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Therapeutic Monoclonal Antibodies

Anantha Naik Nagappa, Debarati Mukherjee & Konda AnushaWednesday, September 22, 2004, 08:00 Hrs  [IST]

The discovery of hybridoma technology by Milstein and Kohler in 1975 allowed researchers to isolate specifically defined monoclonal antibodies (MAB). Although their potential in clinical use was immediately felt, it took more than a decade before a therapeutic monoclonal antibody became available in clinics. One of the major limitations was regarding the origin of MAB from mouse and administering to human beings. It acted as a foreign antibody, stimulating an immune reaction, and leading to adversities in therapeutics. Advancements in molecular biology later made it possible to develop human MAB in a way that is acceptable to the human immune systems.

Table 1. Therapeutic antibodies for treatment of cancer

Product Therapeutic application Manufacturer/ Inventor
Campath B-cell lympholytic luekemia Mellinium pharma Inc.
Gemtuzumab Acute myeloid leukemia Cell tech.
Herceptin Matastatic breast cancer Genetech.
Panorex Colorectal cancer Centocor  GSK
Rituximab Non Hodgkin cancer Genetech
Bexxar Non Hodgkin lymphoma Coraxia GSK
Edrecolomab Colorectal cancer Glaxo-wellcome
Alemtuzumab Bull chronic lympholytic leukemia ILEX Pharmaceuticals
Mylotrag Acute myelogeneuos leukemia Wyeth-Ayerst Research
IMC-C225 Head and Neck cancer Imclone systems
Smartin 195 Acute myeloid leukemia  
Mitomomab Melanoma and Small cell lung cancer Imclone systems
Generally, MAB is being used as invaluable reagents in diagnostics. In fact, they have played a major role in deciphering the functions of various bio-molecules in cryptic biosynthetic pathways. These have also become the reagents of choice for identification and characterization of tumor specific antigens and have become a valuable tool in the classification of cancer. Previously, as they were derived from murine sources, they had limited applications in therapeutic reagents. The repeated application to human subjects challenged the human immune system, leading to severe immune reactions. In order to circumvent the immunogenicity of murine antibodies, the development of humanized MAB, initialized with the strategy described below: - * Immortalizing the human bursa derived cells. * Chimeric antibodies comprising human and mice, in which a constant part from human antibodies are coined to a variable part of light and heavy chains from mouse in which 70% of the antibody comprising of human was retained. * Humanized antibodies prepare by getting complementary determining regions of murine antibodies on to a human antibody framework, which has 90% resemblance to humans. * Manipulation of CPR region towards the target antigen by linking the variable light and heavy chain segments to a single chain variable fragment. * Use a transgenic map like HUMAB resulting in hybridomas producing 100X human MAB. * Use trans-chromosomic mice having a part of human chromosome that contained complete germ-line clusters of heavy and light chain.

Table 2. Therapeutic antibodies approved for clinical practice.

ProductTherapeuticapplicationManufacturer
OrthocloneOKT3Kidneytransplant rejectionOrthobiotech
ReoproPreventionof blood clotCentocor
RemicadeRhuetoidarthritisCentocor
ZenapaxPreventionof acute kidney transplantReopro
AbciximabInhibitionof platelet functionReopro
Traditionally, MAB have been produced as native molecules in murine hybridoma lines. However, there has been considerable interest in development of recombinant DNA expression of MAB. This would allow the production of humanized antibodies as well as spectrum of antibody derivatives and fusion proteins in a host species of choice. More recently, the production of antibodies in the milk (or other body fluids of transgenic animals and chicken eggs) has emerged as a promising alternative for fermentation based production systems. The main advantages of transgenic animals are potential high yields from renewable sources. However, the potential for scale up is limited and there are concerns that animals could harbor human pathogens such as viruses or prions, or that product could be contaminated with undesirable DNA sequence.

Table 3. Status of antibodies in clinical trails.

ProductApplicationManufacturer/inventorStatus
AvicidinMarker for colorectal cancerNoeRxMonsanatoWithdrawn from phase II clinical trails
CaroRxActs against Streptococcus advari mutants which causes tooth decayMajk et.al.in 1999. Larrik, 2001.Phase II clinical trails successful.
T84.66Markers for epithelial cancersPorrinet.al, 2000Tested for tumor imaging and anti-tumor therapy
AntiHSVPrevention of vaginal herpes simplex virusZeitilinet.al, 1998Preventionin HSV-2 transmission in mouse
38C13Potential for non-Hodgkin's lymphoma.McCormicket. al , 1999Prevents experimental induced lymphomas in mice
PIPPDiagnosis and therapy of tumor producing HCG hormone in leidig's cells, pregnancy detection kit and contraceptionKathmicet.al, 2002Developmental stage.
Plants have emerged recently as a convenient, safe and economical alternative main-stream expression systems for recombinant antibody production, which are based on large scale culture of microbes or animal cells. Several plant-derived antibodies have reached advanced stages of development and out of these, two have progressed to phase II clinical trials. -- The authors Nagappa is with Pharmacy Group; Mukherjee & Konda Anusha are with BioSciences Group at Birla Institute of Technology and Science, Pilani.

 
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