Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-02-08
2002-04-23
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S184100, C424S185100, C424S450000, C530S351000
Reexamination Certificate
active
06375945
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to improved adjuvant compositions, for the stimulation of an immune response suitable for immunotherapy applications. In particular the present invention relates to compositions comprising mixture of a saponin adjuvant with monophosphoryl lipid A or derivative thereof and interleukin 12. In particular, the invention relates to compositions comprising 3 de-o-acylated monosphoryl lipid A, QS21, and IL12. Such compositions are particularly useful in the immunotherapy of tumours.
BACKGROUND OF THE INVENTION
1. Field of the Invention
Cancer is a disease developing from a single cell due to genetic changes. Clinical detection of these tumours occurs mostly in a relatively late stage of disease, when the primary tumour can be removed by surgery, and the existence of micro metastases settled in different organs has often already occurred. Chemotherapy does often not completely eliminate these cells, which then remain as a source for recurrent disease.
Immune cells are able to control all different tissues (with the exception of the brain) and, due to their memory function, can also eliminate hidden cells reentering the circulation (metastasis). Therefore, an activated immune response to tumour cells is expected to be of clinical benefit. Despite their undifferentiated growth, tumour cells are in many aspects indistinguishable from normal cells, and over-expression of certain proteins or expression of mutated proteins is in most cases not sufficient to activate the immune response. This situation results in failure of immune surveillance. Thus, strategies for therapy of disseminated tumours need to specifically activate the immune response to tumour cells and to trigger migratory activity of cytotoxic T cells for example leading to elimination of most and possibly every single tumour cell. Genetic mutation in tumour cells is intense, and strong immune responses are therefore required to prevent further genetic changes of the tumour cells (escape variants) under the pressure of the immune system.
It is now well established that cellular antigens which are not cell surface proteins per se can be the targets of immune rejection through their recognition by immune regulatory and cytotoxic T cells. New potential target antigens for immune-mediated tumour rejection are being identified, based on their recognition by immune T cells, rather than by antibodies. Such antigens may or may not induce antibody formation. It is now recognized that the expression of tumour antigens by a cell is in itself not sufficient for induction of an immune response to these antigens. Initiation of a tumour rejection response requires a series of immune amplification phenomena dependent on the intervention of antigen presenting cells, which are responsible for delivery of a series of activation signals which ultimately leads to the rejection of the tumour.
Tumour rejection antigens which are presented on tumour cells and which are recognised by cytotoxic T cells can lead to lysis of the cell. To achieve this, in a clinical setting a vaccine composition comprising a rumour rejection antigen needs to be presented in a suitable adjuvant system to enable a suitable immune response to be mounted. However, activation of the immune systems requires activation signals which are initiated by antigen presenting cells and are not activated by the tumour cells themselves.
Vaccination with isolated tumour rejection antigens has been envisaged either by recombinant proteins, by the use of live recombinant vectors or by DNA vectors. Preferably subunit antigens will be used. However, to ensure these are effective, powerful adjuvant systems are required.
Accordingly, the present invention provides an adjuvant composition comprising a combination of a saponin adjuvant in combination with monophosphoryl lipid A or derivative thereof together with the cytokine Interleukin 12.
2. Description of the Related Art
Immunologically active saponin fractions having adjuvant activity derived from the bark of the South American tree Quillaja Saponaria Molina are known in the art. For example QS21, also known as QA21, is an Hplc purified fraction from the Quillaja Saponaria Molina tree and it's method of its production is disclosed (as QA21) in U.S. Pat. No. 5,057,540. Quillaja saponin has also been disclosed as an adjuvant by Scott et al, Int. Archs. Allergy Appl. Immun., 1985, 77, 409.
Monosphoryl lipid A and derivatives thereof are known in the art. A preferred derivative is 3 de-o-acylated monophosphoryl lipid A, and is known from British Patent No. 2220211.
Interleukin 12 (IL-12) is known. For a review see Trinchieri G. Interleukin-12—A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Immunology 13: 251.276, 1995. It is a heterodimeric cytokine produced mostly by phagocytic cells in response to bacteria, bacterial products, and intracellular parasites, and to some degree by B lymphocytes. In particular, IL-12 is produced by antigen presenting cells and instrumental in induction of TH-1 cell responses. IL-12 induces IFN-gamma from NK and T cells, acts as a growth factor for activated NK and T cells, enhances the cytotoxic activity of NK cells, and induces cytotoxic T lymphocyte generation.
REFERENCES:
patent: WO 94/00153 (1994-01-01), None
patent: WO 95/17209 (1995-06-01), None
patent: WO 96/10423 (1996-04-01), None
patent: WO 96/11019 (1996-04-01), None
patent: WO 97/01640 (1997-01-01), None
Boon Thierry
Silla Silvia
Uyttenhove Catherine
Hamud Fona
Kerekes Zoltan
Kinzig Charles M.
Kunz Gary L.
SmithKline Beecham Biologicals (s.a.)
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