Cow antibodies
Veterinarian and researcher Dr Azad Kumar Kaushik is studying antibodies from cattle in the hope of developing novel drugs and vaccines. Here, he reveals his fortuitous entry into the field, and the talented team members who have made his work possible
What intrigues you about the Could you explain the need for new mechanisms of immunity? antibody-based vaccines?
As a veterinary medicine student, I was There are many controversies surrounding intrigued by the generation of immunity vaccines in the public domain. Some of against a variety of infectious agents, the concerns may be related to the quality especially the concept of an almost of available vaccines or components; endless generation of diversity, while alternatively, individual host genetics being tolerant to self-constituents. might influence response to a particular This led me to the Pasteur Institute vaccine. Hence, there is a need for better to study the origin of autoantibodies quality vaccines against various infectious against red blood cells involved in agents that have minimal side effects and haemolytic anaemia, seen in systemic are suitable for use in large populations, autoimmune disease. including immunocompromised individuals and neonates. Furthermore, successful Can you discuss some of your vaccines are yet to be developed against key findings? certain pathogens, such as HIV and Plasmodium falciparum.
We noted that the same host genetic elements encoded physiological With a world-leading team in bovine autoantibodies, antibodies to infectious antibody genetics, what distinguishes agents and pathogenic autoantibodies, your laboratory from others? using similar mechanisms. Our later
research showed that impaired My laboratory is small with limited B-lymphocyte development, due to resources, but rich in human intellect and underlying genetic factors evident at ingenuity; a nurturing environment exists birth, provides the trigger that gets for advancing scholarships, exchanging amplified by environmental factors ideas and flourishing creativity. I have had resulting in production of pathogenic the good fortune of working with some autoantibodies seen in systemic outstanding colleagues, whose passion, autoimmune disease like lupus. These creativity and efforts put us in the top studies of the immune system in health league of bovine immunoglobulin genetics. and disease across species led me to The commonwealth scholar, Dr Surinder bovine antibodies upon my return to S Saini, discovered the exceptionally long veterinary profession. CDR3H in cattle antibodies, at a time when cDNA sequencing was a time-consuming Why do you focus specifically on the challenge. Dr Farbod Shojaei discovered bovine immune system? the single long germline IGHD gene in the cattle, capable of encoding 49 codons Given their medical significance, most of CDR3H. Dr Madhuri Koti discovered studies had focused on human and mouse the molecular basis of exceptionally immune systems. As a veterinarian, I long CDR3H in cattle antibodies beyond was aware that the immune system germline potential via CSNS insertion. must have evolved for each species to While Dr Koti first engineered bovine scFv meet varying individual host defence that neutralises BoHV-1, Ms Yfke Pasman, requirements. When taking up the enhanced bovine scFv’s anti-viral potency position of Clinical Immunologist at via multimerisation. Ms Pasman is currently the Ontario Veterinary College – a enhancing the understanding of cattle move away from the human medicine antibody structure-function relationships environment – I needed to embark upon for developing the next generation of a new research path. I decided to study vaccines, immunodiagnostics and antithe bovine immune system as I knew viral drugs. Such wonderful, dedicated that little was understood about cattle and passionate colleagues distinguish our antibody genetics. laboratory from others in the field.
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Mega antibodies: next-generation therapeutics
Researchers from a worldleading laboratory at the University of Guleph in Canada are studying the antibodies of cows, paving the way for new vaccines and medicines to prevent and treat human disease
WHEN ASKED TO think about cows and the resources they provide, milk and beef might be the first to come to mind, but there is actually something else produced by cows – unique to them – that makes them a valuable therapeutic resource: antibodies. Cows produce the largest sized antibodies of the whole of the animal kingdom. These massive antibodies are distinctively poised for more effective at attacking diverse bacteria and viruses, and have the potential for use in humans as well.
Dr Azad Kumar Kaushik, Associate
Professor of Immunology at the University of Guleph in Ontario, was captivated by the processes of immunity at an early age and has been working on them, in humans and animals, ever since. After years of studying the structure of immune systems across multiple species, his laboratory is now focused on the bovine immune system.
Supported by the Canadian Natural Science and Engineering Research Council (NSERC), Kaushik’s investigations have identified and classified the genetic elements encoding bovine antibodies, as well as discovered novel mechanisms that enable production of such a vast array of antibodies beyond germline potential. His current research is conducted with a view to engineering antibodies for next-generation therapeutic and diagnostic tools.
