Traditional Monoclonal Antibodies and Recombinant Antibodies

Traditional Monoclonal Antibodies and Recombinant Antibodies Introduction: Antibody is a special molecule that present in our bodies to fight against infections and stimulate immune response. Typical antibody is a Y shaped molecule consists of two H (heavy) and two (light) chains. Two antigen-binding fragments (Fabs) are linked with a constant region (Fc)(Brekke and Sandlie 2003). After the discovery of murine monoclonal antibodies produced by hybridoma cells developed by Kohlor and Milstein(Kohler and Milstein 1975), the role of monoclonal antibodies in therapeutics and clinical diagnostics are increasingly important in the last three decades (Laffly and Sodoyer 2005). The term monoclonal antibody is defined as an antibody molecule which is monospecific and derived from a single B cell clone. Results in using fully murine monoclonal antibodies in therapeutics are not ideal and problems aroused in triggering unwanted human immune responses. These problems force the generation of recombinant antibodies in the replacement of traditional monoclonal antibodies. Tailor-made recombinant antibodies fragments increase flexibility both in immunotherapy and immunodiagnostics. The application of minimal form of functional antibodies single-chain antibodies (scFvs) are the most popular form of recombinant antibodies fragments as diagnostic agents (Hagemeyer et al. 2009). In this assignment, the comparison between traditional monoclonal antibodies and recombinant antibodies as therapeutics agents and diagnostics tools will be discussed. From the example of tragedy TGN 1412, the potential risk of using recombinant antibodies in therapeutic agents should not be ignored. Finally, future perspective of recombinant antibodies in gene therapy and using polyclonal antibodies as novel immunotherapeutic strategy will be discussed. Theoretically, probably any kind of monoclonal antibodies can be produced with the aid of hybridoma technique. The continuous culture of hybridoma cells creates an inexhaustible supply of monoclonal antibodies in the laboratories by cell culture or rodent(Nelson, Reynolds et al. 2000). Its highly specificity, stability and homogeneity are ideal for diagnostics and in therapeutic purposes. After the introduction of the first FDA approved drugs OKT3 launched into the market in 1986, the results of using fully murine monoclonal antibodies in human was not promising (Chatenoud, Baudrihaye et al. 1986; Chatenoud, Jonker et al. 1986). This is because murine originated monoclonal antibodies triggered several immunogenic responses in human body. One of the problems arise is human anti-mouse antibodies (HAMA) or anti-globulin antibodies (HAGA) response (DeNardo, Bradt et al. 2003; Presta 2006) generated against the administrated murine antibodies. Studies showed that around 30-75% of patients with solid tumors and relapsed B-cell malignancies developed HAMA response after exposure to murine antibodies (Smith, Nelson et al. 2004; Majidi, Barar et al. 2009). The activation of HAMA response is mainly due to the host antibodies generated against the idiotopes of the administered murine antibodies. Moreover, rapid clearance of murine Abs shortens its serum half-life and relatively ineffective to trigger cytotoxic effect (e.g. ADCC and CDC) compared to human antibodies hindered murine Abs as therapeutics agents (Presta 2006). Based on the above unresolved problems, with the aid of genetic engineering, murine monoclonal antibodies are modified to become less immunogenic and enhance potency in therapeutics and diagnostics. Three different types of recombinant antibodies are generated: chimeric, humanized and human antibody. In chimerization, the murine variable region is fused with the human constant region forming chimeric antibodies(Presta 2006). This modification imitates the human immune system. Although chimeric antibodies is less immunogenic but may trigger human anti-chimeric antibody responses (HACA)(Baert, Noman et al. 2003). Further maturation technique is humanization (hyperchimeric). In this technique, only the complementarity determining regions (CDRs) from the murine antibody was grafted into a human constant and variable regions (Smith, Nelson et al. 2004). By resurfacing, reshaping and hyperchimerisation of hyperchimeric antibody, the antibody binding affinity improved. Although the above me thods minimize immunogenicity, but immune response result of xenografting may occur. Finally, human antibodies can be generated by transgenic mice and in vitro combinatorial libraries (Brekke and Loset 