Therapeutic antibodies Monoclonal antibodies that are used totreat disease by targeting specific cells are termed therapeutic antibodies. Monoclonalantibodies are highly specific and have a high affinity to their targetmolecules, antibody therapy aims to manipulate these properties of antibodiesin order to tackle various foreign species that cause disease. This POSTnoteexamines the future of therapeutic antibodies and the possible challenges thatmay come with the use of monoclonal antibodies in treating disease. Overview § Antibodies are proteins regulated by the immune system as a means ofdistinguish and neutralise foreign species, they may bemanipulated in order to use them to target specific cells to treat certaintypes of diseases.
§ As of 2009, 22 therapeuticantibodies had been approved for clinical use (Chames et al. 2009) and this number had risen significantly since then, asof 2017 there are 53 monoclonal antibodies that have been approved in both theEU (by the EMA) and the US (by the FDA) (Animal Cell Technology IndustrialPlatform, 2017). it Is estimated that by 2020 approximately 70 monoclonalantibodies will have been approved for clinical use (Ecker et al. 2014), showing the growing popularity and success oftherapeutic antibodies. § In 2013 global sales ofmonoclonal antibody products made up half of biopharmaceutical product sales,it is predicted that by 2020, sales of therapeutic antibodies will reach asmuch as $125 billion (Ecker et al.2014), this shows the vast profit potential of this sector. § On account of the fact thattherapeutic antibodies have a long serum half-life, additional safety measuresmust be taken which has led to the composition of the European guideline(Schneider, 2008).
§ As patents for pre-existingtherapeutic antibodies expire, there will be a surge in the production ofbiosimilar therapeutic antibodies (Ecker etal. 2014) Background Antibioticresistance Antibiotics when initially created wererevolutionary, they had the ability to treat bacterial infections, however overthe decades due to over usage, these bacteria have adapted to the antibioticsso much so that they are now resistant to the antibiotics. This means that whenthese harmful bacteria come into contact with the antibiotics, they are stillable to thrive and multiply, causing illness for the host. These bacterialinfections include Tuberculosis, Pneumonia and Gonorrhoea (WHO, 2017).
Antibiotic resistance is one of the most key issues facing the health sectorand it is now of the upmost importance to find an alternative treatment toantibiotics otherwise the world may find itself in a crisis very soon. IT is inthe national interest to find a solution as not only is this leading to highermortality rates, but it is also leading to longer hospital stays whichsubsequently means it is costing the government more. Therapeutic antibodiescould provide an alternative and even more specific treatment. Antibodiesand monoclonal antibodiesAntibodies are Y-shaped proteins regulated by the Immune system, that bind to specific targetmolecules of a complementary shape (antigens) in order to exert their effect(box 1).Therapeutic antibodies are geneticallyengineered monoclonal antibodies with high specificity and functionality(Brekke and Sandile, 2003).In 1975, Kholer and Milstein developed amethod to produce monoclonal antibodies through their mouse hybridoma technique,this was the first step in the usageof monoclonal antibodies as therapeutics. The early experiments involvedinjecting murine monoclonal antibodies into humans, these were recognised bythe immune system as foreign and were destroyed. Later, antibodyengineering meant that one could produce chimeric antibodies (Figure 2)consisting of 2 mouse variable domains and 2 human constant domains.
TheseChimera are 70% human containing a Human Fc region, allowing them to interactwith human effector cells and decreasing the chances of provoking an Immune response. More recently it hasbeen possible to further reduce the murine portion of the chimeric antibody.(Chames et al 2009).
Therapeuticantibodies act in one of 4 ways (box 2); they either block the action of themolecule of interest or, they target specific cells (which are causing disease),or they act as signalling molecules or they are used to deliver DNA or antigensto immune cells which activate a specific Immune response (Brekke andSandile,2003). Box1 Figure 1. A diagramshowing the structure of a standard antibody molecule. This diagram highlights the different chainsand domains that make up an antibody molecule. Taken from BioXCell – Guide tothe structure and classification of antibodies. Antibodiesare proteins with a sugar group and so are known as glycoproteins.
As shown in figure1, Each antibody contains two antigen-binding fragments (Fabs) and two constant(Fc) regions which are joined together by the hinge (flexible) region. Theconstant region is responsible for binding to effector molecules of the immunesystem. There are also two variable domains which recognize and bind the antigens.
