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47-591: Sometimes the chimeric anti- CD20 monoclonal antibody, rituximab , is added to this treatment regimen to form the R-CHOP regimen. R-miniCHOP is indicated in elderly patients (>80 years) with diffuse large B-cell lymphoma due to less toxicity from the reduced dose in comparison to R-CHOP. R-Maxi-CHOP is used in mantle cell lymphoma and is given in 21-day intervals, alternating with R-HDAC (rituximab + high-dose cytarabine). In most other non-Hodgkin lymphomas (excluding some aggressive forms), standard-dose [R]-CHOP

94-550: A fever develops in the neutropenic period, urgent medical assessment is required for neutropenic sepsis , as infections in patients with low neutrophil counts may progress rapidly. Allopurinol is typically co-administered prophylactically to prevent hyperuricemia that results from tumor lysis syndrome , the result of rapid death of tumor cells. A pivotal study published in 1993 compared CHOP to several other chemotherapy regimens (e.g. m-BACOD , ProMACE-CytaBOM , MACOP-B ) for advanced non-Hodgkin's lymphoma. CHOP emerged as

141-450: A barrier to zoonotic transmission of viruses. In addition, glycosylation is often used by viruses to shield the underlying viral protein from immune recognition. A significant example is the dense glycan shield of the envelope spike of the human immunodeficiency virus . Overall, glycosylation needs to be understood by the likely evolutionary selection pressures that have shaped it. In one model, diversification can be considered purely as

188-495: A consequence, they are also hard to treat. However, thanks to the many advances that have been made in next-generation sequencing , scientists can now understand better these disorders and have discovered new CDGs. It has been reported that mammalian glycosylation can improve the therapeutic efficacy of biotherapeutics . For example, therapeutic efficacy of recombinant human interferon gamma , expressed in HEK ;293 platform,

235-468: A decreased level, skin elasticity is reduced which is an important symptom of aging. They are also the precursors of many hormones and regulate and modify their receptor mechanisms at the DNA level. There are different enzymes to remove the glycans from the proteins or remove some part of the sugar chain. Notch signalling is a cell signalling pathway whose role is, among many others, to control

282-514: A greater risk of toxicity from the drugs, an option is to use an attenuated drug regimen, called miniCHOP. The combination is generally well tolerated. Chemotherapy-induced nausea and vomiting may require antiemetics (such as ondansetron ), and hemorrhagic cystitis is prevented with administration of mesna . Alopecia (hair loss) is common. Neutropenia generally develops in the second week. During this period, many clinicians recommend pegfilgrastim or prophylactic use of ciprofloxacin . If

329-474: A large randomized controlled trial and preliminary results from a Phase III trial were negative. Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include : A link between the immune system 's B cells and diabetes mellitus has been determined. In cases of obesity , the presence of fatty tissues surrounding the body's major organ systems results in cell necrosis and insulin insensitivity along

376-450: A result of endogenous functionality (such as cell trafficking ). However, it is more likely that diversification is driven by evasion of pathogen infection mechanism (e.g. Helicobacter attachment to terminal saccharide residues) and that diversity within the multicellular organism is then exploited endogenously. Glycosylation can also modulate the thermodynamic and kinetic stability of the proteins. Glycosylation increases diversity in

423-406: A variety of structural and functional roles in membrane and secreted proteins. The majority of proteins synthesized in the rough endoplasmic reticulum undergo glycosylation. Glycosylation is also present in the cytoplasm and nucleus as the O -GlcNAc modification. Aglycosylation is a feature of engineered antibodies to bypass glycosylation. Five classes of glycans are produced: Glycosylation

470-832: Is a 33-37 kDa non-glycosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasma cells . CD20 is used as a therapeutical target of B-cell malignancies and autoimmune diseases. In humans CD20 is encoded by the MS4A1 gene localized to 11q12. The gene is 16 kbp long and consists of 8 exons. There are at least 3 mRNA transcripts (resulting from alternative splicing ), that are all translated into an identical full-length CD20 protein product. Variants 1 and 2 are poorly translated due to inhibitory upstream open reading frames and stem-loop structures within their 5' untranslated regions . The relative abundance of translation-competent variant 3, as opposed to

517-504: Is a special form of glycosylation that features the formation of a GPI anchor . In this kind of glycosylation a protein is attached to a lipid anchor, via a glycan chain. (See also prenylation .) Glycosylation can also be effected using the tools of synthetic organic chemistry . Unlike the biochemical processes, synthetic glycochemistry relies heavily on protecting groups (e.g. the 4,6- O -benzylidene) in order to achieve desired regioselectivity. The other challenge of chemical glycosylation

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564-399: Is a spontaneous reaction and a type of post-translational modification of proteins meaning it alters their structure and biological activity. It is the covalent attachment between the carbonil group of a reducing sugar (mainly glucose and fructose) and the amino acid side chain of the protein. In this process the intervention of an enzyme is not needed. It takes place across and close to

611-439: Is a transmembrane protein consisting of four hydrophobic transmembrane domains, one intracellular domain and two extracellular loops. There are three different forms of CD20 according to variable phosphorylation. CD20 is located on the cell surface as homo-dimeric and homo-tetrameric oligomers. It is associated with other cell-surface and cytoplasmic proteins connected to the signal transduction ( CD53 , CD81 , CD82 ). CD20

658-416: Is added to the first tryptophan residue in the sequence W–X–X–W (W indicates tryptophan; X is any amino acid). A C-C bond is formed between the first carbon of the alpha-mannose and the second carbon of the tryptophan. However, not all the sequences that have this pattern are mannosylated. It has been established that, in fact, only two thirds are and that there is a clear preference for

705-527: Is also known to be physically coupled to major histocompatibility complex class II (MHCII), CD40 and B-cell receptor (BCR). The biological function of CD20 as well as its natural ligand is not fully elucidated. CD20 deletion in mice does not impair B-cell differentiation, isotype switch, maturation, proliferation or tissue localization. However, CD20−/− mice show decreased humoral immunity responses in both T-cell dependent and T-cell independent manner. Functional studies suggest that CD20 molecule

752-487: Is an important parameter in the optimization of many glycoprotein-based drugs such as monoclonal antibodies . Glycosylation also underpins the ABO blood group system. It is the presence or absence of glycosyltransferases which dictates which blood group antigens are presented and hence what antibody specificities are exhibited. This immunological role may well have driven the diversification of glycan heterogeneity and creates

799-458: Is another group of proteins that undergo C -mannosylation, type I cytokine receptors . C -mannosylation is unusual because the sugar is linked to a carbon rather than a reactive atom such as nitrogen or oxygen . In 2011, the first crystal structure of a protein containing this type of glycosylation was determined—that of human complement component 8. Currently it is established that 18% of human proteins , secreted and transmembrane undergo

846-464: Is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor ) in order to form a glycoconjugate . In biology (but not always in chemistry), glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation (also 'non-enzymatic glycation' and 'non-enzymatic glycosylation') may refer to a non-enzymatic reaction. Glycosylation is a form of co-translational and post-translational modification . Glycans serve

893-472: Is generally performed after three cycles to assess whether the disease is responding to treatment. In patients with a history of cardiovascular disease , doxorubicin (which is cardiotoxic ) is often deemed to be too great a risk and is omitted from the regimen. The combination is then referred to as COP (cyclophosphamide, Oncovin, and prednisone or prednisolone) or CVP (cyclophosphamide, vincristine, and prednisone or prednisolone). As elderly patients have

940-580: Is generally used as first-line therapy. Normal cells are more able than cancer cells to repair damage from chemotherapy drugs. This regimen can also be combined with the monoclonal antibody rituximab if the lymphoma is of B cell origin; this combination is called R-CHOP . In 2002, a randomized controlled trial showed a higher complete response rate for R-CHOP vs CHOP in elderly patients with Diffuse Large-B-Cell Lymphoma (76% vs 63%). Typically, courses are administered at an interval of two or three weeks (CHOP-14 and CHOP-21 respectively). A staging CT scan

987-461: Is required for efficient BCR signaling. It possibly acts as a calcium channel (CD20 has structural similarities with some known ion channels ) or is directly connected to calcium flux. It is not fully understood, if other molecular pathways or B and T-cell interactions might be affected by CD20 levels on the B-cell surface. CD20 is expressed on all stages of B cell development from pre-B cells in

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1034-435: Is the process by which a carbohydrate is covalently attached to a target macromolecule , typically proteins and lipids . This modification serves various functions. For instance, some proteins do not fold correctly unless they are glycosylated. In other cases, proteins are not stable unless they contain oligosaccharides linked at the amide nitrogen of certain asparagine residues. The influence of glycosylation on

1081-402: Is the stereoselectivity that each glycosidic linkage has two stereo-outcomes, α/β or cis / trans . Generally, the α- or cis -glycoside is more challenging to synthesis. New methods have been developed based on solvent participation or the formation of bicyclic sulfonium ions as chiral-auxiliary groups. The non-enzymatic glycosylation is also known as glycation or non-enzymatic glycation. It

1128-509: The Golgi apparatus . The Notch proteins go through these organelles in their maturation process and can be subject to different types of glycosylation: N-linked glycosylation and O-linked glycosylation (more specifically: O-linked glucose and O-linked fucose). All of the Notch proteins are modified by an O-fucose, because they share a common trait: O-fucosylation consensus sequences . One of

1175-422: The cell differentiation process in equivalent precursor cells . This means it is crucial in embryonic development, to the point that it has been tested on mice that the removal of glycans in Notch proteins can result in embryonic death or malformations of vital organs like the heart. Some of the specific modulators that control this process are glycosyltransferases located in the endoplasmic reticulum and

1222-505: The metabolic syndrome . Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result, did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin insensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes

1269-456: The proteome , because almost every aspect of glycosylation can be modified, including: There are various mechanisms for glycosylation, although most share several common features: N -linked glycosylation is a very prevalent form of glycosylation and is important for the folding of many eukaryotic glycoproteins and for cell–cell and cell– extracellular matrix attachment. The N -linked glycosylation process occurs in eukaryotes in

1316-411: The body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as an autoimmune disease rather than a purely metabolic one and focus treatment for it on immune system modulation. Glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan '), i.e. a glycosyl donor ,

1363-487: The bone-marrow through immature, naive , mature and memory cells in lymphoid tissues and blood. The expression is lost on plasma blasts and plasma cells . CD20 is a marker of B cell malignancies. It is found on B-cell lymphomas , hairy cell leukemia , B-cell chronic lymphocytic leukemia , and melanoma cancer stem cells . Immunohistochemistry can be used to determine the presence of CD20 on cells in histological tissue sections. Because CD20 remains present on

1410-446: The boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. An inflammation response that mobilizes both T and B cells results in the creation of antibodies against these cells, causing them to become less responsive to insulin by an as-yet-unknown mechanism and promoting hypertension , hypertriglyceridemia , and arteriosclerosis , hallmarks of

1457-454: The brownish color and the aromas and flavors of some foods. It is demonstrated that cooking at high temperature results in various food products having high levels of AGEs. Having elevated levels of AGEs in the body has a direct impact on the development of many diseases. It has a direct implication in diabetes mellitus type 2 that can lead to many complications such as: cataracts , renal failure , heart damage... And, if they are present at

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1504-488: The cells of most B-cell neoplasms , and is absent on otherwise similar appearing T-cell neoplasms, it can be very useful in diagnosing conditions such as B-cell lymphomas and leukaemias. However, the presence or absence of CD20 in such tumours is not relevant to prognosis, with the progression of the disease being much the same in either case. CD20 positive cells are also sometimes found in cases of Hodgkins disease , myeloma , and thymoma . Even though B cells represent

1551-474: The efficacy of the [R]-CHOEP regimen with escalating the chemotherapy doses. This mode was called [R]-High-CHOEP . However, it did not show more effectiveness than standard-dose [R]-CHOEP while adding more toxicity and cost. In order to try improving efficacy of the [R]-CHOEP, some researchers tried to escalate chemotherapy to very high doses, requiring autologous stem cell support in each cycle. Doses in that regimen were increased from cycle to cycle. This regimen

1598-500: The folding and stability of glycoprotein is twofold. Firstly, the highly soluble glycans may have a direct physicochemical stabilisation effect. Secondly, N -linked glycans mediate a critical quality control check point in glycoprotein folding in the endoplasmic reticulum. Glycosylation also plays a role in cell-to-cell adhesion (a mechanism employed by cells of the immune system ) via sugar-binding proteins called lectins , which recognize specific carbohydrate moieties. Glycosylation

1645-638: The literature. Fucose and GlcNAc have been found only in Dictyostelium discoideum , mannose in Leishmania mexicana , and xylose in Trypanosoma cruzi . Mannose has recently been reported in a vertebrate, the mouse, Mus musculus , on the cell-surface laminin receptor alpha dystroglycan . It has been suggested this rare finding may be linked to the fact that alpha dystroglycan is highly conserved from lower vertebrates to mammals. A mannose sugar

1692-529: The lumen of the endoplasmic reticulum and widely in archaea , but very rarely in bacteria . In addition to their function in protein folding and cellular attachment, the N -linked glycans of a protein can modulate a protein's function, in some cases acting as an on/off switch. O -linked glycosylation is a form of glycosylation that occurs in eukaryotes in the Golgi apparatus , but also occurs in archaea and bacteria . Xylose , fucose , mannose , and GlcNAc phosphoserine glycans have been reported in

1739-409: The majority of CD20+ cells, a subset of CD3+ T cells also expresses CD20. CD20+ T cells are mostly CD8+ effector memory T cells with proinflammatory features. Further work is needed to understand the contribution of these cells to immune responses. The targeting of CD20 molecule is highly effective way to deplete B-cell populations. Thus, anti-CD20 monoclonal antibodies (mAbs) play a crucial role in

1786-399: The management of B cell malignancies as well as some inflammatory and autoimmune diseases . The first anti-CD20 mAb approved by FDA in 1997 was Rituximab , defining a new epoch in hematooncology . The advantages of CD20 as a therapeutic target are: Mechanism of action of anti-CD20 effects include: Examples of anti-CD20 mAbs and their approval status: ( FDA/ EMA) CD20 is

1833-683: The modulators that intervene in this process is the Fringe, a glycosyltransferase that modifies the O-fucose to activate or deactivate parts of the signalling, acting as a positive or negative regulator, respectively. There are three types of glycosylation disorders sorted by the type of alterations that are made to the glycosylation process: congenital alterations, acquired alterations and non-enzymatic acquired alterations. All these diseases are difficult to diagnose because they do not only affect one organ, they affect many of them and in different ways. As

1880-478: The poorly translated variants 1 and 2, may be a key determinant of CD20 levels in normal and malignant human B cells and their responses to CD20-directed immunotherapies . MS4A1 gene is a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron / exon splice boundaries and display unique expression patterns among hematopoietic cells and non-lymphoid tissues. CD20

1927-422: The process of C-mannosylation. Numerous studies have shown that this process plays an important role in the secretion of Trombospondin type 1 containing proteins which are retained in the endoplasmic reticulum if they do not undergo C-mannosylation This explains why a type of cytokine receptors , erythropoietin receptor remained in the endoplasmic reticulum if it lacked C-mannosylation sites. Glypiation

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1974-523: The regimen with the least toxicity but similar efficacy. However, in Germany in 2012, bendamustine has displaced [R-]CHOP to become the first line treatment of choice for indolent lymphoma (a less aggressive subset of non-Hodgkin lymphoma). In order to develop more effective first-line chemotherapy regimen for aggressive lymphomas, some researchers tried to add (E) toposide to the standard [R]-CHOP regimen. There were also attempts to further improve

2021-489: The second amino acid to be one of the polar ones (Ser, Ala , Gly and Thr) in order for mannosylation to occur. Recently there has been a breakthrough in the technique of predicting whether or not the sequence will have a mannosylation site that provides an accuracy of 93% opposed to the 67% accuracy if we just consider the WXXW motif. Thrombospondins are one of the proteins most commonly modified in this way. However, there

2068-480: The target of the mAbs rituximab , ocrelizumab , obinutuzumab , ofatumumab , ibritumomab tiuxetan , tositumomab , and ublituximab , which are all active agents in the treatment of all B cell lymphomas , leukemias , and B cell-mediated autoimmune diseases. The anti-CD20 mAB ofatumumab ( Genmab ) was approved by FDA in October 2009 for chronic lymphocytic leukemia . The anti-CD20 mAB obinutuzumab (Gazyva)

2115-692: The water channels and the protruding tubules. At first, the reaction forms temporary molecules which later undergo different reactions ( Amadori rearrangements , Schiff base reactions, Maillard reactions , crosslinkings ...) and form permanent residues known as Advanced Glycation end-products (AGEs). AGEs accumulate in long-lived extracellular proteins such as collagen which is the most glycated and structurally abundant protein, especially in humans. Also, some studies have shown lysine may trigger spontaneous non-enzymatic glycosylation. AGEs are responsible for many things. These molecules play an important role especially in nutrition, they are responsible for

2162-660: Was approved by FDA in November 2013 for chronic lymphocytic leukemia . Ocrelizumab was approved by the FDA in March 2017 for multiple sclerosis as the first treatment of the primary progressive form of MS. Clinical trials in rheumatoid arthritis and systemic lupus erythematosus were discontinued in 2010 due to an infection related safety risk. Although phase II trials for the use of Rituximab in myalgic encephalomyelitis showed promising results, these could not be replicated in

2209-443: Was called [R]-MegaCHOEP. But again, such escalation seemed to not improve effectiveness while adding toxicity. CD20 3PP4 , 2OSL , 3BKY 931 12482 ENSG00000156738 ENSMUSG00000024673 P11836 P19437 NM_152866 NM_021950 NM_152867 NM_007641 NP_068769 NP_690605 NP_690606 NP_031667 B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule. It

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