2003; Brekke and Sandlie 2003; Presta 2006). Antibodies which generated under this method are expected to be identical to human antibodies with clinical significant without any side effects. One of the examples in combinatorial library approach for the selection of antibodies is by phage display technology in which antibody variables domain are expressed as fusion protein as coated on the surface of the bacteriophages. Under combinatorial library approaches and transgenic mice, the chance of getting fully human antibodies are higher when compared to hybridoma and chimeric antibody technologies. In addition, single-chain variable fragment (scFv) and Fab fragment can be isolated (Brekke and Loset 2003; Brekke and Sandlie 2003). Therapeutics application Fc portion in an intact antibody trigger effector function which is undesirable for therapeutic applications. Therefore, for a desirable antibodies design for cytokine inactivation or receptor blockage, the main considerations of antibody design are: size, tissue penetration, distribution, half-life, effector function, affinity, stability and immunogenicity. scFv and Fab fragments are preferred as choice of preference when compared to traditional antibodies because of smallest in size, high binding affinity, specificity, good tissue penetration and reducing immunogenicity due to HAMA response. scFv and Fab antibodies have a shorter half-life than whole antibodies and this drawback can be overcome by PEGylation. In addition, the attachment of PEGylation of murine monoclonal antibody reduces HAMA response of the host after administration(Laffly and Sodoyer 2005). Applications of monoclonal antibodies are vastly employed in therapeutic agents (e.g. treatment of cancer) and in clinical diagnostic (e.g. histopathological diagnosis). Humanized mAbs (transgenic mice) (resurfacing, reshaping and hyperchimerisation, etc) Phage display technology (Fabs and Fvs) In recent years MAbs have become very important commercial reagents, and currently contribute to over 30% of biopharmaceuticals in development and production. To date, 10 different MAbs have achieved FDA approval, with others in phase III trials.4 Applications Antibody conjugates (Majidi, Barar et al. 2009) Unconjugated mAbs (Majidi, Barar et al. 2009) rAbs for cancer therapy immunohistology genetic immunotherapy(Pelegrin, Gros et al. 2004) scFv for diagnostics tools (size, immunosensor, inhibition of imnflammation and complement system) (Hagemeyer, von Zur Muhlen et al. 2009) Problems polyclonal vs monoclonal therapeutics (Haurum 2006) TGN1412 incident (Self and Thompson 2006) References: Baert, F., M. Noman, et al. (2003). Influence of immunogenicity on the long-term efficacy of infliximab in Crohns disease. N Engl J Med 348(7): 601-608. Brekke, O. H. and G. A. Loset (2003). New technologies in therapeutic antibody development. Curr Opin Pharmacol 3(5): 544-550. Brekke, O. H. and I. Sandlie (2003). Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov 2(1): 52-62. Chatenoud, L., M. F. Baudrihaye, et al. (1986). Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J Immunol 137(3): 830-838. Chatenoud, L., M. Jonker, et al. (1986). The human immune response to the OKT3 monoclonal antibody is oligoclonal. Science 232(4756): 1406-1408. DeNardo, G. L., B. M. Bradt, et al. (2003). Human antiglobulin response to foreign antibodies: therapeutic benefit? Cancer Immunol Immunother 52(5): 309-316. Hagemeyer, C. E., C. von Zur Muhlen, et al. (2009). Single-chain antibodies as diagnostic tools and therapeutic agents. Thromb Haemost 101(6): 1012-1019. Haurum, J. S. (2006). Recombinant polyclonal antibodies: the next generation of antibody therapeutics? Drug Discov Today 11(13-14): 655-660. Kohler, G. and C. Milstein (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517): 495-497. Laffly, E. and R. Sodoyer (2005). Monoclonal and recombinant antibodies, 30 years after. Hum Antibodies 14(1-2): 33-55. Majidi, J., J. Barar, et al. (2009). Target therapy of cancer: implementation of monoclonal antibodies and nanobodies. Hum Antibodies 18(3): 81-100. Nelson, P. N., G. M. Reynolds, et al. (2000). Monoclonal antibodies. Mol Pathol 53(3): 111-117. Pelegrin, M., L. Gros, et al. (2004). Monoclonal antibody-based genetic immunotherapy. Curr Gene Ther 4(3): 347-356. Presta, L. G. (2006). Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 58(5-6): 640-656. Self, C. H. and S. Thompson (2006). How specific are therapeutic monoclonal antibodies? Lancet 367(9516): 1038-1039. Smith, K. A., P. N. Nelson, et al. (2004). Demystifiedrecombinant antibodies. J Clin Pathol 57(9): 912-917.

