Publications by authors named "Christopher W Cluff"

6 Publications

  • Page 1 of 1

Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results.

Adv Exp Med Biol 2010 ;667:111-23

Glaxo Smith Kline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA.

As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e. g., Melan-A/ MART-1, tyrosinase, gp 100). Some target antigens are specifically expressed in tumors of different types but not in normal tissues (e. g., MAGE-3), while other possible targets are antigens that are expressed at low level in normal tissues and are over-expressed in tumors of different types (e. g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (pS3) or tumor-specific post-translational modified proteins (under glycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, these antigens tend to be poorly inmmunogenic by themselves and vaccines containing them generally require the inclusion of potent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Many adjuvants currently under evaluation for use in cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via toll-like receptors (TLRs) and promote effective uptake, processing and presentation of antigen to T-cells in draining lymph nodes.Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for lipid A have allowed for a better understanding of how this immunostimulant functions with regard to induction of innate and adaptive immune responses.Although several lipid A species, including LPS and synthetic analogs, have been developed and tested as monotherapeutics for the treatment of cancer,1-8 only 3-O-desacyl-4'-monophosphoryl lipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL comprises the lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the l-phosphare have been removed by successive acid and base hydrolysis.9 LPS and MPL induce similar cytokine profiles, but MPLis at least 1OO-fold less toxic.9,10 lOMPL has been administered to more than 300, 000 human subjects in studies of next-generation vaccines.11 In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various cancer vaccines containing MPL, either alone or combined with other immunostimulants, Such as cell wall skeleton (CWS) of Mycobacterium phlei in the adjuvant Detox; Biomira, Inc.), the saponin QS-21 (in the adjuvants AS01B and AS02B; GSK Biologicals) or with QS-21 and CpG oligonucleotides (in the adjuvant AS15; GSK Biologicals) will be summarized. Combining MPL with other immunostimulants has been demonstrated to be advantageous in many cases and may be required to elicit the full complement of activities necessary to achieve an effective immune response and overcome the ability of tumors to evade attack by the immune system. In this chapter, information relating to vaccines targeting specific cancers will be presented in the first section, while information relating to vaccines targeting multiple tumor types by the induction of immune responses to shared TAAs is presented in the second section.
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http://dx.doi.org/10.1007/978-1-4419-1603-7_10DOI Listing
August 2011

The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics.

Bioorg Med Chem Lett 2008 Oct 19;18(20):5350-4. Epub 2008 Sep 19.

GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA.

To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.060DOI Listing
October 2008

Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.

Infect Immun 2005 May;73(5):3044-52

Corixa Corporation, 1900 9th Avenue, Suite 1100, Seattle, WA 98101, USA.

A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.
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http://dx.doi.org/10.1128/IAI.73.5.3044-3052.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087352PMC
May 2005

Structure-activity relationship of synthetic toll-like receptor 4 agonists.

J Biol Chem 2004 Feb 21;279(6):4440-9. Epub 2003 Oct 21.

Corixa Corporation, Seattle, Washington 98104, USA.

Important questions remain regarding the impact of variations in the structure of the lipid A portion of lipopolysaccharide on activation of cells via the Toll-like receptor 4 complex. We have studied a series of synthetic lipid A mimetic compounds known as aminoalkyl glucosaminide phosphates in which the length of the secondary acyl chain has been systematically varied. Using transcriptional profiling of human monocytes and responses of Toll-like receptor 4 complex cell transfectants, we demonstrate a clear dependence of length on secondary acyl chain on Toll-like receptor 4 activation. Compounds with secondary acyl chains less than eight carbons in length have dramatically reduced activity, and substitutions of the left-sided secondary acyl chain had the most important effect on the Toll-like receptor 4 agonist activity of these molecules. The structure-function relationships of these compounds assessed via the induction of chemokines and cytokines following in vivo administration closely mirrored those seen with cell-based studies. This novel set of synthetic lipid A mimetics will be useful for Toll-like receptor 4-based investigations and may have clinical utility as stand-alone immunomodulators.
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http://dx.doi.org/10.1074/jbc.M310760200DOI Listing
February 2004

Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529.

Expert Rev Vaccines 2003 Apr;2(2):219-29

Corixa Corporation, Hamilton, MT 59840, USA.

MPL (Corixa) adjuvant is a chemically modified derivative of lipopolysaccharide that displays greatly reduced toxicity while maintaining most of the immunostimulatory activity of lipopolysaccharide. MPL adjuvant has been used extensively in clinical trials as a component in prophylactic and therapeutic vaccines targeting infectious disease, cancer and allergies. With over 33,000 doses administered to date, MPL adjuvant has emerged as a safe and effective vaccine adjuvant. Recently, scientists at Corixa Corporation have developed a library of synthetic lipid A mimetics (aminoalkyl glucosaminide 4-phosphates) with demonstrated immunostimulatory properties. Similar to MPL adjuvant, these synthetic compounds signal through Toll-like receptor 4 to stimulate the innate immune system. One of these compounds, Ribi.529 (RC-529), has emerged as a leading adjuvant with a similar efficacy and safety profile to MPL adjuvant in both preclinical and clinical studies.
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http://dx.doi.org/10.1586/14760584.2.2.219DOI Listing
April 2003

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

J Endotoxin Res 2002 ;8(6):453-8

Corixa Corporation, Hamilton, Montana 59840, USA.

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.
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http://dx.doi.org/10.1179/096805102125001064DOI Listing
July 2003