Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-05-13
2003-03-18
Wehbe, Anne M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S325000
Reexamination Certificate
active
06534482
ABSTRACT:
FIELD OF THE INVENTION
SUBMISSION ON COMPACT DISC
The contents of the following submission on compact discs are incorporated herein by reference in its entirety: A compact disc copy of the substitute Sequence Listing (COPY 1) (file name: 3996320022.txt, date recorded: Jan. 4, 2002, size:199 KB); a duplicate compact disc copy of the substitute Sequence Listing (COPY 2) (file name: 3996320022.txt, date recorded: Jan. 4, 2002, size: 199 KB); a computer readable form copy of the substitute Sequence Listing (CRF COPY) (file name: 3996320022.txt, date recorded: Jan. 4, 2002, size: 199 KB).
The present invention relates to nucleic acid vaccines encoding multiple CTL and HTL epitopes and MHC targeting sequences.
BACKGROUND OF THE INVENTION
Vaccines are of fundamental importance in modern medicine and have been highly effective in combating certain human diseases. However, despite the successful implementation of vaccination programs that have greatly limited or virtually eliminated several debilitating human diseases, there are a number of diseases that affect millions worldwide for which effective vaccines have not been developed.
Major advances in the field of immunology have led to a greater understanding of the mechanisms involved in the immune response and have provided insights into developing new vaccine strategies (Kuby,
Immunology,
443-457 (3rd ed., 1997), which is incorporated herein by reference). These new vaccine strategies have taken advantage of knowledge gained regarding the mechanisms by which foreign material, termed antigen, is recognized by the immune system and eliminated from the organism. An effective vaccine is one that elicits an immune response to an antigen of interest.
Specialized cells of the immune system are responsible for the protective activity required to combat diseases. An immune response involves two major groups of cells, lymphocytes, or white blood cells, and antigen-presenting cells. The purpose of these immune response cells is to recognize foreign material, such as an infectious organism or a cancer cell, and remove that foreign material from the organism.
Two major types of lymphocytes mediate different aspects of the immune response. B cells display on their cell surface specialized proteins, called antibodies, that bind specifically to foreign material, called antigens. Effector B cells produce soluble forms of the antibody, which circulate throughout the body and function to eliminate antigen from the organism. This branch of the immune system is known as the humoral branch. Memory B cells function to recognize the antigen in future encounters by continuing to express the membrane-bound form of the antibody.
A second major type of lymphocyte is the T cell. T cells also have on their cell surface specialized proteins that recognize antigen but, in contrast to B cells, require that the antigen be bound to a specialized membrane protein complex, the major histocompatibility complex (MHC), on the surface of an antigen-presenting cell. Two major classes of T cells, termed helper T lymphocytes (“HTL”) and cytotoxic T lymphocytes (“CTL”), are often distinguished based on the presence of either CD4 or CD8 protein, respectively, on the cell surface. This branch of the immune system is known as the cell-mediated branch.
The second major class of immune response cells are cells that function in antigen presentation by processing antigen for binding to MHC molecules expressed in the antigen presenting cells. The processed antigen bound to MHC molecules is transferred to the surface of the cell, where the antigen-MHC complex is available to bind to T cells.
MHC molecules can be divided into MHC class I and class II molecules and are recognized by the two classes of T cells. Nearly all cells express MHC class I molecules, which function to present antigen to cytotoxic T lymphocytes. Cytotoxic T lymphocytes typically recognize antigen bound to MHC class I. A subset of cells called antigen-presenting cells express MHC class II molecules. Helper T lymphocytes typically recognize antigen bound to MHC class II molecules. Antigen-presenting cells include dendritic cells, macrophages, B cells, fibroblasts, glial cells, pancreatic beta cells, thymic epithelial cells, thyroid epithelial cells and vascular endothelial cells. These antigen-presenting cells generally express both MHC class I and class II molecules. Also, B cells function as both antibody-producing and antigen-presenting cells.
Once a helper T lymphocyte recognizes an antigen-MHC class II complex on the surface of an antigen-presenting cell, the helper T lymphocyte becomes activated and produces growth factors that activate a variety of cells involved in the immune response, including B cells and cytotoxic T lymphocytes. For example, under the influence of growth factors expressed by activated helper T lymphocytes, a cytotoxic T lymphocyte that recognizes an antigen-MHC class I complex becomes activated. CTLs monitor and eliminate cells that display antigen specifically recognized by the CTL, such as infected cells or tumor cells. Thus, activation of helper T lymphocytes stimulates the activation of both the humoral and cell-mediated branches of the immune system.
An important aspect of the immune response, in particular as it relates to vaccine efficacy, is the manner in which antigen is processed so that it can be recognized by the specialized cells of the immune system. Distinct antigen processing and presentation pathways are utilized. The one is a cytosolic pathway, which results in the antigen being bound to MHC class I molecules. An alternative pathway is an endoplasmic reticulum pathway, which bypasses the cytosol. Another is an endocytic pathway, which results in the antigen being bound to MHC class II molecules. Thus, the cell surface presentation of a particular antigen by a MHC class II or class I molecule to a helper T lymphocyte or a cytotoxic T lymphocyte, respectively, is dependent on the processing pathway for that antigen.
The cytosolic pathway processes endogenous antigens that are expressed inside the cell. The antigen is degraded by a specialized protease complex in the cytosol of the cell, and the resulting antigen peptides are transported into the endoplasmic reticulum, an organelle that processes cell surface molecules. In the endoplasmic reticulum, the antigen peptides bind to MHC class I molecules, which are then transported to the cell surface for presentation to cytotoxic T lymphocytes of the immune system.
Antigens that exist outside the cell are processed by the endocytic pathway. Such antigens are taken into the cell by endocytosis, which brings the antigens into specialized vesicles called endosomes and subsequently to specialized vesicles called lysosomes, where the antigen is degraded by proteases into antigen peptides that bind to MHC class II molecules. The antigen peptide-MHC class II molecule complex is then transported to the cell surface for presentation to helper T lymphocytes of the immune system.
A variety of factors must be considered in the development of an effective vaccine. For example, the extent of activation of either the humoral or cell-mediated branch of the immune system can determine the effectiveness of a vaccine against a particular disease. Furthermore, the development of immunologic memory by inducing memory-cell formation can be important for an effective vaccine against a particular disease (Kuby, supra). For example, protection from infectious diseases caused by pathogens with short incubation periods, such as influenza virus, requires high levels of neutralizing antibody generated by the humoral branch because disease symptoms are already underway before memory cells are activated. Alternatively, protection from infectious diseases caused by pathogens with long incubation periods, such as polio virus, does not require neutralizing antibodies at the time of infection but instead requires memory B cells that can generate neutralizing antibodies to combat the pathogen before it is able to infect target tissues. Therefore, the effectiven
Chesnut Robert W.
Fikes John D.
Hermanson Gary G.
Ishioka Glenn Y.
Livingston Brian
Epimmune Inc.
Morrison & Foerster / LLP
Wehbe Anne M.
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