History of Australian Cattle Dogs :: essays papers

History of Australian Cattle Dogs The Australian Cattle Dog was originally born in Australia. It was bred to help outback ranchers round up their cattle and to withstand the harsh outback conditions. The breed is loyal and devoted to its owner. The joy of owning an Australian Cattle Dog directly relates to the breed origin, why it was bred, the general appearance, its unique traits, simple diet and easy health care. According to Katherine Buetow in â€Å" The History of the Australian Cattle Dog† she states, â€Å"There is continuing controversy over which breeds were actually used in its development. One of the difficulties in researching the history of this breed is that there was a lot of experimentation going on in trying to find the perfect combination of dogs to make up the ultimate heeler that could live and work in the Australian outback †( 1). The Australian Cattle Dog was thoughtfully blended with several different dogs including the dingo, which is native to Australia, to heard cattle for ranchers on the Australian outback. Originally, ranchers let their cattle roam the outback for months or even years to fatten up before rounding them up and taking them to the market for sell. Since this round up could consist of hundreds of miles, they needed a dog that could go with them and survive the round up. This is when the Australian Cattle Dog was born (Sunset 1). The â€Å"Australian Cattle Dog† describes the breed as a unique blend of five different dogs. The breeds are the smooth-coated collie, Dalmatian, kelpie, dingo, and the bull terrier. This diversified blend that makes up the Australian Cattle Dog was obtained by many years of trial and error. There are the blue and red varieties called the Heeler or the Queensland Heeler. The heeler breed is designed to work with cattle, sheep, hogs, and fowl (Beauchamp 10). The trainability of the Australian Cattle Dog is a reflection of its intelligence and strong desire to please their owner. The breed can be taught to work without their owner’s supervision. They can also evaluate and solve complex situations on their own. The Australian Cattle Dog owner knows the breed for its incredible stamina, intelligence, and loyalty. This is why the Australian Cattle Dog naturally takes upon itself to be not only a protector but also a companion (Beauchamp 30). History of Australian Cattle Dogs :: essays papers History of Australian Cattle Dogs The Australian Cattle Dog was originally born in Australia. It was bred to help outback ranchers round up their cattle and to withstand the harsh outback conditions. The breed is loyal and devoted to its owner. The joy of owning an Australian Cattle Dog directly relates to the breed origin, why it was bred, the general appearance, its unique traits, simple diet and easy health care. According to Katherine Buetow in â€Å" The History of the Australian Cattle Dog† she states, â€Å"There is continuing controversy over which breeds were actually used in its development. One of the difficulties in researching the history of this breed is that there was a lot of experimentation going on in trying to find the perfect combination of dogs to make up the ultimate heeler that could live and work in the Australian outback †( 1). The Australian Cattle Dog was thoughtfully blended with several different dogs including the dingo, which is native to Australia, to heard cattle for ranchers on the Australian outback. Originally, ranchers let their cattle roam the outback for months or even years to fatten up before rounding them up and taking them to the market for sell. Since this round up could consist of hundreds of miles, they needed a dog that could go with them and survive the round up. This is when the Australian Cattle Dog was born (Sunset 1). The â€Å"Australian Cattle Dog† describes the breed as a unique blend of five different dogs. The breeds are the smooth-coated collie, Dalmatian, kelpie, dingo, and the bull terrier. This diversified blend that makes up the Australian Cattle Dog was obtained by many years of trial and error. There are the blue and red varieties called the Heeler or the Queensland Heeler. The heeler breed is designed to work with cattle, sheep, hogs, and fowl (Beauchamp 10). The trainability of the Australian Cattle Dog is a reflection of its intelligence and strong desire to please their owner. The breed can be taught to work without their owner’s supervision. They can also evaluate and solve complex situations on their own. The Australian Cattle Dog owner knows the breed for its incredible stamina, intelligence, and loyalty. This is why the Australian Cattle Dog naturally takes upon itself to be not only a protector but also a companion (Beauchamp 30).

