Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide

Small
molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine
adjuvants by enhancing innate immune activation to afford better adaptive
response. Localized TLR7 agonists without systemic exposure can afford
good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific)
is not required for immune priming. To enhance colocalization of antigen
and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically
modified with phosphonates to allow adsorption onto aluminum hydroxide
(alum), a formulation commonly used in vaccines for antigen stabilization
and injection site deposition. The adsorption process is facilitated
by enhancing aqueous solubility of BZN analogs to avoid physical mixture
of two insoluble particulates. These BZN-phosphonates are highly adsorbed
onto alum, which significantly reduced systemic exposure and increased
local retention post injection. This report demonstrates a novel approach
in vaccine adjuvant design using phosphonate modification to afford
adsorption of small molecule immune potentiator (SMIP) onto alum,
thereby enhancing co-delivery with antigen.