No-one can deny the impact of antibody therapeutics on the drug development landscape. By 2008, around a quarter of products in clinical development were biologics, and the majority of those were humanized antibodies. Over the four years to 2012, Rockpool (a biotechnology consultancy) estimates
that more than half of the estimated $54bn growth in pharmaceutical sales will come from biologics. The future for therapeutic antibodies seems set fair, underpinning the high valuations for biotechnology companies with dominant intellectual property in the area.
The attractions of humanized monoclonal antibodies are obvious enough: the large molecular framework ensures exquisite specificity for binding to the chosen target, offering (at least in theory) the prospect of much reduced side-effects compared with conventional small molecule therapeutics. The inferior pharmaceutical properties (such as the need for parenteral administration) and the substantially higher cost of goods for antibody therapeutics, it seems, are counterbalanced by speed of development and improved safety. In this brave new world of biological medicine, antibody therapeutics are just the vanguard of a medicines cabinet stocked with siRNAs, stem cells and diverse, highly specific, therapeutic proteins.
Last month, however, the EMEA recommended suspending Raptiva™, Genentech’s anti-CD11a for the treatment of psoriasis following the third confirmed case of progressive multifocal leukoencephaolopathy (PML), a rare but usually fatal inflammatory brain disease. This followed the addition of a Black Box warning to the product’s label in the US in the wake of the first PML case associated with Raptiva™ in 2008.
Raptiva™ is not the first therapeutic antibody to suffer this problem: Tysabri™, an anti-alphs4 integrin originally approved for the treatment of multiple sclerosis and Crohn’s Disease in 2004, was withdrawn from the market in 2006 following a number of cases of PML, although it has since been returned to the market under a special prescription programme. Rituxan™, an anti-CD20 therapeutic antibody launched in 1997, has also been associated with PML cases particularly among patients with systemic lupus erythromatosis (SLE).
PML is a demyelinating disease (like a highly aggressive form of multiple sclerosis) caused by the reactivation of a polyoma virus called JCV. JC virus is almost endemic among adult populations, with almost 90% of people positive for antibodies against the virus. However, it remains latent unless reactivated usually as result of severe impairment of the immune system. PML is most commonly seen in AIDS patients, and those treated with immunosuppressive drugs including tacrolimus, mycophenolic acid and in rare cases high doses of corticosteroids. It is tempting to assume, therefore, that PML is a side-effect of the highly effective anti-inflammatory activity of Raptiva™, Rituxan™ and Tysabri™.
But these products all have something else in common: they bind with high affinity to cell surface receptors on leukocytes (and in the case of anti-integrins, on other cell types as well). In contrast to therapeutic antibodies targeting soluble mediators (such as the highly successful anti-TNF and anti-VEGF products), antibodies which target cell surface receptors decorate the surface of the target cells with immunoactive protein sequences. The constant regions of these antibodies can bind to, and activate, Fc receptors on other leukocytes, they can modulate complement (a major effector pathway of the innate immune system) and a wide array of target-independent effects can ensue. Any or all of these pathways could contribute to the risk of PML, alongside the intended anti-inflammatory effects of binding to the intended target.
What are the lessons that can be learned? While tragic for the small number of PML sufferers, it is always going to be impossible to detect such rare, but serious, side-effects of any new therapeutic during clinical development. Moreover, at least for Tysabri™ and Rituxan™, these products provide such a degree of efficacy for treatment of diseases that were otherwise very severe and poorly managed that they remain a valuable therapeutic option despite the PML risk.
Of greater concern, however, is the possibility that PML represents a class effect of antibodies binding to cell surface targets on leukocytes. If that were the case, then the consequences would be significant: antibody therapies targeting cell surface proteins are being developed currently for milder diseases, where risk of PML cannot be sustained in return for therapeutic efficacy (as in the case of Raptiva™, at least in the eyes of the European regulators). It may be time to take off the rose-tinted spectacles and see antibodies as no less susceptible to target-independent effects than small molecules.
Even if it eventually emerges that PML has nothing to do with persistent antibody binding to cell surface targets, and is purely a side-effect of aggressive anti-inflammatory intervention, this episode nevertheless fires a warning shot across the bows of drug developers. Globally, we have embraced a shift towards therapeutic antibodies with the fervour of an alcoholic downing a breakfast gin, but we still have too little clinical experience with them as a class to fully understand the long term consequences of treatment, particularly with agents that bind to cellular, rather than soluble targets, and so accumulate at particular sites.
Small molecule therapeutics may have already have had their golden age in the last quarter of the twentieth century – they were, after all, the only show in town. But the recent experience with PML reminds us that all classes of therapeutic interventions carry the risk of unintended consequences, and that a balanced global portfolio of drug development capability is the best prospect for improving healthcare, and with it, returns for healthcare investors.
This article was written by David Grainger. David is a scientist directing an internationally recognized research laboratory in the Department of Medicine at Cambridge University, focused on inflammation. David is a biotech entrepreneur and investor, having founded several biotech companies, and he runs a successful consultancy business, TCP Innovations. He is also a Senior Partner at Total Medical Ventures, a life sciences boutique investment group, and a Principal at ATPBio.