Pygmalion effect Essay

Would you go under the knife to enhance your career opportunities? Why or why not?   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   If financial resources are not an issue, it would be best to consider cosmetic surgery if doing it would make a people feel more confident about themselves. While the idea of obtaining skills and looking good can uplift chances for career advancement, physical appearance has become a primary source of confidence for everyone. Hirsch (1988) indicated that cosmetic surgery, good dental care, hair transplants, and anti-wrinkle drugs have been ways not only to improve social lives, but also to enhance career opportunities. Most people now view that the price of cosmetic surgery has become reasonable to think that the results would increase their self confidence and marketability at work. In a survey conducted by the American Academy of Facial and Plastic Reconstructive Surgery (AAFPRS), they indicated that 43 percent of cosmetic surgeons said most male patients were undergoing procedures for career reasons. Actually men would choose nonsurgical procedures often like fat injections, Botox injections and microdermabrasion than surgical procedures because these permit them to return to work very quickly. In an interview, cosmetic Surgeon William Silver said that 10 percent of his male patients tell him they â€Å"want cosmetic surgery to ensure they aren’t overlooked when it comes time for a promotion† (Palmquist, 2004). Some researchers also revealed that physical improvements definitely produce greater psychological and emotional benefits, which would help a person enhance his or her career path. More research claim that doors are more open to really good-looking people (Crampton and Jitendra, 1995). This is why there is no harm in availing cosmetic surgery to look good and feel confident when it means it will make you a happier and more productive individual that would translate to greater chances to notch better opportunities at work. What negative stereotypes are fueling the use of cosmetic surgery to change ones appearance? It is said that stereotypes can often lead to poor decisions, can create barriers for people like women, older individuals, people of color, and people with disabilities, and can undermine loyalty and job satisfaction (Kreitner and Kinicki, 2004). In case of using cosmetic surgery to change appearance, the negative stereotype working is that the concept of better looking people are better workers than plain looking people. This concept of being biased to appearance can apply to age discrimination too, where younger people tend to ignore or put down ideas provided by older people because they think it’s not applicable anymore or â€Å"old school†.   This is why most aging workers would choose to go under the knife because they do not want to appear older and keep up with the younger competition. To what extent does the Pygmalion effect, Galatea effect, and Golem effect play a role in this case? Explain   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In Greek mythology, Pygmalion fell in love with the statue he made that he prayed to Aphrodite to make this statue a real person. Aphrodite heeded the request of Pygmalion and the statue became real, in the person of Galatea. The essence of this story in our case is that Pygmalion effect or self-fulfilling prophecy maintained that people’s expectations or beliefs determine their behavior and performance, thus serving to make their expectations come true. In short, people strive to validate our perceptions of reality, no matter how faulty they may be. Thus, the self-fulfilling prophecy is a vital perceptual outcome we need to better understand because it can make or break any employee’s self-concept and achievement (Kreitner and Kinicki, 2004).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The self-fulfilling prophecy can explain the results of how bigger expectations can turn out to benefit the regular workers to obtain their maximum potential. Kreitner and Kinicki (2004) presented a model (Figure 1) that attempted to outline how supervisory expectations affect employee performance. It exhibited that â€Å"high supervisory expectancy produces better leadership (linkage 1), which subsequently leads employees to develop higher self-expectations (linkage 2). Higher expectations motivate workers to exert more effort (linkage 3), ultimately increasing performance (linkage 4) and supervisory expectancies (linkage 5)†. Figure 1. Model of Self-Fulfilling Prophecy (Source: Kreitner and Kinicki, 2004) On the other hand, the term Golem effect represents the negative side of the performance enhancing process. The Golem effect is what you call to a â€Å"loss in performance resulting from low leader expectations†. For example, when a manager sees a tattoo on particular employee and thinks that this employee is a trouble-maker, he or she will be watchful of this characteristic. The employee will soon observe the suspicions of the manager and will soon screw up to validate the ill expectations of the manager. Thus, the Golem effect is the entire opposite of the Pygmalion effect. Based on this case and what you learned in this chapter, do the skills that come with age and experience count for less than appearance in today’s organization? Discuss your rationale. I think that age and experience counts the most than appearance when it comes to knowing the right skills needed in today’s organizations. Although appearance is important, today’s organizations are already frowning upon discriminating people with regards to how they look and their age. It is important that we recognize the fact that everyone has the potential to increase his or her performance, even without undergoing plastic surgery or looking better. It all boils down to how employees feel about themselves, how they respect each other and how satisfied they are in their jobs.   Works Cited Crampton, Suzanne M., and Jitendra M. Mishra. â€Å"Developing and packaging the total corporate image† SAM Advanced Management Journal 60.3 (Summer 1995): 30-40. Hirsch, Jean Edward. â€Å"Vanity prompts more people to risk plastic surgery despite cost†. New York Times (July 14, 1988). Kreitner, Robert and Kinicki, Angelo. Chapter 7: Social Perception and Attributions, Organizational Behavior, 6th ed. NY: The McGraw-Hill Companies, 2004. Palmquist, Susan. â€Å"Handsome ambitions†. Psychology Today 37.4 (July-August 2004): 33.

A Student Board Representative For My School District

Fifteen years ago, I served as the student board representative for my school district. All I can really remember is being entertained by emotional parent complaints and listening to jargon-filled presentations. Upon receiving my first pink slip from that same district seven years later, I spoke at a school board meeting for the first time. Three years later, I was motivated by another pink slip to speak in front of a school board--this time as a teacher for my current school district, San Diego County Office of Education (SDCOE) Juvenile Court and Community Schools (JCCS). Since that first pink slip scare with JCCS, I have been a regular attendee at SDCOE board meetings. I try my best to pay attention and even take notes when JCCS is on the agenda. I have spoken on behalf of my students and coworkers and even helped to introduce my site’s student board representative. 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