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Genovax has two projects in the development phase: here is a short outline.

GX 101

Treatment of systemic lupus erythematosus with a tolerogenic gene product constituted by a Consensus peptide-Fc immunoglobulin chimera.

Systemic lupus erythematosus (SLE) is characterized by the reactivity of lymphocytes against endogenous antigens with the subsequent production of autoantibodies.

Some of these autoantibodies are pathogenic inducing tissue damage by different mechanisms. It has been shown that autoreactive B lymphocytes (the cells producing autoantibodies) can process and present in a MHC class II context peptides derived from their own immunoglobulin idiotypes and that some of these idiotypes are able to activate autoreactive, disease-inducing T cells.

Thus, both nuclear antigens and specific autoantibody-derived V regions can function as autoantigens inducing and maintaining the autoimmune response in SLE.

An artificial peptide has been synthesized which encompasses sequences of variable region-derived peptides from different anti-dsDNA autoantibodies. This synthetic "consensus" peptide (pCons) has been shown to effectively prevent disease onset when injected in young mice and to arrest the disease in about 50% of mice with already developed disease.

This effect has been shown to be mediated by induction of regulatory T lymphocyte activation, including both CD4+CD25+ and CD8+CD28- T cells.

In order to increase peptide stability and its availability for antigen presenting cell capture, processing and presentation to regulatory T lymphocytes a molecular chimera has been produced assembling the pCons sequence with that of a human IgG Fc region (Ig-pCons).

The gene coding for such engineered construct has been inserted in a plasmid under the control of a CMV promoter (pCMV vector from Stratagene).

Control plasmids, coding for the Fc IgG region alone or for a negative gene construct (Ig-pNeg) constituted by an unrelated, non-tolerogenic peptide (pNeg) fused to the Fc IgG region, have been also produced.

The efficient expression of all peptides when transfected in COS-7 cells at both transcriptional and transduction levels was demostrated. The antigenic specificity of the Ig-pCons gene product compared with that of control gene products was also demonstrated by the specific reactivity of a pCons specific T cell line toward the Ig-pCons molecule.

In order to test the tolerogenic therapeutic effect in vivo of Ig-pCons gene product in a model of gene vaccination, the plasmid coding for Ig-pCons has been transfected into spleen B lymphocytes of lupus prone mice by spontaneous transgenesis.

Such a procedure allows B lymphocyte plasmid transfection without any cell manipulation taking advantage of the capacity of B cells to spontaneously endocytose and express external DNA. Hence, this procedure is optimal for gene vaccination protocols in humans as demonstrated by the absence of side effects observed in a clinical trial performed in prostate cancer patients after FDA approval ( identifier NCT00061035) (Zanetti M. Protocol #0207-545: a phase I/II, escalating dose, open-label evaluation of safety, feasibility, and tolerability of transgenic lymphocyte immunization (TLI) vaccine subjects with histologically proven prostate adenocarcinoma. Hum Gene Ther. 2003 Feb 10;14(3):301-2).

Transfected cells were then i.v. injected in syngenic mice at a pre-nephritic age (20-22 weeks old). Control groups of mice were constituted by untreated mice or mice receiving syngenic B cells transfected with empty plasmid, plasmid coding for Fc Ig or for Ig-pNeg.

Treatment with cells transfected with Ig-pCons was associated with protection from renal disease and significantly increased survival. Ig-pCons treated mice also shown reduced circulating immunoglobulin levels and increased concentration of TGF-Β secreting regulatory CD8+CD28- T lymphocytes. Interestingly, these cells, purified from Ig-pCons treated mice and injected into pre-nephritic mice were able to efficiently protect them from nephritis onset.

The final goal of the project is to achieve a new biological treatment for human lupus. Ig-pCons gene construct appears to be a good candidate for this purpose since it is able to prevent disease onset in lupus-prone mice and pCons induces activation of human regulatory T lymphocytes. Aims of this project are:

  1. To repeat the experiments of protection from SLE development in lupus-prone mice by gene vaccination using a modified form of the gene construct including the signal peptide in the molecule with the aim of increasing its secretion by transfected cells and its availability to other antigen presenting cells.
  2. To produce and purify Ig-pCons gene product in order to obtain amounts of protein sufficient to perform the experiments of protection and survival evaluation directly immunizing lupus-prone mice with the protein.
  3. To perform all the tests necessary to achieve the approval by AIFA and EMEA for clinical application in human SLE patients for both the plasmid and protein forms of Ig-pCons.

GX 301

Objectives: to evaluate the efficacy of a new therapeutic approach against prostate cancer, based on the use of telomerase derived peptides as immunogens, and with two adjuvants.

The results of present therapies against advanced prostate cancer are unsatisfactory. Recent findings demonstrate that tumors express a molecule, the telomerase, which is absent in the vast majority of normal cells: the immune system of cancer patients can develop an immune response against this molecule. Hence this molecule is considered a tumor-associated antigen and can be used in anti-cancer immunotherapy. GX301 is based on the use immunogenic peptides derived from human telomerase, administered together with adjuvants.

In September 2012 the GX301 project, with its know-how and its patents, was sold to the company Mediolanum Farmaceutici S.p.A., which is undertaking the relevant development.

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