OVERCOMING LIMITED DIVERSITY
Kaushik’s investigations of the bovine immune system began by identifying the genetic elements that encode the antibody. The team discovered that the limited germline diversity of the cow genome has led to the creation of the largest antibodies known in any species. Exceptionally long third complementary determining regions of Cattle antibodies could form the basis of new:
Vaccines Therapeutics Diagnostics Immunomodulatory the heavy chain (CD3RH) are generated, over The team took genetic material from a cell 50 amino acids in length. As well as creating producing antibodies against BoHV-1 and atypical antigen-binding site diversity, the modifi ed the gene producing the antibody. size of the antibodies also makes them They inserted the new gene into yeast cells suitable to work with. A major barrier to to produce the antibodies en masse, before successful antibody-based immunotherapies adding them to infected cells to investigate in the past has been the lack of a suitable their ability to attack the virus. Kaushik’s vehicle to transfer immunity from animals scFv was found to neutralise the virus, to the lab, but the size and fl exibility of preventing its attachment to host cells and the bovine antibody overcomes this. In the subsequent replication. longer term, modifi ed bovine antibodies could be used to target diseases where traditional therapies fail, helping the body to recognise and protect from pathogens that would otherwise go undetected.
Kaushik hopes to develop
The researchers went on to fi nd that drugs and vaccines for humans, CD3RH is encoded by a single, again unusually long, gene – IGHD – which is particularly against common capable of encoding a striking 49 codons.
It does so in concert with the insertion of infections of the intestine a conserved short nucleotide sequence (CSNS) at a specifi c junction of IGHV and IGHD that further increases CDR3H size.
Building on these past successes, Kaushik’s MAKING MEGABODIES team is presently focused on the next stage on from genetics: structure and function. Based on these promising fi ndings, Kaushik hopes to develop drugs and vaccines for Antibodies are multi-functional molecules, humans, particularly against common they recognise antigens, engulf pathogens, infections of the intestine. The potential and much more. Each function is designated here is huge. By coupling the antibodies to a specifi c structure. “It is therefore with drugs, they could be used to target possible to genetically manipulate and specifi c locations in the body to destroy the generate an engineered molecule for a pathogen or diseased tissue. “Our discovery desired function,” Kaushik explains. of large sized bovine antibodies, which I call ‘megabodies’, will have a huge impact TACKLING A BOVINE VIRUS not just on veterinary science but also on human medicine,” Kaushik enthuses.
Through his studies, Kaushik successfully the future, he hopes to capitalise on the developed powerful antibody fragments rise in popularity of using antibodies for called single chain fragment variables therapeutic purposes by further developing (scFv). Importantly, these scFv are able his research on structure-function to to neutralise Bovine Herpes Virus-1 understand, exploit and even engineer (BoHV-1), a major problem in North multifunctional antibodies to prevent and America that costs the cattle industry up treat disease, setting his sights on complex to $100 million each year in Canada alone. autoimmune diseases and even cancer.
INTELLIGENCE POST GENOMIC STRUCTURAL AND FUNCTIONAL ASPECTS OF ANTIBODY IN HEATH AND DISEASE OBJECTIVE
To advance knowledge of the development, ‘structure-function’ relationships and regulation of humoral immunity in health and disease aimed at designing antibodybased therapeutics, diagnostics and novel vaccines across species, including humans.
KEY COLLABORATORS
Dr Éva Nagy, University of Guelph, Canada
Dr Paul A Ramsland, Burnet Institute, Australia
FUNDING
Natural Sciences and Engineering Research Council of Canada (NSERC)
CONTACT
Dr Azad Kumar Kaushik
University of Guelph
Room: SCIE4248
Guelph
Ontario
N1G 2W1
Canada
T +1 519 824 4120 Extension 54389 E akaushik@uoguelph.ca
www.nserc-crsng.gc.ca/ase-oro/DetailsDetailles_eng.asp?id=475525
DR AZAD KUMAR KAUSHIK has published over 85 research articles, two books and four patents on cattle antibodies. He is Consultant to several international organisations (USVIRN and CIgW in USA, and IMGT in France). He was recognised as The Esther Z Greenberg Honors Chair in Biomedical Research, Oklahoma Medical Research Foundation, USA, in 1998. He received BVSc&AH (Honors) in 1976 and MVSc (1978) from the Faculty of Veterinary Science, Hisar, India; followed by a Docteur es Science (DSc) in1987 from the Pasteur Institute (University of Paris VII), Paris, France.
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Source: WHN Media Network
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