WO2008147489A1 - Ligands de récepteur de type péage topique en tant qu'adjuvants de vaccin - Google Patents

Ligands de récepteur de type péage topique en tant qu'adjuvants de vaccin Download PDF

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Publication number
WO2008147489A1
WO2008147489A1 PCT/US2008/004863 US2008004863W WO2008147489A1 WO 2008147489 A1 WO2008147489 A1 WO 2008147489A1 US 2008004863 W US2008004863 W US 2008004863W WO 2008147489 A1 WO2008147489 A1 WO 2008147489A1
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WIPO (PCT)
Prior art keywords
vaccine
imiquimod
ova
adjuvant
site
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PCT/US2008/004863
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English (en)
Inventor
Jean-Claude Bystryn
Original Assignee
Jean-Claude Bystryn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/754,121 external-priority patent/US20090060928A1/en
Application filed by Jean-Claude Bystryn filed Critical Jean-Claude Bystryn
Publication of WO2008147489A1 publication Critical patent/WO2008147489A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2

Definitions

  • a critical element in constructing more effective vaccines against cancer, infections and other diseases is the availability of potent adjuvants that can boost vaccine-induced immune responses and which are safe and simple to use.
  • Adjuvants that promote Th1 responses are particularly desirable, as these responses play a major role in protective immunity.
  • a wide variety of adjuvants are currently available, but all have limitations.
  • Aluminum hydroxide (alum) the only adjuvant approved for use in humans, lacks potency. The strongest adjuvant, Freund's, cannot be used in humans because it causes severe local toxicity.
  • Dendritic cells (DC) are another potent adjuvant, but their application is limited by the cost and time required to make a custom preparation of dendritic cells for each patient.
  • Most other adjuvants are typically admixed with the vaccine, so that each application of the adjuvant with a different vaccine must go through the difficult and lengthy FDA approval process as a new formulation.
  • a potent adjuvant that can be used with vaccines without the need to create a new formulation would have highly desirable value.
  • the present invention provides a method for the administration of toll-like receptor (TLR) ligands separately from the vaccine to achieve this goal.
  • the ligand can be administered topically to skin at a site distal from the vaccine administration, to skin over the site of vaccine immunization, or possibly to a patient orally or by injection.
  • Fig. 1 shows the effect of topical imiquimod on antibody response to OVA immunization.
  • Fig. A Groups of mice were immunized to OVA alone or followed by topical application of imiquimod to the site of immunization 3x/wk. or to OVA in ILK-2 liposomes. One week following 4 weekly immunizations, sera was collected and tested for anti-OVA IgG antibodies by ELISA. Anti-OVA IgG responses was greater in mice treated with imiquimod than in those immunized to OVA alone. It was as strong as that induced by IL-2 liposomes as the adjuvant.
  • Fig. A Groups of mice were immunized to OVA alone or followed by topical application of imiquimod to the site of immunization 3x/wk. or to OVA in ILK-2 liposomes.
  • One week following 4 weekly immunizations sera was collected and tested for anti-OVA IgG antibodies by ELISA.
  • IgGI 1 lgG2a, lgG2b, and lgG3 anti-OVA antibodies was measured in these groups by ELISA, using subclass specific antibodies as probes.
  • lgG2a and lgG2b antibody responses were markedly boosted by imiquimod, whereas IgGI responses were reduced compared to OVA only immunized mice. No response was seen in PBS immunized controls.
  • Fig 2 shows the effect of topical imiquimod on vaccine-induced T-cell responses:.
  • Fig. 1A Mice were immunized to OVA with or without topical application of imiquimod treatment 1x or 3x/wk following each immunization. Spleen cells were collected from each group 1 week following 4 immunizations, and tested by ELISPOT (based on gamma-interferon release) for T-cell response to OVA positive target cells (E.G7-OVA).
  • Fig. 2B Mice were immunized to OVA with topical application of imiquimod 3x/week or with OVA encapsulated into IL-2 liposomes. Imiquimod boosted T-cell responses more strongly than IL-2 liposomes.
  • Fig. 3A shows the effect of topical imiquimod on antibody (A) and cellular (B) responses to OVA immunization.
  • Fig. 3A Groups of mice were immunized to OVA alone or followed by topical application of imiquimod to the site of immunization 1x/wk. or to a site distal to the immunization. One week following 4 weekly immunizations, sera was collected and tested for anti-OVA IgG subclass antibodies by ELISA. Anti-OVA IgG responses was greater in mice treated with imiquimod both locally and distally than in those immunized to OVA alone.
  • Fig. 3B Triplicate mice were sacrificed 1 week after 4 immunizations and cellular immune responses to OVA-expressing target E.G7-OVA cells determined by ELIspot assay
  • TLR ligands are emerging as a new class of vaccine adjuvants.
  • TLR are expressed on a variety of antigen presenting cells (APC), and when activated stimulate the differentiation and maturation of several populations of immune cells and release of a broad range of cytokines and other immunomodulatory molecules (1-3).
  • APC antigen presenting cells
  • TLR7 is expressed to various degrees on all subpopulations of human APCs including myeloid and plasmacytoid DC (4,5).
  • TLR9 is expressed only on plasmacytoid DC and B cells (5-7).
  • TLR7 and TLR8 Several ligands have been identified that can bind to and activate each of these TLRs. Each ligand activates distinct TLRs. The best studied are the imidazoquinoline molecules imiquimod and resiquimod which activate TLR7 and TLR8 (5,8,9) and certain CpG oligonucleotides (CpG ODN) which react only with TLR9 (6,7,10,11).
  • TLR 7 and 8 ligands such as imiquimod and resiquimod bind to TLR 7 and 8 and by so doing activate plasmacytoid DC (pDC) and NK cells in blood (12), induce the maturation of pDC (12), rapidly upregulate the expression of costimulatory molecules CD40, CD80, and CD86 and MHC class II, and stimulate the production of other cytokines (IL-1 , IL-1 R, IL-6, IL- 8 and IL-12) (13).
  • Topical application of both agents to skin attracts CD4+ CD3- pDC (14), induces the synthesis of IFN-alpha and gamma (15), and enhances maturation of Langerhans cells and their ability to present antigen (2) at the site of topical application.
