Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Patent
1997-02-11
1999-11-09
Elliott, George C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
4242781, 530351, A61K 3819, A61K 3820, A61K 3900, C07K 1452
Patent
active
059809116
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to adjuvants which comprise a combination of at least two cytokines or functional derivatives thereof. More particularly, the present invention is directed to an adjuvant such as a vaccine adjuvant comprising at least two cytokines or functional derivatives thereof wherein the cytokines are selected from IL-1.beta. and TNF.alpha. or IL-1.beta. and GM-CSF. The present invention is further directed to genetic adjuvants encoding at least two cytokines or derivatives thereof either separately or fused together. The present invention also contemplates a method for enhancing an immune response to an antigen comprising the administration of at least two cytokines which act in synergy to enhance an immune response to said antigen. The present invention is particularly useful in pharmaceutical vaccines and genetic vaccines in humans and livestock animals.
Bibliographic details of the publications referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide sequences referred to in the specification are defined following the bibliography.
Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements of integers but not the exclusion of any other element or integer or group of elements or integers.
The increasing sophistication of molecular biological and protein chemical techniques has, and continues to, revolutionise vaccine development. Frequently, however, recombinant and synthetic molecules exhibit less immunogenicity relative to the whole organism or cell from which they are derived. In order to increase the efficiency of such vaccines, considerable research has been directed to the development of immunological adjuvants.
Adjuvants promote the immune response in a number of ways (East et al, 1993). First, some adjuvants maintain a depot of antigen at the site of injection, as demonstrated by the correlation between persistence of antigen at the site of injection and maintenance of serum antibody levels. Second, adjuvants are capable of promoting accumulation of immunoreactive cells at the site of injection and in the draining lymph nodes, which ensures optimal exposure of specific immunoresponsive cells to the antigen. Adjuvants also modify the activities of cells that are concerned with generating and maintaining the immune response. Additionally, adjuvants modify the presentation of antigen to the immune system.
Cytokines such as interleukins (IL-1 to 13), colony stimulating factors (CSFs), tumour necrosis factors (TNF-.alpha. and .beta.) and interferons (IFN-.alpha., .beta. and .gamma.) are the hormones of the immune system which control and determine the nature of the immune response (Balkwill and Burke, 1989). Adjuvants with the capacity for immune modulation achieve their activity primarily by modification of cytokine production, probably by direct action upon T cells or macrophages (Cox and Coulter, 1992). Cytokines regulate various aspects of the immune response to vaccination including cellular traffic at the site of vaccination (Zimmerman et al., 1992), antigen presentation (Valle et al., 1991), the phenotype of the T helper cell response (Romagnani, 1992), maturation and differentiation of the B cell response (Snapper and Mond, 1993) and differentiation of non-specific killer cells such as eosinophils and mast cells (Clutterbuck et al., 1989). Recombinant cytokines not only have the potential to enhance the immune response to a vaccine antigen but also alter the immune response leading to different effector mechanisms.
As an alternative to chemical adjuvants, the use of cytokines as natural adjuvants is attracting considerable interest (reviewed by Heath and Playfair, 1992). Various cytokines have been shown to be effective immunological adjuvants in a variety of model systems, enhancing protection induced by bacter
REFERENCES:
Arroyo et al. (1990) Active specific immunotherapy with vaccinia colon oncolysate enhances the immunomodulatory and antitumor effects of interleukin-2 and interferon alpha in a murine hepatic metastases model. Cancer Immunol. Immunother. 31:305-311, Aug. 1990.
Schijns et al. (1994) Modulation of antiviral immune responses by exogenous cytokines: effects of tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and interferon-gamma on the immunogenicity of an inactivated rabies vaccine. J. Gen. Virol. 7, Jan. 1994.
Heath, et al. (1992) "Cytokines as Immunological Adjuvants", Vaccine 10:427-434.
McCullough et al. (1991) "The Immune Response Against Foot-and-Mouth Disease Virus: Influence of the T Lymphocyte Growth Factors IL-1 and IL-2 on the Murine Humoral Repsonse in vivo", Immunol. Lett. 31:41-46.
Reddy et al. (1993) "Immunopotentiation of Bovine Respiratory Disease Virus Vaccines by Interleukin-1B and Interleukin-2*", Veterinary Immunology and Immunopathology 37:25-38.
Corner Leigh Austin
McWaters Peter
Rothel James Stuart
Seow Heng Fong
Wood Paul Richard
Commonwealth Scientific and Industrial Research Organisation
Elliott George C.
Schwartzman Robert
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