Antibodies can be grouped into 5 groups;IgG, IgM, IgA, IgE and IgD, each class has a distinct structure, IgM is thefirst to be produced in an immune response (Brekke and Sandile, 2003). Antibodiesare responsible for; neutralizing disease causing microorganisms, activatingother cells responsible for an immune response and activating the complementsystem (Institute for Quality and Efficiency in Health Care, 2016) which is asystem which amplifies the antibodies’ ability to destroy disease causingmicroorganisms. Antibodies are ideal due to their ability to bind with highspecificity and affinity to a number of molecules (Chames et al, 2009).
Figure2. A diagram showing the formation of a chimeric antibody. The moleculeconsists of human and mouse sequences, as you can see the chimera ispredominantly made of human sequences, which reduces the likelihood of theproduction of Human Anti-Mouse Antibodies (HAMA) and ultimately destruction bythe immune system. Adapted from absoluteantibody.com – Chimeric monoclonalantibodies, 2017. Currentlegislation Currently,there is no legislation specifically pertaining to therapeutic antibodies,however the following legislation applies to therapeutic antibodies as they arecovered under the same branch of medicinal products. In the EU§ Regulation(EU) no 1027/2012 of the European Parliament amending Regulation (EC) no726/2004 as regards pharmacovigilance.
This regulation is with regards to thesteps which must be taken in order for a medicine to be authorized and stepswhich can be taken to increase safety of medicinal products. § “newregulation EU no 536/2014 of the European parliament and of the council onclinical trials on medical products for human use” which provides guidelines asto how clinical trials must be carried out Outside the EUInthe USA the FDA have set out guidelines on the use of monoclonal antibodies asa drugs. The guideline outlines the steps manufacturers need to take in termsof ensuring safety and drug purification. This guideline provides a frameworkfor manufacturers to follow prior to applying for drug approval by the FDA(FDA, 2001).
Box2 Asstated earlier, there are 4 main mechanisms in which therapeutic antibodiesdestroy or neutralize their targets. The first is that they can block theaction of their target molecule which is causing the disease. This is done bypreventing the growth factors or cytokines from reaching target receptors. Theantibody will bind to the receptor which stops the target molecule itself frombinding to the receptor in order to exert its effects. Alternatively, the antibodywill bind to the growth factor which will also stop it from binding to thereceptor. The second mechanism in which therapeutic antibodies can work is bytargeting specific cells.
With this mechanism, the antibodies are directed tothe specific cells of interest, the antibodies will be carrying a particular molecule,which will somehow aid in the destruction of the target cells (i.e. an enzymeor toxin or cytokine) which will be delivered to the target cells and will exerttheir effects. For example, therapeutic antibodies carrying toxins can eradicatecancer cells (which would be the target cells in this case). Moreover, thethird mechanism is that therapeutic antibodies can act as signalling molecules,this will induce cross linking of receptors that are connected to moleculesthat regulate cell division or apoptosis, which will result in the terminationof cell division (preventing the diseased cells from multiplying) and willresult in programmed cell death of the pre-existing cells. The final mechanismin which therapeutic antibodies can act is that they can deliver DNA orAntigens to Immune cells.
The immune cells then activate a specific immuneresponse against the antigen. Current therapeutic antibodies in use 6years ago there were a total of 22 therapeutic antibodies approved for clinicaluse, most of these were therapeutic antibodies to treat cancers and immunedisorders. (Chames et al 2009). Thereare currently 53 therapeutic antibodies approved for clinical use (Animal CellTechnology Industrial Platform, 2017). Some antibodies were approved forclinical use but have since been discontinued.
As of 2003, 20% of allbiopharmaceutical products in clinical trials were monoclonal antibodies(Brekke and Sandile, 2003) showing just how popular this particular field ofresearch medicine is. Onesuccessful therapeutic antibody has been Rituximab (also known as Rituxan) whichwas approved by the FDA in 1997(Dotan etal 2010). It is used in cancer treatment (Chames et al 2009). Rituximab is used to treat non-Hodgkin lymphoma (NHL),it targets CD20 proteins which are found on the surface of certain white bloodcells known as B-cells. Rituximab binds to CD20 which the immune systemrecognises as a cell that needs to be destroyed. The marked B cells are thendestroyed, destroying both the normal B cells and abnormal NHL B cells (thenormal B-cells then regenerate). Rituximab is given as part of chemotherapy atthe start of each cycle (Macmillan, 2015). B-cell Lymphoma’s make up 85% of allNHL’s, showing the vast market there is for this drug (Dotan et al 2010).
