Immunotope Technology
Transcription
Immunotope Technology
immunotope Immunotope Technology Immunotope focuses on the identification of immunotherapeutic target proteins for the development of novel therapeutics and diagnostics for cancer, infectious disease and autoimmune disorders. Immunotope’s antigen discovery and immunotherapeutic development efforts are based upon the Company's ability to identify: • Endogenous antigenic peptides associated with class I and II major histocompatibility complex (MHC) molecules • Autoantibody-reactive proteins identified using serological analysis • Membrane proteins on the surface of diseased cells that are putative targets for novel monoclonal antibody therapeutics. Immunotope obtains a comprehensive survey of the immunologically processed antigens on normal and diseased cells (immunoproteomics) using a combination of ultra-sensitive mass spectrometry, immunology and differential analysis. Immunotope’s analytical mass spectrometry capabilities allow the identification of individual peptides at the attomole level in complex mixtures. Immunotope’s proprietary antigen identification technology has been developed over the past four years by Immunotope’s scientific founder, Dr. Ramila Philip, and the approach has been clinically validated in Phase I/II melanoma clinical trials. Immunotope Technology Immunotope three methodologies to support and expand its immunoproteomics technology platform: (1) Cytotoxic T-cell- (CTL) based discovery using ultrasensitive techniques pioneered by Immunotope; (2) HighThroughput Peptide Sequencing (HTPS); and (3) Differential Analysis of T cell epitopes (DATE™ analysis). Antigens present at the level of one to ten copies (attomole level) per cell have been identified using these methods. CTL- based Technology When tumor-specific cytotoxic or helper T cells are available, a T cellbased methodology is employed to analyze the mixture of over 10,000 MHCassociated peptides obtained by isolation of MHC Class I and Class II epitopes from diseased cells and to identify the peptides recognized by the CTL. Using a combination of sophisticated immunology and high sensitivity mass spectrometry methods, Immunotope identifies the small number of peptides that elicit strong T cell-mediated immune responses against cancer, infectious diseases and autoimmunity. Mounting clinical evidence has shown that immunotherapeutic vaccines composed of defined antigens that are also presented as MHC-associated epitopes on diseased cells are correlated with positive clinical outcomes. Immunotope proprietary 1 immunotope High-Throughput Sequencing (HTS) and Differential Analysis Immunotope uses an automated, data-dependent high throughput mass spectrometric technique (HTS) to sequence all of the peptides extracted from class I and II MHC molecules on a diseased cell. For each indication, Immunotope generates a large EpiMap™ immunoproteomics database of information about the cellular proteins that are processed into peptides and presented to the immune system on the surfaces of the cells by MHC molecules. Immunotope also uses novel peptide isolation, purification and mass spectrometry technologies to determine which MHC-associated peptides and surface-expressed proteins are differentially displayed on normal vs. diseased cells by directly comparing the peptides or proteins from the diseased and normal tissues. Differential analysis methodology is also applied to identify autoantigens by screening serum autoantibodies in patients. Immunotope can compare the MHC-associated antigens with the autoantigen database to identify theranostic antigens that can be used for both diagnostics and therapeutics. Disease-associated intracellular and surface proteins are also candidate targets for drug discovery. Diagnostics developed from novel serum biomarkers There is substantial evidence that the serum of cancer patients contains circulating levels of antibodies that recognize tumor-associated antigens (TAA) even at very early stages of disease. Immunotope’s diagnostics discovery program is focused on identification of novel serum biomarkers for early detection and development of noninvasive serum-based diagnostics for ovarian cancer and hepatocellular carcinoma. Tumor-reactive antibodies present in cancer patient serum are used to identify target antigens that are present at very early stages, before tumors are detectable by other commonly used methods, such as imaging. Advantages of Immunotope Technologies Immunotope’s immunoproteomics technologies identify antigenic proteins that are endogenously processed and presented by class I and class II MHC-molecules. A key advantage of our methodology over competing approaches that use predictive algorithms, or ‘reverse vaccinology’, is that prior identification of the source protein of the presented antigen is not required. In fact, we have identified several important peptide antigens that do not match known binding motifs. We are able to identify post-translational modifications (i.e., glycosylation, deamidation, cysteinylation, and phosphorylation) that can profoundly influence peptide recognition by cytotoxic T cells. Direct identification of endogenous MHC-associated peptides is also very powerful because it identifies multiple “shared” antigens in the same tumor type from several different patients as well as antigens common to different tumor