Abstract
Immune responses to therapeutic proteins and peptides can adversely affect their safety and efficacy; consequently, immunogenicity risk-assessments are part of the development, licensure and clinical use of these products. In most cases the development of anti-drug antibodies is mediated by T cells which requires antigen presentation by Major Histocompatibility Complex Class II (MHCII) molecules (also called Human Leucocyte Antigen, HLA in humans). Immune responses to many protein therapeutics are thus HLA-restricted and it is important that the distribution of HLA variants used in the immunogenicity assessments provides adequate coverage of the target population. Due to biases inherent to the collection of samples in a blood bank or donor pool, simple random sampling will not achieve a truly representative sample of the population of interest. To help select a donor cohort we introduce SampPick, an implementation of simulated annealing which optimizes cohort selection to closely match the frequency distribution of a target population or subpopulation. With inputs of a target background frequency distribution for a population and a set of available, HLA-typed donors, the algorithm will iteratively create a cohort of donors of a user selected size that will closely match the target population rather than a random sample. In addition to optimizing the HLA types of donor cohorts, the software presented can be used to optimize donor cohorts for any other biallelic or monoallelic trait.
Highlights
Protein and peptide therapeutics include seven of the 10 top-selling drugs [1] and provide medical interventions for diseases that are otherwise untreatable
A critical unresolved concern when setting up clinical trials is that adequate and representative HLA distribution is achieved so that the results can be extrapolated to the affected population
Multiple studies have shown that HLA alleles play a central role in the immunological cascade and some immune responses are HLA-restricted [24]
Summary
Protein and peptide therapeutics include seven of the 10 top-selling drugs [1] and provide medical interventions for diseases that are otherwise untreatable. Immunogenicity, the undesired immune response to a protein or peptide therapeutic, is a key concern during drug-development and licensure. Within 5 years, 30–70% of patients receiving TNF-alfa inhibitors experience “secondary failure” due to immunogenicity [6]. About a quarter of hemophilia A patients develop so-called inhibitors, i.e., neutralizing antibodies (NABs) to Factor VIII, leading to severely diminished quality. Matching Sample Cohorts to Subpopulation of life and medical costs that can exceed USD 1 million per year. The most egregious consequence of immunogenicity is not that a drug will fail to be marketed but that medications with a market value of almost 100 billion dollars that treat millions of individuals are sub-optimal
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