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.
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Alex
A
Cortez
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Yongkai
Y
Li
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Andrew T
AT
Miller
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Xiaoyue
X
Zhang
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Kathy
K
Yue
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Jillian
J
Maginnis
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Janice
J
Hampton
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
De Shon
de S
Hall
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Michael
M
Shapiro
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Bishnu
B
Nayak
GSK Vaccines , Via Florentina, 1, 53100, Siena, Italy.
Ugo
U
D'Oro
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Chun
C
Li
GSK Vaccines , Via Florentina, 1, 53100, Siena, Italy.
David
D
Skibinski
GSK Vaccines , 45 Sydney Street, Cambridge, Massachusetts 02139, United States.
M Lamine
ML
Mbow
GSK Vaccines , 45 Sydney Street, Cambridge, Massachusetts 02139, United States.
Manmohan
M
Singh
GSK Vaccines , 45 Sydney Street, Cambridge, Massachusetts 02139, United States.
Derek T
DT
O'Hagan
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Michael P
MP
Cooke
GSK Vaccines , 45 Sydney Street, Cambridge, Massachusetts 02139, United States.
Nicholas M
NM
Valiante
Genomics Institute of Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Tom Y-H
TY
Wu
D000327:Adsorption; D000536:Aluminum Hydroxide / Q000737:chemistry*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007273:Injections, Intramuscular; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009287:Naphthyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D063065:Organophosphonates / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists*
D009287:Naphthyridines; D063065:Organophosphonates; D051199:Toll-Like Receptor 7; D000536:Aluminum Hydroxide