Clinical Application of Therapeutic Antibodies - Essay Example

Clinical application of therapeutic antibodies Name Institution Date An antibody (Ab), which is also referred to as immunoglobulin (Ig), is a huge protein that is Y-shaped generated by B-cells (Dimitrov, 2009). The immune system uses an antibody to recognize and neutralize objects that are foreign in the body like viruses and bacteria. The antibody identifies a distinctive section of the unfamiliar target, known as an antigen. Every antibody’s “Y” tip has a paratope (a lock-like structure) that is particular for one specific epitope (a key-like structure) on top of an antigen, enabling these 2 structures to attach to one another with exactness (Dimitrov, 2009). Through this attachment mechanism, a microbe can be tagged by an antibody or the antibody can tag a cell that is infected for attack using other immune system’s parts, or its target can be neutralized immediately (for instance, through blocking an element of a microbe which is important for its survival and invasion). Humoral immune system’s main function is to produce antibodies (Dimitrov, 2009). This paper will discuss the various clinical applications of therapeutic antibodies. Basic types of antibodies and a brief summary of polyclonal antibodies and monoclonal antibodies The 5 basic types of immunoglobulins or antibodies are IgG, IgA, IgD, IgE and IgM. These are differentiated by the kind of heavy chian that is located within the molecule. Gamma-chains which are the heavy chains are found in IgG molecules; mu-chains are found in IgMs; alpha-chains are found in IgAs; epsilon-chains are in IgEs; and IgDs contain the delta-chains. Differentiations in polypeptides which are heavy chain enable these antibodies to operate in different kinds of immune reactions and at specific phases of the immune reaction. Basically, Fc fragment has the polypeptide protein chains that are responsible for these differentiations. Although there are 5 different kinds of heavy chains, only 2 major kinds of light chains have been known: lambda (λ) and kappa (κ) (Dimitrov, 2009). Classes of antibody vary in valency due to diverse numbers of units (monomers) that are Y-like that merge to create the whole protein. For instance, in humans, operating IgM antibodies generally have 5 units that are Y-shaped (pentamer) having a sum of 10 light chains, 10 antigen-binding regions and 10 heavy chains (Dimitrov, 2009). IgG immunoglobulin IgG, which is a monomer is actually the leading class of Ig present within human serum (Geisberger et al, 2006). Generated as a component of secondary immune reaction to antigens, IgG makes up almost 75 percent of the whole serum Ig. Of the Ig class, IgG is actually the only one that is able to traverse the human placenta, and its greatest responsibility is to protect the newborn in the course of the initial months of the newborn’s life (Geisberger et al, 2006). Due to its virtual abundance and as well as outstanding specificity to antigens, this Ig is the chief antibody used within clinical diagnostics and immunological research. IgG’s properties as outlined by (Geisberger et al, 2006) include: Molecular weight (MW) of 150,000 H-chain class (MW): gamma (53,000) Concentration of serum: 10-16mg/mL Total immunoglobulin percentage: 75% Glycosylation in terms of weight: 3% Distribution: extra- and intravascular Function: secondary reaction (Geisberger et al, 2006) IgM immunoglobulins In mammals, serum IgM presents as pentamer. It prevails in primary immune reactions to various antigens and is actually the most competent immunoglobulin that is complement fixing and makes up nearly 10 percent of typical human serum immunoglobulin content (Subramanian, 2004). Additionally, IgM is expressed as a monomer on the B lymphocytes’ plasma membrane. IgM is the antigen receptor of B cell and the every H chain contains an extra hydrophobic area for anchoring within the membrane. IgM’s monomers are attached together through disulfide bonds as well as a joining (J) chain. Every of the 5 monomers has made up of 2 light chains (lambda or kappa) and 2 heavy chains (Subramanian, 2004). Not similar to IgG, the IgM monomers’ heavy chain is made up of 1 variable and 4 constant region, the extra constant domain substituting the hinge region. Cell agglutination can be caused by IgM due to epitopes’ recognition on attacking microorganisms (Dimitrov, 2009). This immune complex of antibody-antigen is then demolished through complement fixation or endocytosis that is receptor mediated by macrophages. Basically, IgM is the primary class of immunoglobulin that the neonate produces and has a function in a number of autoimmune diseases’ pathogenesis (Dimitrov, 2009). IgM’s properties as outlined by (Subramanian, 2004) include: Molecular weight of 900,000 H-chain class: mu (65,000) Concentration of serum: 0.5-2mg/mL Percent of whole Ig: 10 percent