Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents.
Toll-like receptor (TLR) agonists are being developed for use as vaccine adjuvants and as stand-alone immunomodulators because of their ability to stimulate innate and adaptive immune responses. Among the most thoroughly studied TLR agonists are the lipid A molecules that target the TLR4 complex. One promising candidate, monophosphoryl lipid A, which is a derivative of lipid A from Salmonella minnesota, has proven to be safe and effective as a vaccine adjuvant in > 120,000 human doses. A new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs), have been engineered specifically to target human TLR4 and are showing promise as vaccine adjuvants and as monotherapeutic agents capable of eliciting nonspecific protection against a wide range of infectious pathogens. In this review, the authors provide an update of the preclinical and clinical experiences with the TLR4 agonists, MPL (Corixa Corporation) adjuvant and the AGPs.
Baldridge
Jory R
JR
Corixa Corporation, 553 Old Corvallis Road, Hamilton, MT 59840, USA. jbaldridge@corixa.com
McGowan
Patrick
P
Evans
Jay T
JT
Cluff
Christopher
C
Mossman
Sally
S
Johnson
David
D
Persing
David
D
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D001428:Bacterial Vaccines / Q000008:administration & dosage; D002648:Child; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006017:Glycolipids / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011528:Protozoan Infections / Q000188:drug therapy / Q000517:prevention & control; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000502:physiology; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014765:Viral Vaccines / Q000008:administration & dosage; D014777:Virus Diseases / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D014779:Virus Replication / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D001428:Bacterial Vaccines; D006017:Glycolipids; D007155:Immunologic Factors; D008050:Lipid A; D008562:Membrane Glycoproteins; C500573:RC 527; C475764:RC529; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014765:Viral Vaccines; C048436:monophosphoryl lipid A