Polyclonal antibodies developed in transgenic chickens

By Katrina Megget

- Last updated on GMT

Related tags Immune system

The era of human polyclonal antibodies has dawned as efforts get
underway to produce the next generation therapeutics in transgenic
chickens.

Origen Therapeutics has been awarded a $2m (€1.4m) three-year grant from the National Institute of Standards and Technology (NIST) to develop human polyclonal antibodies by creating genetically modified chickens. The chickens will deposit large amounts of the antibodies into their eggs. Monoclonal antibodies (MAbs) are the current therapeutic antibody of choice and command a market of $20bn (€14.1bn) annually. Produced in a single type of immune cell, MAbs attack a single antigen type on the surface of a pathogen. Polyclonal antibodies (PAbs) on the other hand, are produced from different B cells (immune cells) but all attack the same pathogen. Each antibody binds to a different surface antigens on the pathogen increasing the efficiency of the immune response. Up till now, the polyclonal antibody market has been stifled due to technology. Currently the only PAbs are in the form of gamma globulin purified from donated blood of human volunteers. But with lingering safety concerns of blood borne diseases and the ethical impossibility to immunize blood donors with a disease causing agent to stimulate an antibody response, the human donor approach has its limitations. Origen believed that human polyclonal antibodies "will be an important class of products in the near future"​ as they have the ability to target multiple disease indications including infections, cancer and autoimmune diseases while also having the means to provide pre-treatment in the form of passive immunity. "We believe there are significant and growing unmet medical needs that would benefit from the introduction of these products . . . There is a growing interest in moving beyond monoclonal antibodies and Origen believes this is the rationale next step"​ Origen finance and business development executive vice president Michael Fitzpatrick told in-PharmaTechnologist.com. Enter the transgenic animal system. "In transgenic chickens, we will introduce human versions of these antibody genes . . . When the transgenic chicken is immunised with an antigen such as Staphylococcus aureus, it's B cells will be activated and will produce human antibodies that bind specifically to the Staph bacteria. These antibodies will then form the basis for the polyclonal antibody therapeutic,"​ Fitzpatrick said. The California-based company has so far developed the technology for inserting genetic modifications into the chicken genome. The technology involves removing or inactivating the genes that encode for chicken antibodies and in their place inserting gene sequences for human polyclonal antibodies. The modifications are carried out in cell cultures of chicken primordial germ cells. These genetically modified cells are then injected into the developing vascular system of an early stage chicken embryo. The next step, which the grant enables, will be to apply the technology to insert human antibody sequences into the chicken and then to test and verify that the human sequence antibodies are produced as expected. The antibodies will be extracted from the eggs produced by the transgenic chickens. Found in the egg yolk, the antibodies would be extracted by separating the yolk from the egg white - using conventional methods commonly found in the food industry - then mixing the yolk with water and chilling the mixture. The yolk materials and antibodies separate with the yolk materials sinking and the antibodies staying suspended in the solution. A variety of fractionation and purification steps is then required to collect the pure antibody. The PAbs can be collected at levels of about 200mg per egg. Origen estimates that if 100mg is collected per egg, a flock of 3,500 hens will produce approximately 75kg of antibody per year. "For some disease indications, this could exceed total worldwide demand for product, all produced from a very small number of hens,"​ Fitzpatrick said. The company is aiming to target Staphylococcus aureus​ once the platform technology is completed. "Antibiotic resistance is a growing medical problem, especially in the acute care units of hospitals . . . There is a growing unmet medical need for therapies in this area as the antibiotic resistant strains become commonplace. Polyclonal antibodies have been driven by evolution to target complex organisms like bacteria, so a bacterial infection would logically be susceptible to this mode of treatment,"​ Fitzpatrick said. According to Origen, the use of transgenic chickens is a practical choice for the production of PAbs because chickens are known to have a robust immune response to human antigens, the antibodies are easily collected from the eggs and the system is easily scalable. As yet, the company has no manufacturing site for the PAbs. The grant, known as an Advanced Technology Programme (ATP) grant, was awarded by NIST, which is a division of the US Department of Commerce and is one of the last awarded under the programme. Japan-based Kirin acquired Hematech's technology in 2005 which involves the development of human polyclonal antibodies in transgenic cows.

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