Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529

Abstract

Earlier we showed that the structural requirements for adjuvanticity among the aminoalkyl glucosaminide 4-phosphate (AGP) class of synthetic immunostimulants may be less strict than those for other endotoxic activities, including the induction of nitric oxide synthase in murine macrophages and cytokine production in human whole blood. The known role of nitric oxide and pro-inflammatory cytokines in the activation of host defenses against infection prompted us to examine the ability of certain AGPs to enhance non-specific resistance in mice to Listeria monocytogenes and influenza infections as well as to stimulate the production of pro-inflammatory cytokines in mouse splenocytes, human PBMCs, and human U937 histiocytic lymphoma cells. Intranasal administration of RC-524 or RC-529 to mice 2 days prior to a lethal influenza challenge provided significant protection in each case. Similarly, the intravenous administration of these AGPs induced resistance to L. monocytogenes infection as measured by survival or reduction of bacteria in the spleen. Activation of the innate immune response by AGPs appears to involve activation of Toll-like receptor 4 (TLR4) because RC-524 failed to elicit a protective effect in C3H/HeJ mice which have a defect in TLR4 signaling or induce significant cytokine levels in C3H/HeJ splenocytes. Both AGPs also stimulated pro-inflammatory cytokine release in human cell cultures in a dose-dependent manner.

Self-Adjuvanting Lipopeptide Vaccines

“…(6)), an adjuvant consisting of a mixture of six glycolipids, obtained through the sequential acid and base hydrolysis of Salmonella minnesota R595 LPS [115]. Synthetic analogues of LPS have also been synthesized [116][117][118][119][120][121][122][123][124][125][126] with the aim to reduce the toxicity of LPS whilst offering the capacity to optimize the adjuvant to promote specific immune responses. These analogues also offer other advantages over LPS and MPL, including the capacity to obtain the adjuvant in a highly pure state, as a single chemical entity rather than a mixture, as well as a lack of potentially toxic bacterial trace contaminants.…”

A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses

“…Monohosphoryl Lipid A (MPL) [61,62] TLR4 agonist TRIF/MyD88 Phase III Adjuvant for virus or oncology Aminoalkyl glucosaminide 4 -phosphate (AGP) (RC529 and RC524) [71] TLR4 agonist TRIF Preclinical Adjuvant for virus or oncology Bufalin [72] TLR 3&4 antagonist TRIF Preclinical Under investigation…”

Prophylactic and therapeutic implications of toll‐like receptor ligands

“…46 AGPs have been shown to induce nonspecific protection against Listeria monocytogenes, influenza virus, and respiratory syncytial virus challenges. [47][48][49] E6020 is a fully synthetic molecule which can be incorporated into a broad range of vaccines, eliciting an immunostimulatory response through TLR4. 50 Unmethylated CpG oligodeoxynucleotides (CpG ODNs) are short single-stranded DNA molecules which are abundantly found in viral and bacterial DNA, but not in vertebrate genomes.…”