Abstract
“Transferon Oral” is a peptide-derived product with immunomodulatory properties obtained from the lysis and dialysis of human buffy coat. Its active pharmaceutical ingredient, generically known as Dialyzable Leucocyte Extract, is a mixture of peptide populations with reproducible proportions among batches. “Transferon Oral” modulates IFN-γ, TNF-α, and IL-6 and increases the survival rate in a herpes infection murine model when oropharyngeally (ORO) administered, which correlate with clinical observations where “Transferon Oral” is used as a therapeutic auxiliary in inflammatory diseases. Notwithstanding, how a peptide-derived product elicits systemic modulation of cytokines when ORO administered remains unclear. To shed light on the pharmacology of “Transferon Oral” its peptide components must be known. Ten “Transferon Oral” batches were sequenced by mass spectrometry and the intact peptides were identified. The most abundant peptides were the monomeric human Ubiquitin (Ub), a globular low-molecular mass protein, and an Ub variant which lacks the two-terminal Gly (Ub-GG). Recombinant Ub prevented murine death when ORO administered in a herpes infection murine model. Besides, the percentage of survival increased in groups treated with Transferon Oral+Ub and decreased in groups treated with Ub-depleted “Transferon Oral” respect to the group treated with “Transferon Oral” only. Our findings indicate that the biological properties of “Transferon Oral” are partially associated to the Ub content. They suggest that Ub may activate its extracellular receptor (CXCR-4) in the stomach eliciting systemic immunomodulatory effects via vagus nerve. This is the first report that identifies an active component of “Transferon Oral” with the potential for the development of oral peptide immunomodulators.
Highlights
Immunotherapy involves the stimulation, enhancement, suppression, or desensitization of the immune response to treat malignancies
“Transferon Oral” has been developed as a complex drug owing to its intricate composition, i.e., its peptides components have been regarded as a unique population, and the physicochemical behavior of the peptide fraction has been determined in several batches using a large battery of analytical techniques, such as SDS-PAGE, UPLC, MS, and nuclear magnetic resonance (NMR) (Crommelin et al, 2015)
It was found that each Transferon sample is made up of around 20,000 peptides derived from 593 human proteins
Summary
Immunotherapy involves the stimulation, enhancement, suppression, or desensitization of the immune response to treat malignancies. Stand out the human dialyzable leukocyte extracts (hDLE) which are composed of a low–molecular mass peptide mixture with immunomodulatory properties obtained from the lysis of mammalian cells. Since their first description, made in 1949 by Henry Sherwood Lawrence who coined the term “Transfer factor” (Lawrence, 1949), dialyzable extracts have been developed in some countries such as China, Czech Republic, Cuba, the USA, and Mexico, as auxiliary drugs to treat immune system-related diseases (Ojeda et al, 2005; Zhou et al, 2013; Cardoso et al, 2017). These analyses have evinced the high reproducibility of the peptide components of “Transferon Oral” among all batches, despite its complex composition (MedinaRivero et al, 2014; Medina-Rivero et al, 2016; Vazquez-Leyva et al, 2019)
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