Polyclonals: a Third Generation of Antibody Therapeutics
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IPT 20 2006 31/8/06 09:03 Page 46 Biotechnology Polyclonals: A Third Generation of Antibody Therapeutics Recombinant polyclonal antibodies overcome many of the challenges faced by, first, immunoglobulin therapy, and second, monoclonal antibodies to offer a third generation of antibody therapeutics. By Kaja Tengbjerg and John S Haurum at Symphogen Kaja Tengbjerg, MS, has recently taken up a position as Executive Assistant to John Haurum, CSO, Symphogen. She received a BS in Biochemistry and an MS in Human Biology at the University of Copenhagen, Denmark. She has eight years’ research experience in tumour immunology and antibody discovery. Before joining Symphogen as Scientist in 2001 she worked at the Danish Cancer Society and the University Hospital of Maastricht, the Netherlands. John Haurum, MD, DPhil, is co-founder and Chief Scientific Officer of Symphogen. Dr Haurum received a DPhil in Immunology from the University of Oxford, England, and holds a Scandinavian International Management Institute diploma in Managing Medical Product Innovation. Before founding Symphogen, he took up a position as Assistant Professor at the Danish Cancer Society and completed his medical training. He has extensive research experience in molecular immunology and biochemistry and has published more than 30 articles in international scientific journals. Antibodies have been used as therapeutics in various forms recognised more than a century ago, when it was discovered for over a century. Traditional immunoglobulin therapy that protection against certain toxins was conveyed by has the advantage of reflecting the diversity of the natural substances in the blood – referred to as antitoxins or immune response, but has limited clinical applications. antibodies. Since the first administration by von Behring (1) During the past 10 years, many monoclonal antibodies of antibodies in the form of animal-derived sera in the have been successfully introduced to the market. The 1890s, antibody therapeutics have come a long way. monoclonal antibody approach has the advantage of specificity, but often lacks efficacy in the treatment of Traditional Immunoglobulin Therapy diseases caused by complex antigens. Recombinant Early antibody therapy involved purification of the polyclonal antibodies are expected to have the ability to immunoglobulin fraction of animal and later human tackle complex and highly mutagenic targets, and hold donor plasma, and subsequent infusion in patients. much promise for the future – but their large-scale Plasma-derived immunoglobulin from normal healthy industrial production has, until recently, remained elusive. donors offers the advantage of the polyclonal natural However, new discovery and expression technology immune response, with both a diverse and specific platforms – as discussed in the present review – have repertoire, and remains a preferred choice in the treatment provided a means for the consistent and robust of selected conditions (2). manufacturing of recombinant polyclonal antibody Deriving immunoglobulin from human plasma that compositions, and thus constitutes a third generation of reflects the multitude of binding specificities in the antibody therapeutics to enter clinical development. natural immune response implies that only a small fraction of all the immunoglobulin injected is actually ANTIBODY THERAPEUTICS targeting the particular antigen of interest. One way of A key aspect of the body’s reaction to infection is the enhancing the amount of relevant antibodies is to use activation and clonal expansion of many different antigen- hyperimmune immunoglobulin. These are derived from reactive B lymphocytes. Once these have matured into individuals who have, for instance, recovered from an plasma cells (antibody-producing cells), each clone of cells infection and have developed a high titre of antibodies will secrete its own unique specificity of antibody – thus, the against certain disease-related antigens. The products are invading pathogen will be met by a barrage of antibody therefore highly dependent on donor blood availability, molecules capable of binding at many different sites on its both in terms of quantity and suitability, resulting in surface. The range of specificities and affinities of such a considerable variation between batches. In addition, polyclonal response can shift with time making it ideal for screening technologies may fail to detect donor-derived combating infection. The importance of antibodies was pathogens, and thus immunoglobulin products carry a 46 Innovations in Pharmaceutical Technology IPT 20 2006 31/8/06 09:03 Page 47 potential risk of infectious disease transmission. Today, humanised antibodies, where only the