Solid phase activators of the alternative pathway of complement and their use in vivo

Cooper, Penny

doi:10.1007/978-94-011-2757-8_4

Cited by 10 publications

(19 citation statements)

References 117 publications

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“…Serum ACP levels returned to normal after 16−ndash;24 h post‐treatment. Similar results were obtained in rabbits and dogs using various administration routes 4 .…”

Section: Biological Effects Of Inulinsupporting

confidence: 78%

Inulin‐derived adjuvants efficiently promote both Th1 and Th2 immune responses

2004

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Summary There has been a recent resurgence of interest into new and improved vaccine adjuvants. This interest has been stimulated by the need for new vaccines to combat problematic pathogens such as SARS and HIV, and to counter potential bioterrorist attacks. A major bottleneck in vaccine development is the low immunogenicity of purified subunit or recombinant proteins, creating the need for safe human adjuvants with high potency. A major problem in the search for the ideal adjuvant is that adjuvants that promote cell-mediated (Th1) immunity (e.g. Freund's complete adjuvant) generally have unacceptable local or systemic toxicity that precludes their use in human vaccines. There is a need for a safe, non-toxic adjuvant that is able to stimulate both cell-mediated and humoral immunity. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against hepatitis B, malaria and other pathogens. If such trials are successful, then it is possible that inulinderived adjuvants will one day replace alum as the adjuvant of choice in most human prophylactic vaccines.

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“…Serum ACP levels returned to normal after 16−ndash;24 h post‐treatment. Similar results were obtained in rabbits and dogs using various administration routes 4 .…”

Section: Biological Effects Of Inulinsupporting

confidence: 78%

Inulin‐derived adjuvants efficiently promote both Th1 and Th2 immune responses

2004

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“…The first therapeutic isoform (gamma inulin (GI)) was followed by the more active delta inulin (DI), which is the clinically preferred option . The biological significance of these newer, relatively insoluble inulin forms, in contrast to the more soluble alpha and beta isoforms, is their clinical utility as potent, safe and well-tolerated immune modulators, most notably as vaccine adjuvants (Cooper and Steele 1988;Frazer et al 1999;Silva et al 2004;Lobigs et al 2010;Cooper and Petrovsky 2011;Cristillo et al 2011;Layton et al 2011;Gordon et al 2012;Honda-Okubo et al 2012;Larena et al 2013;Saade et al 2013) but also with anti-cancer effects (Cooper and Carter 1986b;Cooper 1993;Korbelik and Cooper 2007). DI is also a useful reagent for exploring and regulating cellular immune functions in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions

2013

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In studying the molecular basis for the potent immune activity of previously described gamma and delta inulin particles and to assist in production of inulin adjuvants under Good Manufacturing Practice, we identified five new inulin isoforms, bringing the total to seven plus the amorphous form. These isoforms comprise the step-wise inulin developmental series amorphous → alpha-1 (AI-1) → alpha-2 (AI-2) → gamma (GI) → delta (DI) → zeta (ZI) → epsilon (EI) → omega (OI) in which each higher isoform can be made either by precipitating dissolved inulin or by direct conversion from its precursor, both cases using regularly increasing temperatures. At higher temperatures, the shorter inulin polymer chains are released from the particle and so the key difference between isoforms is that each higher isoform comprises longer polymer chains than its precursor. An increasing trend of degree of polymerization is confirmed by end-group analysis using 1 H nuclear magnetic resonance spectroscopy. Inulin isoforms were characterized by the critical temperatures of abrupt phase-shifts (solubilizations or precipitations) in water suspensions. Such (aqueous) "melting" or "freezing" points are diagnostic and occur in strikingly periodic steps reflecting quantal increases in noncovalent bonding strength and increments in average polymer lengths. The (dry) melting points as measured by modulated differential scanning calorimetry similarly increase in regular steps. We conclude that the isoforms differ in repeated increments of a precisely repeating structural element. Each isoform has a different spectrum of biological activities and we show the higher inulin isoforms to be more potent alternative complement pathway activators.

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“…It has also been known for some time that intralesional g-inulin treatment elicits antitumour responses and it was demonstrated that this results from the complement-activating effect (Cooper and Carter, 1986b). Positive responses following multiple treatment regimens were reported with mouse tumours (B16 melanoma model), squamous cell carcinoma in sheep, equine sarcoids, and spontaneous malignancies in dogs (Cooper and Carter 1986b;Cooper, 1993). Our recent related work has shown that complement component C3 and other complement proteins accumulate in tumours treated by PDT (Cecic and Korbelik, 2002;Cecic et al, 2005), and that complement system recognises PDT-treated tumour cells as their target .…”

Section: Discussionmentioning

confidence: 99%

“…The formulation selects the high molecular weight form (up to 16 000) of this inert polysaccharide with the greatest potency for the activation of alternative complement pathway by providing an optimised surface that binds C3b while shielding it from inactivation by factor H (Cooper, 1993). The treatments were performed by intratumoural injection of 0.1 mg (40 ml) of g-inulin suspension immediately after PDT light exposure.…”

Section: C-inulinmentioning

confidence: 99%

Potentiation of photodynamic therapy of cancer by complement: the effect of γ-inulin

Korbelik

Cooper

2006

Br J Cancer

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Host response elicited by photodynamic therapy (PDT) of cancerous lesions is a critical contributor to the clinical outcome, and complement system has emerged as its important element. Amplification of complement action was shown to improve tumour PDT response. In search of a clinically relevant complement activator for use as a PDT adjuvant, this study focused on g-inulin and examined its effects on PDT response of mouse tumours. Intralesional g-inulin (0.1 mg mouse À1 ) delivered immediately after PDT rivaled zymosan (potent classical complement activator) in delaying the recurrence of B16BL6 melanomas. This effect of g-inulin was further enhanced by IFN-g pretreatment. Tumour C3 protein levels, already elevated after individual PDT or g-inulin treatments, increased much higher after their combination. With fibrosarcomas MCA205 and FsaR, adjuvant g-inulin proved highly effective in reducing recurrence rates following PDT using four different photosensitisers (BPD, ce6, Photofrin, and mTHPC). At 3 days after PDT plus g-inulin treatment, over 50% of cells found at the tumour site were CTLs engaged in killing specific targets via perforingranzyme pathway. This study demonstrates that g-inulin is highly effective PDT adjuvant and suggests that by amplifying the activation of complement system, this agent potentiates the development of CTL-mediated immunity against PDT-treated tumours.

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Solid phase activators of the alternative pathway of complement and their use in vivo

Cited by 10 publications

References 117 publications

Inulin‐derived adjuvants efficiently promote both Th1 and Th2 immune responses

Inulin‐derived adjuvants efficiently promote both Th1 and Th2 immune responses

The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions

Potentiation of photodynamic therapy of cancer by complement: the effect of γ-inulin

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