Glycosylation: 12 percent Distribution: principally intravascular Function: primary reaction IgA immunoglobulins IgA presents in both dimeric and monomeric forms in serum, comprising nearly 15 percent of the whole serum immunoglobulin (Subramanian, 2004). Secretory IgA, which is a dimmer, offers the primary mechanism of defense against a number of local infections due to its large quantity within mucosal secretions (like tears and saliva). The leading role of secretory IgA might not be destruction of antigen but prevention of foreign substances’ passage into the system of circulation (Subramanian, 2004). IgA’s properties (Subramanian, 2004) include: MW: 320,000 (mainly secretory) H-chain class (MW): α (55,000) Concentration of serum: 1-4mg/mL Total immunoglobulin percentage: 15 percent Glycosylation: 10 percent Distribution: secretions and intravascular Function: mucus membranes’ protection IgE and IgD immunoglobulins Both IgE and IgD are found within serum in minute quantities compared to other Igs. IgD membrane is an antigen’s receptor found predominantly on established B-lymphocytes (Geisberger et al, 2006). Primarily, IgE defends against invasion of parasites and is also responsible for allergic responses. IgD’s properties as outlined by (Geisberger et al, 2006) include: MW: 180,000 H-chain class (MW): δ (70,000) Concentration of serum: 0-0.4 mg/mL Total immunoglobulin percentage: 0.2 percent Glycosylation: 13 percent Distribution: surface of lymphocyte Function: not known (Geisberger et al, 2006) IgE’s properties MW: 200,000 H-chain class: epsilon (73,000) Concentration of serum: 10-400ng/mL Total immunoglobulin percentage: 0.002 percent Glycosylation: 12 percent Distribution: mast cells and basophils in nasal and saliva secretions Function: protection against parasites Monoclonal and polyclonal antibodies Antibodies (whatever their subclass or class) are manufactured and purified in 2 basic forms for application as immunoassays’ reagents: monoclonal and polyclonal (Beck et al, 2010). Basically, the immunological reaction towards an antigen is heterogeneous, leading to various diverse B-lymphocytes’ cells lines (plasma cells’ precursors) generating antibodies towards the same antigen (Beck et al, 2010). Each of these cells come from regular stem cells, nonetheless, every one develops its own ability to create an antibody which identifies a specific determinant (epitope) lying on the similar antigen (Dimitrov, 2009). As a result of this response that is heterogeneous, serum from immunized animals will have several antibody clones that are antigen-specific, potentially of numerous different classes as well as subclasses of immunoglobulin making up generally two to five percent of the whole immunoglobulin (Dimitrov, 2009). Since it comprises this heterogeneous set of immunoglobulins that are antigen-binding, a purified antibody from samples like this are called polyclonal antibody. Basically purified straight from serum, polyclonal antibodies are particularly valuable in immunoassays as branded secondary antibodies (Dimitrov, 2009). Since a single B-lymphocyte generates and secretes just one detailed antibody molecule, B-lymphocytes’ clones generate monoclonal antibodies (Dimitrov, 2009). Every antibody that a B-cell clone produces is identical to one another, offering a basis of homogeneous antibody with a definite defined specificity. On the other hand, while B-lymphocytes are able to be separated from suspensions of lymph node or spleen cells removed from animals that are immunized, their life span is limited and is not able to be directly cultured to generate antibody in valuable amounts (Beck et al, 2010). Luckily, this limitation has been conquered with hybridoma technology’s development, in which B-lymphocytes that are isolated in suspension are combined with myeloma cells coming from same species in order to create hybrid cell species that are monoclonal that are practically immortal at the same time as maintaining their antibody generating capacities (Beck et al, 2010). Such hybridomas might be kept frozen then cultured as required to generate the particular monoclonal antibody (Zhang et al, 2011). Specifically, monoclonal antibodies are particularly functional as fundamental antibodies in uses that need distinct epitope specificity as well as an unchanging delivery over several years of application (Zhang et al, 2011). Hybridoma clones might be grown within culture cells for antibodies’ collection from ascites fluid. Hybridomas offer cell line that is immortal with the capacity to generate limitless amounts of antibodies that are highly specific (Zhang et al, 2011). Monoclonal antibodies’ high specificity reduces cross-reactivity and background noise, helps offer reproducible outcomes and guarantees efficiency in purification of affinity (Zhang et al, 2011). How antibodies carry out their functional role B cells that are