation or non-degradation; (2). In addition to releasing the drug under certain conditions, it is usually stable in nature. The linkage is characterized by the fact that a cysteine ​​residue or a lysine residue is attached to the antibody with a different DAR-to-antibody linkage position. (1) Connector selection: The linker will greatly affect the pharmacokinetics, therapeutic index and efficacy of ADC drugs. The idealized linker should remain stable so that it does not cause off-target toxicity, and can rapidly disintegrate in the cell to efficiently release the poison. The linker is classified as degradable and non-degradable. Degradable linkers are disulfide disulfides, hydrazone and polypeptide peptide; the non-degradable linker is thioether. The antibody in the ADC of the non-degradable linker will degrade to the amino acid in the cell, and the resulting amino acid-linker-toxin will act. The linker in the degradable linker ADC is degraded, releasing toxins, which can cause bystander killing and attack nearby cancer cells. Therefore, the use of degradable linkers requires a higher stability of the ADC when it circulates in the body, but the killing effect is better. The effect is also related to toxins, which are stronger than charged toxins. (2) Connection method and DAR The focus is on the number of toxins attached to the antibody, which determines the homogeneity of the drug. Too high number will lead to pharmacodynamic instability, increased drug metabolism, decreased half-life, and increased systemic toxicity. The DAR is determined by the connection method. DAR is affected by many factors. Glutathione ligation is currently the most commonly used ligation method. Linking the linker-toxin to the disulfide bond of the antibody is broken, and the amount of ligation on each antibody can be well controlled. Deletion of the disulfide bond reduces the stability of the antibody, while the cysteine ​​linkage uses unstable linkage methods, resulting in less stability than lysine. 2.3 Toxin part Toxins are generally required to be sufficiently toxic to achieve IC50 <1 nmol alone. However, the new ADC drug IMMU-132, which is currently being developed, uses SN-38 toxin, which is less toxic and has the advantage of being able to fully antibody. The downside is that too much toxin linkage can lead to further weakening of stability. Other requirements for ADCs for linked toxins include: adequate water solubility and stability in serum, as ADCs may circulate in the body for several days; there must be functional groups that can be used to couple with Linker; enzymatic degradation of lysosomes must be performed The reaction is insensitive; reduces the polymerization effect and alters the interaction of ADC with pGp, which is the major cause of multi-directional drug resistance (MDR) in tumor cells. 2.4 Core Patent - Sorting of Linkers and Toxins The antibody type (macromolecule part) of the ADC drug is infinite, and the type of linker, the way of connection, and the type of toxin (small molecule part) are limited. . Targeted drugs are the most advanced and mature in current anticancer therapies, and other traditional therapies (including chemotherapy, radiotherapy) and physiotherapy cannot challenge the status of targeted therapies. At present, the most mature and effective targeted therapy is the following: the monoclonal antibody; the fusion protein; diabody; the immunological examination inhibitor; the small molecule targeted drug, such as the fenidine drug; Antibody-conjugated protein toxin; antibody-conjugated radionuclide. At present, most ADC corporation focus on biomacromolecules, chemical small molecule drugs, transmembrane peptide drugs, and innovative R&D companies in the fields of gene therapy and cell therapy. They are committed to helping entrepreneurial teams achieve industrialization and capital. Power to promote the development of the medical and health industry for the benefit of patients worldwide.

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