Rituximab can also be used totreat joint pain and swelling, similarly to cancer treatment, it works bybinding to CD20 ON B-cells which are then destroyed. If the drug has worked itseffects will be evident within 2-16 weeks (Arthritis research, 2017). In 2015,sales of Rituxan reached $7.32 billion (Gibney, 2017) this shows that not onlyis Rituximab a medical success, it is also a financial success.
Challenges Production costs and Dosage Monoclonalantibodies are large molecules (~150kDa) this means that in order to administerthem in an active form, is costly. Additionally, large cultures are needed anda large amount of purification is required which further increases the cost ofproduction. Moreover, it has been shown that the monoclonal antibodies need tobe injected in rather large doses in order for them to provide an appropriatelevel of efficacy (Chames et al. 2009). Murine xenograft modelsshowed that no more than 20% of the dose of monoclonal antibodies administeredwill interact with the tumour (Beckman etal.
2007), this further exemplifies why a large dosage must be administeredwhich leads to higher costs for pharmaceutical companies producing these drugs.Furthermore, another problem faced in the production on therapeutic antibodiesis their ability to penetrate tumours. Tumours have a high fluid pressure,therefore it is hard for the antibodies to diffuse against this gradient inorder to treat the tumours, especially larger tumours as the pressure is higher(Chames et al. 2009).
Safety Aswith any drugs, there are associated side effects. Due to the fact that theantibodies used are chimeric, they are made partly from murine antibodies, thismeans that the immune system will recognise this and elicit an immune response.The severity of the immune response varies on the particular therapeuticantibody in question. However, recently companies have been able to manufacturetherapeutic antibodies which are 85%-90% human by only adding murine hypervariable loops to a fully human antibody (Chames et al. 2009), vastly supressing theimmune response elicited by foreign species. Additionally, the introduction ofpart-murine antibodies into the body can lead to the body producing HumanAnti-Chimeric Antibodies (HACAs) which could then destroy the chimericantibodies, inhibiting them from achieving their specific objective (Niebeckerand Kloft, 2010). Again this particularproblem can be tackled through decreasing the amount of murine antibody used tothe minimum amount needed for the chimeric antibody to still be effective, asknowledge in this field increases it is likely that the amount of murineantibody used shall decrease.
Biosimilars Mostof the monoclonal antibodies on the market today were approved for clinical useover 10 years ago therefore in the upcoming years, patents for these productswill have expired as a patent both in the UK and US lasts only 20 years. For example,Rituximab which was approved for use in 1997, meaning its patent will beexpiring in 2018. The expiration of these patents will cause a surge in theemergence of companies who perhaps did not have the resources or funds to takepart in therapeutic antibodies decades ago producing ‘biosimilars’ which willbe products very similar to the previously patented monoclonal antibodies. Onecould argue that that this will be positive thing as it will cost consumersless to buy these drugs however conversely this will mean that profits of monoclonalantibodies in the medical sector will decrease making it less lucrative (Ecker et al. 2014) which may result inpharmaceutical companies reducing funding for research and development in thissector. Additionally, as patents expire, bogus companies especially in moredeprived countries may start releasing ‘look-alike’ drugs which look similarbut have no effect at all, in order to make money and reduce their costs,leaving victims of such scams still ill. FinancialbenefitsTheusage of therapeutic antibodies in treating clinical ailments is emerging as avery lucrative sector of medicine.
In 2013, profits of monoclonal antibodiesand monoclonal antibodies were $75 billion, this made up 50% of the total salesof all biopharmaceutical products. This shows just how vital monoclonalantibodies are becoming not only in the treatment of disease but in thefinancial stability of pharmaceutical companies and in a larger sense thefinancial gain of economies worldwide. It is predicted that by 2020 sales ofmonoclonal antibody products will reach a staggering $125 billion.
Thefuture of antibodies Monoclonaltherapeutic antibodies have already proved to be both successful and lucrative.Biopharmaceutical companies are now looking to increase the efficacy oftherapeutic antibodies even further and in particular increase the penetrationability of therapeutic antibodies which will lower the dosage required anddecrease costs.