types. Immunotope proprietary 2 immunotope Identification of autoantibody-specific natural epitopes is the first step in the development of autoantibody-based diagnostics for early detection of cancer. Finally, the Company’s approach enables the identification of surface proteins and other epitopes that are differentially displayed as a consequence of changes in gene expression or changes in protein synthesis or metabolism. Progress in Antigen Discovery Cancer Class I MHC-associated peptides from ovarian cancer cells have been analyzed by HTS to identify potential ovarian tumor antigens. An extensive database of peptide mass spectra and protein/gene sources also has been developed. To date, (20) candidate peptide antigens have been identified and 16 of these have been immunologically characterized. Four of these antigens are derived from cell surface proteins. These peptides are derived from proteins implicated in apoptosis, tumor suppressor activity, and cell cycle regulation. Several of these proteins are expressed in multiple tumor types from several different patients, based on analysis of peptides extracted from several tumor samples (Figure 1). Our therapeutic and diagnostic objectives are to identify antigen combinations that will elicit an effective and positive immune response to kill tumors and infected cells and/or to be reliably predictive of the disease state. Figure 1. Representation of shared and unique peptide antigen populations mapped by Immunotope’s peptide analysis of ovarian tumors from multiple patients. In addition to the MHC class I peptide database for ovarian cancer, we have obtained ovarian patient serum autoantigen profiles by screening serum autoantibodies using our differential immunoproteomics technology. We have generated a panel of autoantigens that elicit antibody responses early in the progression of disease. These antigens are potential candidates for diagnostics and immunotherapeutics. Our colon cancer program has produced an EpiMap™ immunoproteomics database of MHC class I-associated epitopes from paired tumor and normal Immunotope proprietary 3 immunotope tissues from the same patient, and has identified a panel of epitopes that are only expressed in cancer cells. We have also generated a database of peptides from colon cancer cell lines and primary tumors. Infectious Diseases Our infectious disease programs focus on hepatitis B/C and HIV, which are collaborations with the Hepatitis B foundation and University of Pennsylvania respectively. We have identified novel epitopes from HBV- and HIV-infected cells that are naturally processed and presented by MHC class I molecules. These epitopes are different from those reported in the literature and that were identified using the motif prediction algorithm. We are in the process of completing the discovery and functional characterization of these epitopes. The identification of these novel epitopes clearly demonstrates the concept that direct identification, rather than prediction is key to successful immunotherapy, since the immune system only recognizes naturally processed epitopes presented by tumor or infected cells, which cannot be reliably predicted by motif algorithms. Business Development and Services Immunotope is generating intellectual property by mining its large diseasespecific EpiMap™ databases of MHC class I and II-associated peptides from normal and diseased cells, and cancer autoantigen databases based on serum autoantibody screening. The EpiMap™ databases contain the identities of indication-specific antigens as well as shared antigens common to multiple indications or stages of the disease. These peptides and their proteins of origin are excellent candidates for cancer, infectious disease and autoimmunity immunotherapies and diagnostics. Immunotope is seeking partnerships to expand its cancer and infectious disease programs. We also offer a range of services that use our proprietary antigen identification and immunoproteomics technologies to identify panels of naturally processed MHC Class I and Class II-associated peptides for customer-specified indications. The products of our analysis can include MHC-processed antigens for development of immunotherapeutic vaccines, antibody targets and diagnostics. We have expertise in autoantigen-based antigen discovery and will screen serum autoantibodies to identify novel diagnostic and antibody therapeutic targets. We can also evaluate antibody responses to other forms of immunization, including whole tumor and heat shock protein-based immunotherapy. Immunotope proprietary 4 immunotope Our services also include: Analysis of MHC processing of proteins in genetic constructs Analysis of antigen specificity post cell based immunotherapies Intellectual Property Strategy The Company’s EpiMap™ and autoantigen databases provide important information on proteins whose expression has been altered as a result of the transformation or infection process. Immunotope has filed patents on several MHC class I-specific peptides derived from proteins that are involved in carcinogenesis and cellular transformation processes. Patents have also been filed on the proteins from which these peptides were derived as immunotherapy targets. These proteins are excellent candidates for the development of diagnostics and immunotherapeutics, including vaccines and antibody targets. Immunotope proprietary 5