Scientists at the U.S. Food and Drug Administration (FDA) have developed a mathematical tool that predicts whether the body will produce antibodies that block the activity of biotherapeutic protein drugs.
The computational tool, called TCPro, simulates the response of the immune system's CD4+ T cells to specific biotherapeutic drugs. CD4+ cells orchestrate the immune system's response to biotherapeutic drugs, including the production of antibodies against them by other cells, called B cells.
The new tool is important because most immune responses to biotherapeutic proteins include development of anti-drug antibodies. Therefore, new drugs must be assessed during the early stage of drug development to determine their potential to cause adverse immune reactions (i.e., determine their immunogenicity risk).
TCPro can be used to assess the potential for antibody formation even before the laboratory testing on biotherapeutics that is routinely done to screen for this risk. Such tests, which are done by culturing human T cells in contact with the drug and then measuring the growth of T cells, can be expensive and time-consuming. The FDA tool provides a rapid and inexpensive preliminary way to screen both new biotherapeutic proteins and new protein fragments added while the drug is being bioengineered.
The key to the TCPro tool is the wide variety of molecules called major histocompatibility (MHC) class II molecules on the surface of the immune system's antigen presenting cells (APCs). APCs are specialized immune cells that absorb and digest foreign proteins into fragments called peptides. APCs from different individuals display different peptides from the drug on their cell surface by binding them to a specific MHC class II molecule. In turn, some T cells recognize and bind the peptides presented by the MHC-II molecules. This triggers the T cells to multiply and initiate the immune system process and provide help for B cells to make antibodies against the product.
However, the genes for MHC proteins are the most diverse in the human genome, which makes it very difficult to collect cells from different individuals to accurately reflect the presence of all possible MHC-II proteins in a patient population. Therefore, the FDA scientists determined whether individuals had genes for specific MHC-II molecules, which would suggest whether APCs of these individuals would interact with CD4+ cells to trigger development of antibodies against specific biotherapeutic proteins.
The advantage of TCPro is that it can test “virtual” groups of individuals and populations of individuals based on the frequency of specific MHC-II genes instead of collecting and assessing large numbers of CD4+ cells from real donors. The mathematical calculations of how CD4+ cells will react are based on knowledge of the presence of MHC-II genes as well as previously published mathematical descriptions of CD4+ cell interactions with specific peptides that MHC-II molecules present.
The FDA scientists showed that predictions of immune reaction risk of 15 protein-based biotherapeutics made by TCPro were consistent with the actual reported clinical experience with these therapeutics. The T cell response is usually obligatory for antibody responses against protein antigens. Although, TCPro does not assess the B cell response, it was shown to be of value in predicting anti-drug antibodies in the panel of products tested.
The AAPS Journal (2019) 21:96
DOI: 10.1208/s12248-019-0368-0
Authors
Osman N. Yogurtcu,1 Zuben E. Sauna,2 Joseph R. McGill,2 Million A. Tegenge,1 and Hong Yang1,3
1 Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US FDA, 10903 New Hampshire Ave, Silver Spring, 20993, Maryland, USA. 2 Office of Tissues and Advanced Therapy, Center for Biologics Evaluation and Research, US FDA, 10903 New Hampshire Ave, Silver Spring, 20993, Maryland, USA. 3 To whom correspondence should be addressed. (e–mail: Hong.Yang@fda.hhs.gov)