  • TLR 9 ligands such as CpG ODN stimulate TLR9 and cause a signaling cascade that culminates in the maturation, differentiation and proliferation of T-cells, monocytes/macrophages and natural killer cells (16). These cells secrete a number of proinflammatory cytokines including IL-1 , IL-6, IL-12, IL-18 and interferon-gamma (16). Activation of immune cells by all of these ligands results in Th-1 dominant immune responses.
  • TLR7 and TLR9 ligands also appear to be effective vaccine adjuvants.
  • Imiquimod and resiquimod both augment specific CD4+ and CD8+ T-cell responses against CMV and HIV-1 in vitro.
  • both ligands enhance the strength and longevity of antigen specific CD4+ and CD8+ T-cell responses against OVA, and anti-viral protective immunity (25) in mice (11).
  • Intramuscular resiquimod given in combination with an HIV DNA vaccine enhanced antigen-specific T-cell proliferative responses by seven-fold and Th-1 antibody responses by five-fold (13).
  • the immune responses are biased towards Th 1 responses.
  • TLR ligand-vaccine combinations have typically been studied with both agents given together by a variety of systemic routes including subcutaneous, intramuscular, and intranasal (16).
  • mice were immunized sc weekly x 4 to 0.1 mg of ovalbumin (OVA). Some groups were in addition treated with 5% imiquimod cream applied topically to the immunization site once or 3x/week Control groups were immunized to PBS, to OVA encapsulated into IL-2 liposomes (which we have previously shown is one of the strongest adjvuanrts available), orto irradiated EG7-OVA cells (a powerful stimulator of anti- OVA T-cell responses). Serum was collected from each mouse at baseline and followingthe 4 th immunization, pooled by immunization group, and assayed for antibodies to OVA by ELISA. As shown in Fig.
  • imiquimod is a potent vaccine adjuvant when applied topically. It can powerfully enhance both antibody and CD8 T-cells responses.
  • the second major discovery that provides the foundation of this invention was a completely unexpected finding. It came to light in the course of control experiments conducted to confirm that imiquimod applied topically directly over the immunization site was an effective vaccine adjuvant.
  • mice were immunized to PBS or to OVA. As shown in Fig. 3A, the anti-OVA IgG subclass response was considerably greater in mice immunized to OVA + topical imiquimod both local and distal to vaccine injection sites than in mice immunized to OVA alone. Endpoint titer analysis determined by ELISA pf serial serum dilutions showed that the lgG2a titers were 1 :312,500 and 1 :62,500 for local and distal imiquimod treatment and were 125 and 25 times stronger than OVA alone respectively. The lgG2b endpoint titers were identical at 1 :62,500 and were both 125 stronger than OVA alone.
  • TLR ligands may be able to enhance stronger or broader type of immune response than any one individual TLR ligand alone. This invention is intended to cover these different possibilities.
  • Novel specific ways of using this invention include: 1) administering the TLR ligand topically away from the site of vaccine immunization as well as topically directly over the site of, but separately from, vaccine administration; 2) administering the TLR adjuvant orally or otherwise systemically (by injection or intranasaly) concurrently with vaccination; 3) enhancing the adjuvant activity of topical TLR ligand by applying them to skin in a patch or other slow release vehicle; 4) and administering the TLR ligand systemically in a slow release vehicle (such as liposomes).
  • This invention applies not only to imiquimod, but to all other TLR7, 8 and 9 ligands.
  • the purpose of the invention is to provide novel methods of using a new class of potent adjuvants (toll-like receptor ligands) that: 1) provide the major advantage that the adjuvant can be used as a universal vaccine adjuvant that does not require the formulation of a new product with each new vaccine that the adjuvant is used with; and 2) permits the adjuvant to be used by topical administration over the site of vaccine immunization, or topically at a site distal from the vaccine or orally or by other systemic administration.
  • potent adjuvants toll-like receptor ligands
  • the purpose of this invention is to provide novel methods of using a powerful new class of vaccine adjuvants (toll-like receptor [TLR] ligands). It provides the major advantage that the adjuvant can be used as a universal adjuvant that does not require the formulation of a new product with each new vaccine that the adjuvant is used with. This is accomplished by formulating the adjuvant as a separate product that is administered to the patient or animal independently, and at a separate site, from the vaccine. The separate site can be on the skin (topical application) or orally or systemically.
  • TLR toll-like receptor
  • the adjuvant is formulated and administered independently of the vaccine and at site different from that of vaccine administration. This is in contradicstinction to the conventional manner of using adjuvants, which is to admix them with the vaccine.
  • the conventional approach means that each new formulation of the same adjuvant with a different vaccine is viewed as a new product which must go through the lengthy and expensive FDA certification process.
  • the adjuvant is formulated and administered separately from the vaccine antigen, and hence is a separate product. As a result, the adjuvant can be used with a variety of vaccines without need to obtain FDA approval f ⁇ each new use.
  • TLR ligand adjuvants appear more powerful than many current adjuvants. They can enhance the effectiveness of current vaccines and/or permit lesser amounts to be used to obtain the same effect. This latter property would be very helpful to extend the availability of vaccines that are in short supply, such as the current influenza vaccines.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mycology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un procédé pour augmenter une réponse immunologique à un Mvaccin, comprenant: l'administration du vaccin par voie sous-cutanée à un patient en besoin de celui-ci; et l'administration d'une composition topique contenant une quantité d'un ligand de récepteur de type péage efficace pour augmenter une réponse immunitaire du patient au vaccin.
PCT/US2008/004863 2007-05-25 2008-04-15 Ligands de récepteur de type péage topique en tant qu'adjuvants de vaccin WO2008147489A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/754,121 2007-05-25
US11/754,121 US20090060928A1 (en) 2006-05-26 2007-05-25 Topical Toll Like Receptor Ligands as Vaccine Adjuvants

