The renin-angiotensin system (RAS) is best known for its regulation of blood pressure and electrolyte balance. However, the RAS has been recognized as a contributor in the regulation of host immune responses. These peptide ligands and their receptors are highly conserved in nearly every species of vertebrate. Peptagen’s lead adjuvant modulates toll like receptor 4 (TLR4) with a dominant Th 1 release of the cytokines TNF-α, IL-1β, and IL-6, as well as, proliferation and activation of cytotoxic T lymphocytes (NK Cells, CD4+, CD8+, CD3, MØ, dendritic cells, and stem cells) in rodents and humans. Further, the receptor signaling activates NF-κB transcription factor nuclear translocation and inducing the expression of Th 1 chemokines. The innate activity of these ligands has been demonstrated in a number of studies of endotoxin shock as well as host resistance to peritonitis.
We have completed initial proof of concept studies that utilize angiotensin ligands as adjuvants for enhancing the innate and adaptive T cell response to peptide antigens including: 1) anthrax recombinant protective antigen (rPA); and, 2) HIV peptide immunogen both combined with the natural peptide sequence Ang-(1–7). The studies evaluated the compositions ability to provide nasal adjuvant activity for the induction of serum and mucosal antigen-specific humoral and cell-mediated immune responses to include serum IgG, mucosal IgA and systemic and mucosal epitope-specific CD8 responses.
We have participated in studies performed under an IND to determine the safety and tolerability of the monotherapy PGN007 following intravenous injections (not as a vaccine adjuvant). When used as a hematopoietic agent, no dose limiting toxicities were observed at doses up to 100 micrograms/kg daily for 7 days. In a second study, the maximum tolerated dose was assessed to be 400 mcg/kg/day. These studies demonstrate that Ang-(1-7), as a monotherapy, may be safely used in humans when the dose is appropriately selected. Angiotensin 1-7 is currently being studied as a therapeutic to increase CD4+ cell counts in AIDs patients in the United States under an IND.
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