first monoclonal antibody fully licenced in 1986.
Abstract
As medicine progresses into a new era of personalised therapy, the use of monoclonal antibodies to treat a wide range of diseases lies at the heart of this new forefront. Since the licencing of the first monoclonal antibody for clinical use 30 years ago, the monoclonal antibody industry has expanded exponentially and is now valued at billions of dollars.
With major advances in genetic sequencing and biomedical research, much research into monoclonal antibodies now focuses on identifying new targets for development and maximising their efficacy for use in clinical practice. However, a balance has to be struck with regards to reducing numbers of side-effects and overall economic cost, which arguably somewhat blighted their early clinical and commercial successes.
Nowadays, there are approximately 30 monoclonal antibodies that have been approved for use in clinical practice with many more currently being tested in clinical trials. Some of the current major limitations include: the use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness. Some of the current research focuses on ways to improve the efficacy of existing monoclonal antibodies through optimising their effects and the addition of beneficial modifications.
This review will focus on the history of monoclonal antibody development – how it has increasingly moved away from using laborious animal models to a more effective phage display system, some of the major drawbacks from a clinical and economical point of view and future innovations that are currently being researched to maximise their effectiveness for future clinical use.
1. Introduction
From the time the first monoclonal antibody was generated in 1975 and the first monoclonal antibody fully licenced in 1986, the field of monoclonal antibody development represents a novel way in which to target specific mutations and defects in protein structure and expression in a wide range of diseases and conditions. Today, with major rapid advancements in genetic sequencing and the translation of basic medical sciences research into clinical practice, humanised monoclonal antibodies are now the fastest growing group of biotechnology-derived molecules in clinical trials currently [1]. The global value of the antibody market is approximately $20 billion per year [2]. About 30 monoclonal antibodies are currently approved by the FDA for use in humans for treating various diseases and conditions including: cancer, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular diseases [3].
2. Generation of monoclonal antibodies using the hybridoma technique
Monoclonal antibodies are monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone [4]. They were first generated in mice in 1975 using a hybridoma technique [5]. The generation of hybridomas involves immunising a certain species against a specific epitope on an antigen and obtaining the B-lymphocytes from the spleen of the animal. The B-lymphocytes are then fused (by chemical- or virus-induced methods) with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) gene and not containing any other immunoglobulin-producing cells. These hybridoma cells are then cultured in vitro in selective medium (i.e. medium containing hypoxanthine-aminopterin-thymidine) where only the hybridomas (i.e. the fusion between the primary B-lymphocytes and myeloma cells) survive as they have inherited immortality from the myeloma cells and selective-resistance from the primary B-lymphocytes (as the myeloma cells lack HGPRT, they cannot synthesise nucleotides de novo as this is inhibited by aminopterin in the selective medium) [4]. The initial culture of hybridomas contains a mixture of antibodies derived from many different primary B-lymphocyte clones, each secreting its own individual specific antibody into the culture medium (i.e. the antibodies are still polyclonal). Each individual clone can be separated by dilution into different culture wells. The cell culture medium can then be screened from many hundreds of different wells for the specific antibody activity required and the desired B-lymphocytes grown from the positive wells and then recloned and retested for activity [6]. The positive hybridomas and monoclonal antibodies generated can then be stored away in liquid nitrogen.
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