Study results published last week in JAMA found that more than a quarter of patients with rheumatoid arthritis developed neutralizing antibodies to adalimumab (Humira). 76 of 272 (28%) rheumatoid arthritis subjects in the study developed neutralizing antibodies to the drug; 67 percent of those subjects developed resistance within the first 28 weeks of treatment. Individuals who developed antibodies were eight times less likely to achieve remission of symptoms and more likely to discontinue use of the drug.

Even though the authors noted that “it wasn’t clear why some patients developed resistance and others did not” and they suggested “genetics may play a role”, the fact that patients who were also treated with T-cell response modifying immunosuppressants such as methotrexate were less likely to develop antibodies offers a clue to the problem. Methotrexate suppresses T cell response. T cell response to the drug is a key driver of immunogenicity.

Why is this Déjà vu all over again? – It is reaffirmation that T-cell driven immunogenicity is critically important to the success of biologics in the clinic. It is also reaffirmation that relying on ‘fully human’ source of the biologic sequence is not the solution for biologics.

By definition, all “fully human” monoclonal antibody sequences are different – and not only do they differ in terms of their T cell epitope content, but they also may differ in terms of their regulatory T cell epitope content. Furthermore, the presentation of those epitopes depends on the HLA of the subjects that are being treated.

There is no mystery to the genetics of the immune response to biologic drugs – it is T cell, and therefore HLA dependent. So, we ask one more time: How long will it take for drug developers to start reducing T cell epitope content before they bring biologics to market, and when will we start measuring the most important biomarker associated with immunogenicity – HLA type?

Before we have ‘”déja vu all over again” with yet another drug, consider joining us at the conference on “Immunogenicity: Determinants and Correlates” in May, when we’ll discuss immunogenicity drivers and what can be done to achieve “quality by design” of biologic drugs.