Which one is not like the other? Why is one patient more likely to develop a side effect like anti-drug antibodies (ADA) than another? While there are many contributors to immunogenicity, most developers agree that T cell epitopes are key, and because they are, our genetic make up (HLA) determines who will, and who won’t get ADA. We previously published studies showing that HLA as one potential biomarker of immunogenicity (see that publication here). We’re using the “Individual T cell Epitope Measure (iTEM)” tool to examine protein sequences for potential immunogenicity, based on an individual subject’s specific HLA phenotype. We recently tuned iTEM for analyzing the HLA-dependent immunogenicity of full proteins such as monoclonal antibodies, and have applied this tool to 23 monoclonal antibodies in clinical use.

 What is iTEM? Individualized T cell epitope measure or iTEM, is a component of the ISPRI platform used for screening biologics sequences and developed by EpiVax. iTEM examines protein sequences for potential immunogenicity based on an individual subject’s HLA phenotype. Each of the input protein’s 9-mer frames is analyzed for potential binding to the individual’s HLA using the EpiMatrix system, resulting in a patient-specific iTEM score. A positive (or negative) iTEM score corresponds to an increased (or decreased) T cell epitope content, compared to a random protein of similar length. Pairs of high, moderate, and low risk HLA haplotypes can be identified for each of the monoclonal antibodies. The same approach was applied to data available from a set of patients exposed to adalimumab and for which both ADA titers and HLA phenotypes were available.

We developed heatmaps summarizing the iTEM scores generated for an input sequence. The color of each cell is representative of the strength of the iTEM score obtained for a given pair of Class II alleles. High-, moderate-, and low-risk HLA haplotypes are represented by red, yellow, and green cells, respectively. The heatmap obtained for adalimumab is shown below.

Heatmap_boxesAdalimumab is a monoclonal antibody with an observed ADA response in 12 % of exposed patients*. Its heatmap revealed that HLA- DR1 and HLA-DR7 are associated with higher putative T cell epitope content, which may contribute to higher levels of ADA in subjects expressing those alleles. For the retrospective set of study patients, potential risk for ADA to adalimumab was determined using iTEM, showing that ADA responses were higher in patients whose iTEM score, or immunogenic risk, was elevated.

Heatmaps were developed for a total of 23 licensed monoclonal antibodies, revealing many pairs of HLA risk alleles that may be linked to higher ADA titers in selected patients.These findings highlighting the value of iTEM in personalized medicine and in determining the best treatment option for individual patients. Stay tuned for an update in this space when the study is public!

* Observed ADA response obtained from Adalimumab’s package insert.