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WO2008147489A1 true WO2008147489A1 (fr) 2008-12-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3324963A4 (fr) * 2015-07-17 2019-03-20 EMV Enhance (HK) Limited Méthodes et compositions destinées à renforcer une réponse immunitaire à une vaccination
WO2022143894A1 (fr) * 2020-12-30 2022-07-07 苏州百迈生物医药有限公司 Suspension d'adjuvant immunitaire à libération auto-prolongée, son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030139364A1 (en) * 2001-10-12 2003-07-24 University Of Iowa Research Foundation Methods and products for enhancing immune responses using imidazoquinoline compounds
US6797276B1 (en) * 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6797276B1 (en) * 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
US20030139364A1 (en) * 2001-10-12 2003-07-24 University Of Iowa Research Foundation Methods and products for enhancing immune responses using imidazoquinoline compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOHNSTON ET AL.: "Topical imiquimod is a potent adjuvant to a weakly-immunogenic protein prototype vaccine", VACCINE, vol. 24, no. 11, March 2006 (2006-03-01), pages 1958 - 1965, XP005294696 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3324963A4 (fr) * 2015-07-17 2019-03-20 EMV Enhance (HK) Limited Méthodes et compositions destinées à renforcer une réponse immunitaire à une vaccination
US11357773B2 (en) * 2015-07-17 2022-06-14 Versitech Limited Methods and compositions for enhancing immune response to vaccination
WO2022143894A1 (fr) * 2020-12-30 2022-07-07 苏州百迈生物医药有限公司 Suspension d'adjuvant immunitaire à libération auto-prolongée, son procédé de préparation et son utilisation

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