If you review any charts of the top 10-20 selling drugs over the past decade you will quickly notice that drugs based on monoclonal antibodies are now overtaking their small molecule alternatives and that trend is only increasing. So what makes a monoclonal antibody such an attractive choice as a biotherapeutic? In this article I will outline the main reasons why they have become a gold standard in the biopharmaceutical industry and what the future is likely to hold. I have to admit now, I am biased and a big fan of antibodies as I initially trained as an Immunologist. Back then (I won’t say exactly when as that will age me!) the head of immunology said there was never a more exciting time to be an immunologist, I thought he just said that every year to convince everyone they had chosen the correct path, but now I think he was right!
In my opinion there are five reasons to justify why a monoclonal antibody makes an ideal biotherapeutic:
Specificity – Possibly the antibodies greatest attribute. Due to their original role in the immune system, antibodies have evolved against a huge number of potential antigens and each is highly specific to that antigen. That means an antibody can be very highly targeted to a specific antigen. This is very powerful as a therapeutic because if the disease causing antigen can be identified then a specific antibody to it can be developed to bind and nullify the antigen, or alternatively with the case of antibody-drug conjugates (ADCs) to specifically deliver a toxic drug to a cell. As the antibody is highly specific there is little danger that it will bind too or affect other antigens so minimal side-effects. To illustrate this if we look at adalimumab then this antibody binds specifically to the inflammatory cytokine TNF-alpha to help control rheumatoid arthritis.
Tolerance - As the antibody is essentially part of the body’s own immune system (especially if it is humanised) then it is seen as a self-antigen and well tolerated by the host’s immune system and unlikely to produce unwanted immune reactions which can be problematic with other biomolecules. Although there is the potential for ‘cytokine storms’ with monoclonal antibody treatments, however modern testing procedures should reduce the risk of these.
Immune System Recruitment – An antibody has two main functions in the immune system: to bind pathogens to inhibit them or trigger them into apoptosis and to bind pathogens to flag them for removal or destruction by other immune cells. Such functions are highly prized in biopharmaceuticals as not only can you specifically target such antigens or adherent cells, but also recruit the destructive force of other parts of the immune system and clear up the mess afterwards.
Longevity – One of the limitations of small molecule drugs is that the body is very effective at breaking them down and removing them so the effects are short-lived, requiring repeated doses. An antibody is well tolerated, as described above, so is able to stick around for long enough to do its job – in fact, an antibody has a life of about two weeks in the bloodstream.
Complex, but not too complex – If you compare an antibody to a small molecule drug then it’s very complex, but for a biomolecule it’s not that complex. If you wish to read more on antibody structure, please do so here. At 150 kDa it’s big, but not huge and the post-translational modifications, such as glycosylation, are not excessive and relatively conserved. This makes their large-scale manufacture (as long as you keep everything in the cell culture constant – easier said than done!) relatively straight-forward. A lot of the complexity in monoclonal antibodies comes in their characterisation as it is essential to fully document the amino acid sequence, glycosylation pattern, degree of aggregation, etc., to ensure efficacy and safety as you are unleashing a powerful weapon when administering an antibody bio therapeutic, something I discussed in a previous article.
These are just my five reasons, I am sure you may be able to add more. Does the monoclonal antibody still have a future though? Over the next couple of decades the answer is yes if you take a look at current biotherapeutic drug approvals and companies’ pipelines as this is still the biomolecule of choice for many. Longer term, the picture is less clear as scientists look at other biomolecules, albeit that some of these are enhanced or variations on the monoclonal antibody. If you are interested in reading about some of these potential biotherapeutics then I would recommend this article.
In summary, there are many reasons why the monoclonal antibody makes the ideal biotherapeutic and why shouldn’t it? Because after all, the immune system has spent thousands of years designing, producing and modifying it to do exactly the job we are now employing it to do.
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