Agenus :: the patient is waiting

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. Agenus’ use of HSPs as vaccines against cancers and infections is thus intended to mimic and enhance what our bodies do normally to combat disease.

The Prophage Series cancer vaccine candidates are autologous vaccines 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.

Agenus’ Prophage Series vaccines include the R-Series for renal cell carcinoma, the G-Series for glioma, the NP-Series for pediatric neurologic tumors and the M-Series for melanoma. The Prophage Series cancer vaccines are applicable to all tumor types.

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 that plays a critical role in attacking cancer cells. Research beginning in the 1990s showed that many tumor antigens are the product of gene mutations that are unique to the tumor of an individual patient or restricted to very few patients [more]. Mutations arise randomly and accumulate in tumor cells, encoding a substantial repertoire of antigens that is also largely unique to each individual patient [more]. 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 [more]. 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 that appears to be associated with prolonged survival of cancer patients. Such antigens are found in autologous cancer vaccines, like those in the Prophage Series vaccines.

The Recombinant Series vaccines are based on the generalized peptide binding property of HSPs. Thus, in addition to tumor antigens, HSPs also bind to antigens of viruses and bacteria inside infected cells. Moreover, it is also possible to produce HSP-peptide complexes synthetically by mixing recombinant HSPs with known peptides. This recombinant approach is used for production of Agenus’ lead product candidate, HerpV, for treatment of genital herpes. Unlike the application of HSPs in the treatment of cancer, HSPs for treatment of infectious disease are off-the-shelf (non-personalized) vaccines.

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

• HSP-peptide complexes elicit cellular immune responses. The ability to elicit both HLA class I and class II restricted T cell responses addresses a serious shortcoming of traditional vaccines, which typically elicit antibody responses. Problematic infections of today, such as HIV, herpes, hepatitis, malaria, and TB, must be targeted through activation of cellular immune responses.
• HSPs are non-live. The non-live nature of HSP-based products addresses safety concerns that accompany the use of live vaccines, including attenuated agents.
• HSPs have been shown to activate cellular immune responses to a large array of antigens. The promiscuous nature of HSP-peptide interaction can be exploited to generate multivalent vaccines that will be a necessary property of any subunit vaccine intended for broad use in humans.

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 that mediate other immune effector mechanisms. The multifaceted nature of immunity elicited by HSPs has led to their being described as the immune system’s “Swiss army knife.” [more]

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QS-21 Stimulon adjuvant is a well characterized, chemically defined, and potent vaccine adjuvant that 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 QS-21 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 Agenus and at least 50 other laboratories around the world, QS-21 has been demonstrated to modulate the humoral immune response (ie, 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 multifaceted 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 in clinical trials to:

• Demonstrate efficacy via parenteral or mucosal administration routes
• Potentiate both prophylactic and therapeutic vaccines
• Potentiate immune responses to viral, bacterial, and parasitic antigens, including recombinant proteins, polysaccharide antigens, DNA vectors, conjugated antigens, multivalent vaccine formulations and notoriously weak antigens
• Exhibit a favorable safety profile
• Integrate easily with most excipients and formulations
• Synergize with other adjuvants as well as approaches using carrier proteins

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