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Toronto 9/15/2005 07:00 AM GMT (WooEB)

Generex Biotechnology Corporation (NasdaqSC: GNBT), a leader in the area of buccal drug delivery, today announced clinical trial results generated by Antigen Express, Inc., the Company's wholly-owned immunotherapeutics subsidiary.

Marta Vadacca of Universit Campus Bio-Medico, Rome, Italy presented a study titled "A Novel Approach to Study T Cell Response to Ii-Key/MHC Class II Epitope Hypbrid Peptides in Type 1 Diabetes."

Type 1 diabetes (T1DM) is the result of the immune-mediated destruction of pancreatic beta cells. T cell recognition of islet antigen(s) via MHC class has been postulated as a key mechanism in the induction of such immune response. It is unclear which autoantigen(s) and determinant(s) are targets of the autoimmune attack towards beta cells. A number of antigens have been associated with T1DM, insulin and insulin peptides being probably the most relevant ones, however a T cell assay for insulin/peptides with high sensitivity and specificity is still missing. A novel approach to study antigen presentation via HLA class II is represented by Ii protein. It has been shown that a peptide of the Ii protein (Ii-key) enhances in vitro antigenic peptide presentation. These Ii-key peptides act at an allosteric site on MHC class II molecules to facilitate charging and presentation of peptides into the antigenic binding site. In previous studies it was demonstrated that Ii-key hybrids consisting of antigenic peptide-flexible-linker-Ii-Key peptide enhance presentation of antigenic peptides. The aim of this study was to apply this novel technique to establish the validity of Ii-Key/MHC class II insulin epitope hybrids for detecting anti-insulin responses in T1DM patients.

Insulin peptides shown to be recognized by T1DM CD4+ T cells were selected from data available in the literature. Sequences of the human insulin were obtained from Genebank. Predicted DRB1*0301 and DRB1*0401 epitopes were identified by application of the Rammensee SYFPEITH program (http://syfpeithi.bmi-heidelberg.com/Scripts/MHCServer.dll/EpPredict.htm) to the sequences of the experimentally characterized peptides containing DR-presented sequences. Within a homologous series, the longest and shortest hybrids were taken for initial synthesis plus the shortest peptide of 9 amino acids being considered to act as control. Five series (15 hybrids and five epitope-controls) were analyzed. The present study was carried out using mononuclear cells from 23 T1DM patients (18 males) (age range 7-41 years) with different disease duration including recent onset T1DM. Fresh peripheral blood mononuclear cells were prepared from heparinised blood using standard Ficoll Hypaque separation and cultured for 24hrs at 37C for interferon gamma analysis using ELISPOT assays (BD Pharmingen) according to the manufacturers instructions.

Three patients (13%) showed strong activity with the longest hybrid of two different series and no activity with the shorter hybrids or all hybrids shorter than that one. A more potent activity was detected in presence of higher distance between the Ii-key moiety and the MHC class II epitope. Hybrids containing shorter spacer sequences were all less potent than hybrids with longer spacer sequence. Responder rates were lower in T1DM patients of longer disease duration than in patients with recent onset disease.

Data from this novel approach shows that some hybrids, and not the epitope-peptide only, induce strong T cell reactivity in some patients with T1DM. The increased potency of MHC class II epitope presentation created by the Ii-key moiety in a hybrid should allow effective responses in those cases which are low responder to the epitope-peptide only. If these results are confirmed, they could offer the potential for a new diagnostic tool for studying T cell mediated immune responses in T1DM.

About Generex

Generex is engaged in the research and development of drug delivery systems and technologies. Generex has developed a proprietary platform technology for the delivery of drugs into the human body through the oral cavity (with no deposit in the lungs). The Companys proprietary liquid formulations allow drugs typically administered by injection to be absorbed into the body by the lining of the inner mouth using the Companys proprietary RapidMist device. The Companys flagship product, oral insulin (Oral-lyn), which has been approved for commercial sale in Ecuador for the treatment of patients with Type-1 and Type-2 diabetes, is in various stages of clinical trials around the world. Antigen Express is a wholly owned subsidiary of Generex. The core platform technologies of Antigen Express comprise immunotherapeutics for the treatment of malignant, infectious, allergic, and autoimmune diseases.

For more information, visit the Generex website at www.generex.com and the Antigen Express website at www.antigenexpress.com.

Safe Harbor Statement: This release and oral statements made from time to time by Generex representatives concerning the same subject matter may contain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements can be identified by introductory words such as "expects," "plans," "intends," "believes," "will," "estimates," forecasts," "projects" or words of similar meaning, and by the fact that they do not relate strictly to historical or current facts. Forward-looking statements frequently are used in discussing potential product applications, potential collaborations, product development activities, clinical studies, regulatory submissions and approvals, and similar operating matters. Many factors may cause actual results to differ from forward-looking statements, including inaccurate assumptions and a broad variety of risks and uncertainties, some of which are known and others of which are not. Known risks and uncertainties include those identified from time to time in the reports filed by Generex with the Securities and Exchange Commission, which should be considered together with any forward-looking statement. No forward-looking statement is a guarantee of future results or events, and one should avoid placing undue reliance on such statements. Generex claims the protection of the safe harbor for forward-looking statements that is contained in the Private Securities Litigation Reform Act.

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