Function of CD20
The protein has no known natural ligand[2] and its function is unclear. It is suspected that it acts as a calcium channel in the cell membran
Tags: Clusters of differentiation, Proteins
The antibody binds to the cluster of differentiation 20 (CD20). CD20 is widely expressed on B-cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells. The exact mode of action of rituximab is unclear, but the following effects have been found:[8] The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Rituximab has a general regulatory
Ofatumumab (HuMax-CD20) is a human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is under development for treatment of certain B-cell cancers as well as rheumatoid arthritis (RA).
The efficacy and success of Rituximab has led to a few other anti CD20 monoclonal antibodies being developed: ocrelizumab, humanized (90%-95% human) B-cell depleting agent. ofatumumab (HuMax-CD20) a fully-human B-cell depleting agent.[14] Third-generation anti-CD20s have a glycoengineered Fc fragment (Fc)[15] with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity).[16] Modifications in the variable regions (variable regions)[17] can enhance apoptosis. DXL625 (CD20) is a pre-clinical stage antibody currently being developed by InNexus Biotechnology Inc. for the prospective treatment of non-Hodgkin's lymphoma. The value of a humanized molecule in oncology has not been demonstrated to this date. Another approach to B lymphocyte
CD20 is expressed on all stages of B cell development except the first and last; it is present from pre-pre B cells through memory cells, but not on either pro-B cells or plasma cells.[3] It is found on B-cell lymphomas, hairy cell leukemia, and B-cell chronic lymphocytic leukemia. It is also found on skin/melanoma cancer stem cells.
CD20 is a non-glycosylated phosphoprotein expressed on the surface of all mature B-cells. Membrane-spanning 4-domains, subfamily A, member 1, also known as MS4A1, is a human gene.[1] This gene encodes 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 nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing
Atacicept is a recombinant fusion protein built with the extracellular ligand binding portion of TACI. It blocks activation of TACI by April and BLyS. It is being developed by Zymogenetics and Serono/Merck KgaA. Early stage trials are ongoing in B cell malignancies (Multiple Myeloma), Systemic Lupus Erythematosus and Rheumatoid arthritis.[3] BR3-Fc is a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R. It blocks activation of this receptor by BLys. It is in early stage development by Biogen and Genentech.[3] Anti-CD20 monoclonals: Rituximab is approved. Ocrelizumab, Ofatumumab and 3rd generation anti CD20 monoclonals are being developed.[3]
Ocrelizumab is a humanized anti CD20 monoclonal antibody. It targets mature B lymphocytes. As of May 2007 it is in clinical trials (phase III) for rheumatoid arthritis, multiple sclerosis and lupus erythematosus.[1]
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20. Rituximab is used in the treatment of B cell non-Hodgkin's lymphoma, B-cell leukemias, and some autoimmune disorders.
BLyS (also known as BAFF) plays a key role in B lymphocyte differentiation, survival and activation.[1] Three membrane receptors are concerned: BCMA (B cell maturation antigen) TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor) BAFF-R (also known as BR3) These receptors are not present in early B cell precursors or in pre-B cells (stage at which CD20 receptors appear). They are present in primary mature B cells and in mature B cells (in this last stage, CD20 receptors have disappeared). BLyS is secreted, sometimes under the influence of interferon-gamma, by a variety of cells: monocytes and macrophages, bone marrow stromal cells, astrocytes, synoviocytes
It is the target of the monoclonal antibodies rituximab, Ibritumomab tiuxetan, and tositumomab, which are all active agents in the treatment of all B cell lymphomas and leukemias. Additional antibody therapeutics under development (phase II or III clinical trials) include AME-133v (Applied Molecular Evolution), Ocrelizumab (Roche), Ofatumumab (Genmab), TRU-015 (Trubion) and IMMU-106 (Immunomedics).[5] FMC7 appears to be a conformational variant.[
Belimumab is a monoclonal antibody that binds to BlyS. It is possible that belimumab binds essentially to circulating soluble BlyS, therefore not inducing an antibody-dependent cellular cytotoxicity that could be expected from a IgG1-type antibody. Nevertheless, it does reduce the number of circulating B cells, but seemingly less, and for less time, than anti-CD20 monoclonals (this impression was given at the June 2007 European League against Rheumatism symposium). Only comparative trials will clarify this impression.
Treatment with Zevalin showed higher response rates in clinical trials compared to treatment with only Rituxan (similar to Zevalin, but without the attached radioisotope), and showed very promising results for patients who no longer respond to Rituxan. In patients With Relapsed or Refractory Low-Grade, Follicular, or Transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the OR was 80% / 50% and CR was 34% / 20%, comparing Zevalin to Rituxan. [6] However, in a Phase II study on Zevalin with the more aggressive mantle cell lymphoma, the OR was only 42% and CR was 26%[7].
The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors), allowing radiation from the attached isotope (mostly beta emission) to kill it and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
The main function of crystallins at least in the lens of the eye is probably to increase the refractive index while not obstructing light. However, this is not their only function. It is becoming increasingly clear that crystallins may have a several metabolic and regulatory functions, both within the lens and in other parts of the body [5].
Status of clinical trials conducted by Genmab and GSK, as of late 2007. Chronic lymphocytic leukemia – Phase III relapsed follicular non-Hodgkin’s lymphoma (NHL) – Phase III Rheumatoid arthritis (RA): Phase II – NCT00291928 – HuMax-CD20 in patients adult RA patients who have failed one or more DMARDs Phase III – OFA110635/GEN410 – Ofatumumab in adult RA patients who have had an inadequate response to methotrexate Phase III – OFA110634/GEN411 – Ofatumumab in adult RA patients who have had an inadequate response to TNF-alpha antagonist therapy Diffuse large B cell lymphoma (DLBCL) – Phase II