The human body naturally produces antibodies to attack any potentially harmful foreign molecule. However, these antibodies cannot always tell which molecules are actually damaging invaders and which are complex drugs designed to treat life-threatening diseases. Antibodies that mistake a drug as something harmful attach to the drug and render it useless in treating the intended disease. Scientists and physicians struggle with counteracting this natural reaction because not all patients have the same immune response. The consequences of this lack of immunogenicity data appears across disease states, ranging from ineffective treatment to terrible side effects.
Take for example the recent SPIRE study where induced anti-drug antibodies presented an unexpected roadblock. In the final phase of this study, a significant number of the 30,000 participating patients, who had previously had success using the drug, began to see a rise in their cholesterol levels once again. The researchers found that their bodies had begun producing antibodies to bococizumab, and were forced to end the trial and the drug’s development (Ridker PM et al (2017) N Engl J Med 2017; 376:1517-1 526).
In addition to merely rendering a drug ineffective, anti-drug antibodies can cause a drug to have detrimental effects on the body. A recent article from the New York Times demonstrates this through the story of Magglio Boscarino, a young boy diagnosed as an infant with Pompe disease. This rare, degenerative genetic enzyme deficiency leads to a buildup of glycogen in the body, and the only treatment is enzyme infusions. However, after 4 successful treatments, the fifth infusion caused Magglio to fall into anaphylactic shock and stop breathing. At first these clinical signs were not correlated with the infusion, but after another treatment with the same results, the clinicians realized his body was producing antibodies to the infused protein, causing the severe reaction.
A Rock and a Hard Place
Because there were no alternative treatments available for Magglio, doctors continued the infusions for another year and a half, treating the adverse effects that resulted, all the while watching him deteriorate. And Magglio was not the only Pompe disease patient having these reactions; the development of anti-drug antibodies was all too common in children with Pompe disease, and they did not typically survive it.
Bypassing the Immune Reaction
Dr. Priya Kishani, a pediatrician at Duke University, realized the solution was to ‘trick’ the immune system into leaving the infused protein alone. Patients that had not yet started generating anti-drug antibodies were given a chemotherapy drug designed to preemptively wipe out the antibody-producing cells. For patients like Magglio, who were already producing anti-drug antibodies, another drug, bortezomib directed against proteasomes, was added to eliminate those antibody-producing cells. As the immune reactions of the Pompe disease patients were brought under control, the original infusion treatment began working again without side effects. Magglio himself was able to tolerate treatment again, and is now in 4th grade.
The Need for Immunogenicity Testing
Having stories like these in the limelight further stresses the importance of immunogenicity testing, because any biologic protein drug can provoke the immune system into action. In fact, up to 87% of patients taking these types of drugs will begin to develop antibodies against the drug during their treatment. Understanding the direct causes of these reactions, and how best to counter them, will be invaluable in ensuring patients receive the life-saving treatments they need, without compromising other areas of their health.
Because of the complexity inherent in assessing immune-mediated adverse effects of biological drugs, it is critical to understand the interplay of adaptive and innate immune responses. It takes a world-class bioanalytical partner, with proven expertise in this more recent area of focus, to help developers understand the incidence, kinetics, and magnitude of anti-drug antibody, its neutralizing capacity, cross-reactivity with endogenous molecules or other marketed biologic drugs, and the related clinical impact – all information which can be used to enhance clinical management of patients treated with biologic drugs.
I myself was involved in some of the very first cases of immunogenicity, and my team here at BioAgilytix is helping to pioneer the field with some of the deepest immunogenicity testing expertise available in the world. If you are looking to gain a more complete understanding of the immune response your drug candidate may be causing, look no further than BioAgilytix, and speak to me about your project today.