Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand.
The immunotherapeutic activity of Toll-like receptor (TLR) activators has been difficult to exploit because of side effects related to the release and systemic dispersion of proinflammatory cytokines. To overcome this barrier, we have synthesized a versatile TLR7 agonist, 4-[6-amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzaldehyde (UC-1V150), bearing a free aldehyde that could be coupled to many different auxiliary chemical entities through a linker molecule with a hydrazine or amino group without any loss of activity. UC-1V150 was covalently coupled to mouse serum albumin (MSA) at a 5:1 molar ratio to yield a stable molecule with a characteristically altered UV spectrum. Compared with the unconjugated TLR7 agonist, the UC-1V150/MSA was a 10- to 100-fold more potent inducer of cytokine production in vitro by mouse bone marrow-derived macrophage and human peripheral blood mononuclear cells. When administrated to the lung, the conjugate induced a prolonged local release of cytokines at levels 10-fold or more higher than those found in serum. Under the same conditions, the untethered TLR7 ligand induced quick systemic cytokine release with resultant toxicity. In addition, two pulmonary infectious disease models were investigated wherein mice were pretreated with the conjugate and then challenged with either Bacillus anthracis spores or H1N1 influenza A virus. Significant delay in mortality was observed in both disease models with UC-1V150/MSA-pretreated mice, indicating the potential usefulness of the conjugate as a localized and targeted immunotherapeutic agent.
Wu
Christina C N
CC
*The Rebecca and John Moores Cancer Center and Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0820.
Hayashi
Tomoko
T
Takabayashi
Kenji
K
Sabet
Mojgan
M
Smee
Donald F
DF
Guiney
Donald D
DD
Cottam
Howard B
HB
Carson
Dennis A
DA
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D005260:Female; D007167:Immunotherapy / Q000295:instrumentation / Q000379:methods*; D008024:Ligands; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D012709:Serum Albumin / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
D000447:Aldehydes; D008024:Ligands; D012709:Serum Albumin; D051199:Toll-Like Receptor 7