antigen-binding hyperimmune immunoglobulin is used for the parts of the antibody are of animal origin, whereas the prophylaxis or treatment of a number of infectious remaining regions of the antibody are replaced by human diseases caused by, for example, hepatitis B virus, counterparts. Another way has been to completely avoid cytomegalovirus, and tetanus or botulinum intoxication, non-human antibodies through the development of new as well as prophylaxis of Rhesus D allo-immunisation. technologies, such as phage display and human antibody Animal-derived immunoglobulins essentially overcome transgenic animals. the shortage of supply for human plasma-derived Phage display allows target-specific screening of large products. Thymoglobulin (Genzyme) – a hyperimmune so-called combinatorial antibody libraries for the immunoglobulin purified from blood of rabbits identification of potentially useful antibodies, which immunised with human T-lymphocytes – is successfully subsequently can be produced in large quantities. The used in the treatment or prevention of solid organ technology uses bacteria and bacterial viruses (phages) to transplant rejection. However, the animal origin of these express and select recombinant antibodies that have the products constitutes a manufacturing challenge, since the target recognition qualities of natural human antibodies presence of even small amounts of otherwise innocuous (6). However, this method relies on random pairing of the animal protein – such as animal albumin – would add to antibody heavy and light chains, which disrupts the the inherent risks of anti-animal responses associated with original pairing of the antibody chains, potentially leading their use in humans. Like human immunoglobulin to new reactivity as well as cross-reactivity patterns. products, animal-derived immunoglobulins also contain a Transgenic animals, on the other hand, are majority of irrelevant antibody molecules not binding to engineered to replace their endogenous antibody genes the intended target, and potentially carry the risk of with genes encoding human antibody sequences. transmitting infectious pathogens (including prions) which Following immunisation with the appropriate target considerably limit their clinical applications (3). antigen, these transgenic animals develop target-specific immune responses and can thereby act as a source for Monoclonal Antibodies antibodies homologous to human antibodies (3). In the 1980s, Nobel Prize-winners Kohler and Milstein developed a method of producing highly specific POLYCLONALS VERSUS MONOCLONALS antibodies: monoclonal antibodies (mAb). Hybridoma A natural antibody-mediated immune response involves cells secreting antibodies of the appropriate a series of direct and indirect effector mechanisms. These characteristics could be obtained by fusing antibody- are triggered by the synergistic action of antibodies, with producing cells with immortalised cells, and then a plurality of specificities binding several epitopes. The subsequent single cell cloning (4). epitope-specific nature of monoclonal antibodies does Monoclonal antibodies have revolutionised the use of not generate such a concerted action. Another inherent pharmaceuticals of biological origin in all aspects of feature of monoclonal antibodies, which might have medicine (5). They provide the ability to have an implications for their clinical use, is the fact that all the unlimited supply of a single antibody that is clearly molecules compete for the same antigenic epitope and defined, and of reproducible affinity and specificity. In epitope density consequently becomes a limiting factor. theory, mAb technologies allow the development of an The only way to improve efficacy is to increase the dose antibody against any target of choice, whereas plasma- of drug; however, this also increases the risk of side effects derived immunoglobulin products are highly dependent resulting from the excess of unbound antibodies binding on sufficient and suitable blood donors. to tissues other than the target. Nonetheless, mAb products have been successfully The Development of Recombinant Antibodies introduced into the clinical management of cancer, for Adverse immune reactivity against non-human proteins example: Rituxan (Genentech/Biogen Idec), an anti-CD20 after repeated use of hybridoma antibodies, which are antibody approved for treatment of various B cell mainly derived from rodents, are a concern in a clinical malignancies; and Herceptin (Genentech/Roche), an anti- setting as these might lead to hyper-responsiveness and Her2 antibody used in certain breast cancer indications. – in severe cases – anaphylaxis in immunocompetent Both antibodies have improved the clinical response rates of individuals. These issues have been addressed by different anti-cancer treatment, but