activated separate into either cells that are antibody-producing known as plasma cells, which secrete memory cells or soluble antibody that survive within the human body for some years later so as to enable the system of immunity to recall an antigen and do a faster response upon future contacts (Dimitrov, 2009). During the stages of pre- and neonatal of life, antibodies’ presence is provided through immunization that is passive from mothers (Dimitrov, 2009). Early productions of endogenous antibodies vary for various types of antibodies, and normally are seen during the initial years of one’s life. Because antibodies freely exist within the bloodstream, it is right to say that they are component of the humoral system of immunity (Dimitrov, 2009). Circulating antibodies are generally generated by clonal B cells which particularly react to just one antigen (for example the fragment of the virus capsid protein) (Dimitrov, 2009). The contribution of antibodies to immunity is done in 3 ways: prevention of entrance of pathogens or damaging cells through attachment; they stimulate pathogens’ removal by macrophages as well as other cells through pathogen coating; and they activate pathogens’ destruction through stimulation of other responses of immunity like the complement pathway (Dimitrov, 2009). The properties, target and uses of monoclonal antibody Antibodies that are monoclonal are generated through cell fusion mechanism, whereby murine spleen cells of immunity are combined with a murine myeloma in order to generate large amounts of specific antibodies that are homogeneous (Dimitrov, 2009). Monoclonal antibody therapy uses mAb (monoclonal antibodies) to distinctively attach to target proteins or cells (Beck et al, 2010). This might then trigger the immune system of the patient to attack the targeted cells. Creating a mAb particular to nearly any cell/extracellular surface target is possible, and hence there is abundance of development as well as research presently being carried out to produce monoclonals for various serious diseases like Alzheimer’s disease, multiple sclerosis, rheumatoid arthritis and diverse kinds of cancers (Zhang et al, 2011). Various ways are presented in which mAbs are able to be applied for therapy. For instance: mAb therapy is able to be used for destruction of tumor cells that are malignant and prevention of tumor growth through blockage of cell receptors that are specific (Beck et al, 2010). Monoclonal antibodies have actually been produced and approved for treatment of cardiovascular disease, cancer, viral infection, inflammatory diseases, transplant rejection, macular degeneration, and multiple sclerosis (Beck et al, 2010). Monoclonal antibodies that are anti-cancer can be under attack against cells that are malignant through various mechanisms: for instance radioimmunotherapy (RIT) entails the application of murine antibodies that are radioactively conjugated against cellular antigens (Zhang et al, 2011). A lot of research presently involved their use to lymphomas, because these are malignancies that are highly radioactive (Zhang et al, 2011). To restrict exposure of radiation, there was specific selection of murine antibodies, since their immunogenicity that is high promotes quick clearance from human body. One of the examples used for management of non-Hodgkins lymphoma is Tositumomab (Beck et al, 2010). Monoclonal antibodies that are used for diseases that are autoimmune entail adalimumab and infliximab, which are useful in ulcerative Colitis, Crohn’s disease and rheumatoid arthritis through their capacity to attach to and hold back TNF-α (Beck et al, 2010). Daclizumab and basiliximab slow down IL-2 on T cells that are activated and hence facilitate preventing kidney transplants’ acute rejection (Beck et al, 2010). Omalizumab slows down IgE and is helpful in asthma that ranges from moderate to chronic (Beck et al, 2010). In conclusion, this paper has outlined the basic types of antibodies and has also discussed the clinical application of therapeutic antibodies, monoclonal antibodies in particular. Clearly development of therapeutic antibodies has a great deal in clinical application like in the treatment of cancer and autoimmune diseases. Reference Zhang, T., Bourret, J. & Cano, T. (2011). Isolation and characterization of therapeutic antibody charge variants using cation exchange displacement chromatography. J Chromatogr A, 1218(31),5079–86. Beck, A., Wurch,T., Bailly, C. & Corvaia, N. (2010). Strategies and challenges for the next generation of therapeutic antibodies. Nat. Rev. Immunol, 10(5), 345–52. Geisberger, R., Lamers, M. & Achatz, G. (2006). The riddle of the dual expression of IgM and IgD, Immunology 118(4), 889–898. Dimitrov, A. S. (2009). Therapeutic antibodies: Methods and protocols. New York, NY: Humana. Subramanian, G. (2004). Antibodies. New York: Kluwer Academic/Plenum Publishers. Read More