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Heat Shock Proteins


Background

Heat shock proteins (HSPs), also called stress proteins, are a group of proteins that are present in all cells (normal cells, cancer cells and infected cells) in all life forms. They act like ‘chaperones,’ making sure that the cell’s proteins are in the right shape and in the right place at the right time which is essential for their function. More recent research has demonstrated that HSPs play an essential role in the presentation of pieces of proteins (or peptides) on the cell surface to help the immune system recognize diseased cells. In carrying out this function, HSPs bind to essentially every peptide in the cell, forming HSP-peptide complexes inside the cell. When a cell has become so sick that it dies, it can in some circumstances spill out all of its contents, including HSPs. This kind of messy, unplanned death is called necrosis and only occurs when something is very wrong with the cell. HSPs release from dying cells send a ‘danger signal’ to the immune system leading to generation of immune responses that can help to get rid of an infection or disease. Antigenics’ use of HSPs as vaccines against cancers and infections is thus intended to mimic and enhance what our bodies do normally to combat disease.

Heat shock proteins in immunity to cancer

The application of an HSP-based therapeutic approach to cancer is supported by seminal research showing that HSPs isolated from cancer cells elicit immunity to cancers whereas HSP preparations from normal tissues do not. Further, the immunity elicited by HSPs was observed to be individually cancer specific. That is, HSPs elicit immunity only to the particular tumor from which they are derived.

Complementing the research demonstrating HSPs elicit tumor-specific immunity are studies that have examined the nature of tumor antigens recognized by T cells, the arm of the immune system which plays a critical role in attacking cancer cells. Research beginning in the 1990s showed that many tumor antigens are the product of gene mutations which are unique to the tumor of an individual patient or restricted to very few patients [click here for a listing of such mutations]. Mutations arise randomly and accumulate in tumor cells, encoding a substantial repertoire of antigens which is also largely unique to each individual patient [click here for reference]. The specific immunogenicity of HSP preparations can thus be attributed to their being complexed to the unique repertoire of antigenic peptides that exists in different cancers.

Other research has shown that the immune response to the unique, tumor specific antigens is associated with tumor regression and prolonged survival in cancer patients [click here for references]. Collectively, these studies provide a strong rationale for administering cancer vaccines that contain a broad repertoire of tumor specific antigens- with the aim of further enhancing the very type of immune response which appears to be associated with prolonged survival of cancer patients. Such antigens are found in autologous cancer vaccines, like Oncophage.

Heat shock proteins in immunity to infectious diseases

The peptide binding property of HSPs has been shown to be a general one, not limited to tumor antigens. Thus, HSPs also bind to antigens of viruses and bacteria inside infected cells. Like in the case of cancer cells, HSPs isolated from infected cells remain associated with peptides specific to that pathogen and these HSP-peptide complexes may be used as vaccines against infectious agents. It is also possible to produce HSP-peptide complexes synthetically by mixing recombinant HSPs with known peptides. Unlike the application of HSPs in treatment of cancer, HSPs for treatment of infectious disease are off-the-shelf (non-personalized) vaccines.

The key properties of HSPs which make them imminently suitable for vaccination against infectious agents include:

Heat shock protein mechanism of action

Whether HSP-peptide complexes are isolated from cells or made synthetically, they represent a potent means of activating the immune system. Upon injection into the skin, HSP-peptide complexes interact with the immune system’s antigen-presenting cells (APCs) at the site of injection. APCs express receptors for HSPs, including CD91, leading to internalization of the complexes and migration of APCs to the lymph nodes. There, the APCs re-present the antigenic peptides on their surfaces. This triggers a cancer or pathogen-specific T cell response as well as release of immune system substances called cytokines which mediate other immune effector mechanisms. The multi-faceted nature of immunity elicited by HSPs has led to their being described as the immune system’s “Swiss army knife.” [click here for reference]


HSP References

QS-21 Adjuvant

QS-21 is a well characterized, chemically defined and potent vaccine adjuvant which has consistently stimulated strong cell-mediated and humoral immune responses when combined with a variety of vaccine antigens in preclinical studies– findings that have also been confirmed in clinical research. Since the 1940s the predominant adjuvant used in FDA-licensed vaccines is alum. Since then scientists have searched for better adjuvants, evaluating hundreds of potential candidates. Until the discovery of the Stimulon® (e.g., QS-21) adjuvants, results had been largely mediocre and disappointing.

QS-21 is isolated through a proprietary process from the bark of the Quillaja saponaria Molina tree, a species native to South America. The final product is lyophilized to yield a white powder that can be resolubilized in buffer and conventional diluents for use in vaccine formulations. The manufacture of QS-21 is robust and reproducible.

In numerous immunogenicity studies conducted by Antigenics and at least 50 other laboratories around the world, QS-21 has been demonstrated to modulate the humoral immune response (i.e., stimulation of antibody quantity, avidity, affinity, persistence, duration and/or isotype switching) to vaccine antigens. Because the type and subclass of antibody required for protective immunity differs among pathogens, the multi-faceted nature of humoral immunity generated by QS21 may be particularly advantageous in vaccine development.

QS-21 has also been shown to induce CD8+ cytotoxic T lymphocyte (CTL) cellular immune response to vaccine antigens and to decrease the minimum dose of antigen required to achieve an immune response. This dose-sparing effect is important for economical use of antigen. Additional studies compared the immunogenicity of QS-21 to other common adjuvants. QS-21 compared favorably for generation of antibody responses, for generation of cytotoxic T lymphocyte responses to subunit vaccines, and for stimulation of both Th1- and Th2-associated cytokines.

When incorporated into vaccines, QS-21 has also been shown to: