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Worcester, MA, United States

Antigen Express Inc. | Date: 2010-07-26

Disclosed is a nucleic acid molecule comprising a first expressible sequence encoding a protein of interest or polypeptide of interest which contains an MHC Class II-presented epitope, or said encoded protein or peptide. In addition, the nucleic acid molecule comprises a second expressible nucleic acid sequence encoding an antigen presentation enhancing hybrid polypeptide, or said encoded protein or peptide. The antigen presentation enhancing hybrid polypeptide includes the following elements: i) an N-terminal element consisting essentially of 4-16 residues of the mammalian Ii-Key peptide LRMKLPKPPKPVSKMR (SEQ ID NO: 1) and non-N-terminal deletion modifications thereof that retain antigen presentation enhancing activity; ii) a C-terminal element comprising an MHC Class II-presented epitope in the form of a polypeptide or peptidomimetic structure which binds to the antigenic peptide binding site of an MHC class II molecule, the MHC Class II-presented epitope being contained in the protein of interest of step a); and iii) an intervening peptidyl structure linking the N-terminal and C-terminal elements of the hybrid, the peptidyl structure having a length of about 20 amino acids or less.

Perez S.A.,Cancer Immunology and Immunotherapy Center | Kallinteris N.L.,Antigen Express Inc. | Bisias S.,Saint Savas Cancer Hospital | Tzonis P.K.,Cancer Immunology and Immunotherapy Center | And 6 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Active immunotherapy is emerging as a potential therapeutic approach for prostate cancer. We conducted the first phase I trial of an Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant granulocyte macrophage colony-stimulating factor as adjuvant in patients with HER-2/neu+ prostate cancer. The primary end points of the study were to evaluate toxicity and monitor patients' immune responses to the vaccine. Experimental Design: Thirty-two HER-2/neu+, castrate-sensitive, and castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients completed all six vaccination cycles with AE37. Immunologic responses in the total patient population were monitored by delayed-type hypersensitivity and IFN-γ ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency and plasma HER-2/neu and transforming growth factor-â levels were also determined. Immunologic responses were also analyzed among groups of patients with different clinical characteristics. Local/systemic toxicities were monitored throughout the study. Results: Toxicities beyond grade 2 were not observed. Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-γ-based ELISPOT assay. Intracellular IFN-γ analyses revealed that AE37 elicited both CD4+ and CD8+ T-cell responses. Eighty percent of the patients developed a positive delayed-type hypersensitivity reaction to AE36. Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-β levels. Patients with less extensive disease developed better immunologic responses on vaccination. Conclusion: AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer. ©2010 AACR. Source

Wambre E.,Stallergenes SA | Bonvalet M.,Stallergenes SA | Bodo V.B.,Stallergenes SA | Maillere B.,CEA Saclay Nuclear Research Center | And 10 more authors.
Clinical and Experimental Allergy | Year: 2011

Summary: Background A better understanding of allergen-specific CD4+ T cell responses is needed to help improving immunological therapies.Objective To compare CD4+ T cell responses against seasonal (Bet v 1) and perennial (Der p 1, Der p 2) allergens.Methods Major histocompatibility complex class II peptide tetramers were engineered to monitor allergen-specific T cell responses. After in vitro expansion, tetramer+ cells were tested for surface markers using cytofluorometry. Cytokine gene expression and production were assessed using quantitative PCR and cytokine surface capture assays, respectively.Results Tetramer+ cells were detected in 19 patients allergic to house dust mites (HDM), seven allergic to birch pollen, 13 allergic to both and nine non-allergics with either an HLA-DRB1*0101, *0301, *1501 or an HLA-DPB1*0401 background. High-avidity T cells are elicited against the immunodominant Bet v 1141-155 epitope, whereas broader low-avidity T cell responses are induced against Der p 116-30,110-124,171-185 and Der p 226-40,107-121 epitopes. Responses against Bet v 1 involve effector (CDL62 low, CCR7 low) or central (CD62L+, CCR7+) memory cells in allergic and non-allergic individuals, respectively, whereas central memory cells are mostly detected against mite allergens. In non-allergics, both mite and Bet v 1-specific T cells produce IFN-γ and IL-10. In contrast to Bet v 1-driven Th2 responses, mite allergens induce highly polymorphic responses in allergics, including Th1, Th2/Th17 or mixed Th1/Th2 profiles. Mite-specific T cell frequencies in the blood remain in the range of 1-6 × 10-4 CD4+ T cells throughout the year.Conclusion Different memory CD4+ T cell responses are elicited in the context of chronic vs. seasonal stimulation with the allergen(s). The heterogeneity in the patterns of CD4+ T cell responses observed in patients allergic to HDMs should be taken into account for specific immunotherapy. © 2010 Blackwell Publishing Ltd. Source

Perez S.A.,Cancer Immunology and Immunotherapy Center | Von Hofe E.,Antigen Express Inc. | Kallinteris N.L.,Antigen Express Inc. | Gritzapis A.D.,Cancer Immunology and Immunotherapy Center | And 3 more authors.
Cancer | Year: 2010

The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides. © 2010 American Cancer Society. Source

Vadacca M.,Biomedical University of Rome | Valorani M.G.,Queen Mary, University of London | Valorani M.G.,Research Group BIOS | Von Hofe E.,Antigen Express Inc. | And 4 more authors.
Hormone and Metabolic Research | Year: 2011

In order to determine whether the Ii-Key technology can enhance the presentation of specific epitopes associated with type 1 diabetes, we have designed and synthesized a series of Ii-Key/proinsulin and GAD epitope hybrid peptides. Peptides of proinsulin and GAD shown to be recognized by CD4+ T cells of type 1 diabetes patients have been selected from the literature and modified with Ii-Key. A total of 23 Caucasian type 1 diabetes subjects and 17 normal subjects as controls were included in the study. Reactive T cells were identified using an IFN-γ ELISPOT assay. We selected 5 proinsulin and 5 GAD epitopes. Regarding the activity of the proinsulin Ii-Key hybrids, 3 out of 15 patients (20%) demonstrated a positive response to one or more Ii-Key hybrid peptides compared to no responders in the control subjects. Two out of 8 patients demonstrated a positive response to one or more Ii-Key/GAD65 hybrids. Proinsulin Ii-Key hybrids and peptides were recognized only by DR3/DR4 0302+ve diabetic patients. Control subjects showed no detectable response to stimulation with Ii-Key hybrids or peptides, neither for proinsulin nor GAD65. We have now shown that the use of Ii-Key-modified MHC class II epitopes, derived from proteins associated with insulin-secreting cells, can detect the presence of specifically activated CD4+ T helper cells with greater sensitivity than unmodified epitopes in the standard ELISPOT assay. The use of these technologies may be of use in identifying patients at the earliest stages of type 1 diabetes. © Georg Thieme Verlag KG Stuttgart. Source

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