Compositions and methods for use of IL-12 as an adjuvant

Details Compositions and methods for use of IL-12 as an adjuvant Compositions and methods for use of IL-12 as an adjuvant

1999-03-01

2001-01-02

Park, Hankyel (Department: 1645)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S005000, C435S339100, C424S184100, C424S208100, C424S191100, C424S204100, C424S234100, C424S269100, C530S350000

Utility Patent

active

06168923

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to adjuvantation, and to the use of IL-12 as an adjuvant in pharmaceutical compositions, particularly in vaccines against infections requiring enhanced cell mediated immune (CMI) responses for effective protection against infection by a pathogen.
BACKGROUND OF THE INVENTION
The immune system uses many mechanisms for attacking pathogens, but not all of these are activated after immunization. Protective immunity induced by vaccination is dependent on the capacity of the vaccine to elicit the appropriate immune response to either resist, control, or eliminate the pathogen. Depending on the pathogen, this may require a cell-mediated or humoral immune response, which, in turn, is determined by the nature of the T cells that develop after immunization. For example, many bacterial, protozoal and intracellular parasitic and viral infections appear to require a strong cell-mediated immune response for protection, while other pathogens, such as helminths, primarily respond to a humoral, or antibody, response.
The current paradigm of the role of T cells in the particular immune response is that CD4
+
T cells can be separated into subsets on the basis of the repertoire of cytokines produced and that the distinct cytokine profile observed in these cells determines their function. This T cell model includes two major subsets: T
H
1 cells that produce IL-2 and interferon &ggr; (IFN-&ggr;) and mediate cellular immune responses, and T
H
2 cells that produce IL-4, IL-5, and IL-10 and augment humoral immune responses [T. R. Mosmann et al,
J. Immunol.,
126:2348 (1986)].
Many vaccine compositions employ adjuvants, that is, substances which enhance the immune response when administered together with an immunogen or antigen. Adjuvants are thought to function in several ways, including by increasing the surface area of antigen, prolonging the retention of the antigen in the body thus allowing time for the lymphoid system to have access to the antigen, slowing the release of antigen, targeting antigen to macrophages, activating macrophages, or otherwise eliciting non-specific activation of the cells of the immune system [see, e.g., H. S. Warren et al,
Annu. Rev. Immunol.,
4:369 (1986)]. Currently, an essential role of adjuvants in vaccines is to direct CD4
+
T cell subset differentiation, although how adjuvants perform this function is poorly understood.
The ability of a adjuvant to induce and increase a specific type of immune response and the identification of that ability is thus a key factor in the selection of particular adjuvants for vaccine use against a particular pathogen. Typical adjuvants include water and oil emulsions, e.g., Freund's adjuvant, and chemical compounds such as aluminum hydroxide or alum. At present, alum is the only adjuvant approved in the United States for human vaccines; it has been determined that alum induces the production of T
H
2 cells.
Many of the most effective adjuvants include bacteria or their products, e.g., microorganisms such as the attenuated strain of
Mycobacterium bovis,
bacillus Calmette-Guerin (BCG); microorganism components, e.g., alum-precipitated diphtheria toxoid, bacterial lipopolysaccharide and endotoxins. However, the role that the bacteria play is ill-defined. Recently, it has been noted that many bacteria or their products, lipopolysaccharide,
Staphylococcus aureus, Mycobacterium tuberculosis,
and
C. parvum,
stimulate IL-12 production by macrophages [A. D'Andrea et al,
J. Exp. Med.,
176:1387 (1992)].
However, despite their immunostimulating properties, many bacterial adjuvants have toxic or other negative effects, particularly in humans. For example, such a large population has been exposed to some of the bacterial adjuvants, like BCG, that there is a danger of eliciting a secondary response with future use as a vaccine adjuvant. Heat-killed bacteria, being non-native to mammalian hosts, also risk causing toxic effects in the host. In fact, the only currently well-accepted adjuvant for human use is the compound, alum.
Thus, there exists a need in the art for additional adjuvants which are useful in stimulating or enhancing the host's immune responses without inducing a toxic effect, and which are suitable for use in pharmaceutical compositions, such as vaccines.
BRIEF SUMMARY OF THE INVENTION
In one aspect the present invention provides a pharmaceutical composition useful as a vaccine comprising an antigen from a pathogenic microorganism and an effective adjuvanting amount of the protein, Interleukin-12 (IL-12), the resulting composition capable of eliciting the vaccinated host's cell-mediated immunity for a protective response to the pathogen. Preferably the pathogen against which the vaccine is directed is an intracellular parasite, such as a virus, bacterium, or protozoan. The pathogen may also be an extracellular parasite, e.g., a helminth or bacterium. The antigen may be a whole cell, a protein, a protein subunit or fragment. Also preferably the IL-12 is recombinant IL-12 or a biologically active fragment thereof.
In another aspect, the invention provides for a composition comprising DNA sequences encoding the antigen from a pathogenic microorganism, a subunit, or a fragment thereof, rather than the protein or peptide itself. These DNA sequences, together with appropriate promoter sequences, may be employed directly (“naked DNA”) as an antigen administered with, or close in time to, the IL-12 adjuvant. Alternatively, these DNA sequences may be transduced in alternate vaccine strains of the pathogenic microorganism, and upon expression in vivo may provide the antigen of the vaccine.
In still another aspect, the invention provides for the use of DNA sequences encoding IL-12, a subunit, or a fragment thereof. These DNA sequences, together with appropriate promoter sequences, may be employed directly (“naked DNA”) as an adjuvant administered with, or close in time to, the antigen of the pathogenic microorganism. Alternatively, these DNA sequences may be transduced in alternate vaccine strains of the pathogenic microorganism, and upon expression in vivo may adjuvant the-vaccine.
In yet a further embodiment, the DNA sequences encoding the antigen, a subunit, or a fragment thereof may be operably linked to, or co-transfected with the DNA sequences encoding IL-12, as subunit, or a fragment thereof.
In another aspect, the invention provides a method for preparing a vaccine composition containing an antigen from a pathogenic microorganism with enhanced ability to elicit the vaccinated host's CMI response against a pathogen or a DNA sequence encoding the antigen by adding to the vaccine composition an effective amount of the protein IL-12, an IL-12 subunit, or a biologically active fragment thereof or alternatively DNA sequences encoding IL-12, a subunit of IL-12, or a fragment thereof.
In still a further aspect the invention provides a method for increasing the ability of a vaccine composition containing an antigen from a pathogen (as protein and/or subunit, ‘naked’ DNA, or transduced DNA or a biologically active fragment thereof) to elicit the vaccinate's CMI for a protective immune response against the pathogen by administering to the vaccinate either simultaneously with or sequentially to the vaccine composition, an effective adjuvanting amount of IL-12 (as protein and/or subunit, ‘naked’ DNA, or transduced DNA or a biologically active fragment thereof).
In another aspect, the invention provides a therapeutic composition for the treatment or amelioration of the symptoms of cancer, and a method for adjuvanting a therapeutic cancer “vaccine”. A cancer vaccine or therapeutic may comprise an antigen expressed on the surface of a cancer cell. This antigen may be naturally present on the cancer cell. Alternatively, the cancer cell may be manipulated ex vivo and transfected with a selected antigen, which it then expresses when introduced into the patient. An exemplary therapeutic composition described herein

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