Antibody Therapeutics

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1. What is an Antibody?
Monoclonal antibodies are produced by the B-cells of the immune system and are a key component of the body's armoury for fighting disease. Each antibody is able to recognise and bind to a specific target, known as an antigen. Antibodies contribute to immunity in three ways: they prevent pathogens from entering or damaging cells by binding to them; they stimulate the removal of pathogens by macrophages and other cells by coating the pathogen, bringing it to the attention of these cells; and they trigger the destruction of pathogens by stimulating other immune responses such as the complement pathway.

Antibodies are composed of two identical heavy chain molecules and two light chains. The ability to bind to different antigens comes from the variable regions of the light and heavy chains (VL and VH), as the antigen binding site is formed at the interface of these two domains. Each variable region contains three Complementarity Determining Regions (CDRs), which are the most variable sections. These are the regions of the antibody that bind directly to the antigen. The diversity of the variable regions comes initially from the recombination of numerous genetic segments. Antibodies with higher specificity and affinity for particular targets are created in the body following antibody-antigen binding, as this triggers somatic mutation leading to selection of mutants with enhanced antigen binding.

2. Drug development process
The process of developing an antibody drug involves several steps and can take many years. Before any drug candidates are selected researchers carry out numerous studies to confirm the validity of a particular target. Antibodies can then be found that interact with the target, for example by screening antibody libraries such as n-CoDeR®. As binding an antigen is only one feature of a successful therapeutic antibody, the drug candidates are tested both in vitro and in vivo to see which of them meets the requirements for efficacy and safety. The most successful candidate is taken forward to the next phase of development.

A larger amount of antibody is required for preclinical and clinical development, so production of the molecule needs to be ramped up. This involves creating stable mammalian cell lines that express and secrete the antibody, as these can be grown on a large scale in fermenters. Before studies can begin in humans, in vivo studies must be conducted to check the safety of the drug candidate and to answer questions about its behaviour, for example how long does the drug remain in the body and how is it broken down? These help to set an appropriate dose level for clinical studies, which can be carried out following approvals from the relevant authorities. Three phases of clinical studies are required before a drug can be approved for sale. Phase I studies examine the safety and behaviour of the drug in healthy people; Phase II studies analyse the effects of the treatment in a small group of patients; and Phase III studies look at the drug's effect in a wider range of patients, comparing its effects to currently available treatments. If these are all successful then a drug may be approved for commercialisation.

3. BioInvent's approach
BioInvent is developing a number of antibody drugs, both on its own and in conjunction with partners. BioInvent has two projects in development, BI-505 and BI-1206.

To support the discovery of new antibody candidates, BioInvent has created a library of antibodies, called n-CoDeR®, that contains 30 billion functional human antibody genes. These fully human antibodies all contain the same naturally occurring antibody framework structure but have different antibody binding segments. The library has been designed to contain antibodies that can bind to a wider range of antigens than would be possible using naturally occurring antibodies alone. High affinity antibodies can be fished out of the library using cells, proteins or peptides as bait, leading to a wider variety of antibodies than found in nature. Because n-CoDeR® antibodies are fully human, they are less likely to cause patients to have an immune reaction against the antibody themselves. In addition, the framework has been designed to minimise the antibodies' immunogenicity and maximise its stability, making the antibodies ideal for developing into drugs.

4. Market overview
BioInvent operates in a market that is based on antibody-based drugs in the field of oncology, focusing on haematological oncology, also called blood cell cancer. The market for antibody-based drugs is still considered the strongest segment in the research-based pharmaceutical industry. Annual sales growth is estimated at around 8 percent for the years 2010–2016, which is significantly higher than the estimated growth for traditional pharmaceuticals, primarily small molecules. Some slowing down is expected over the next few years compared with the last decade due to the expiry of patents for some of the drugs launched more than ten years ago. However, the ongoing launch of new and improved antibodies will prevent a significant growth decline for the market as a whole. During the period 2004–2010 the market value of antibody-based drugs in the field of oncology increased from USD 10 billion to USD 40 billion, and by 2016 the total value is expected to exceed USD 65 billion [1].

Around 30 percent of all research in new, original drugs consists of research in the antibody field. 75 percent of 360 antibodies in clinical development phases I–III are currently in the areas of cancer and immunology. Drugs based on antibodies have a favourable risk profile and several studies have shown that a significant higher proportion of projects in the antibody field today reach the market, compared with traditional medications.

[1] Reported sales from each respective company