Technology Platforms
The Company is applying LAG-3 protein-based immunotherapeutics to treat infectious diseases and cancer where the major type of immune response that will counter the disease process is the T cell response. Description of the LAG-3 molecule and variants is available at the NIH-sponsored PROW database.
Immunostimulatory Factors:
A soluble LAG-3 protein is a high affinity MHC class II ligand that strongly stimulates the immune response. IMP321 is a recombinant soluble human LAG-3Ig fusion protein. MHC class II proteins play a fundamental role in life-essential processes and are associated with many areas of biology and medicine. One important feature of MHC class II proteins is their recognition by the immune system. Research has demonstrated that the MHC class II proteins expressed at the surface of antigen presenting cells, such as dendritic cells, monocytes, macrophages or B lymphocytes are key elements for antigen recognition (self/non-self discrimination) as well as the development of appropriate T cell responses. Many aspects of the immune system can be activated by soluble LAG-3 proteins, giving rise to greatly enhanced cellular (e.g. T cell) responses. In particular, one type of immune response, mediated by cytotoxic T lymphocytes (CTL), or "killer cells," can be effectively triggered by MHC class II+ dendritic cells activated by LAG-3 proteins. These CTL are thought to be one of the body's most potent defenses against diseased cells, such as those infected by viruses or altered by cancer.
Examples of diseases requiring a boost of the existing T-cell mediated immunity
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Cancer |
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Carcinomas (colorectal, pancreatic, stomach, lung, renal, bladder), melanoma, NHL |
| Viral infections |
HIV HBV and HCV Herpes simplex virus Epstein Barr virus Human papillomavirus |
AIDS Hepatitis B and C Herpes, Zoster
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| Intra-cellular bacteria |
Listeria Mycobacteria |
Listeriosis Leprosy, Tuberculosis |
| Intra-cellular parasites |
Plasmodium |
Malaria |
ImmuFact®: Natural T-Cell Immunostimulants
The induction of the T cell response depends on the ability of specialised "antigen presenting cells" to present the antigen to the receptors on T-cells ("antigen presentation"). This both stimulates the T-cells ("T cell priming") and enables them to recognise the pathogen. LAG-3 plays a central role in this process.
Promising results have been achieved with soluble recombinant LAG-3 derived molecules, such as sLAG-3 (or IMP321) showing efficient induction of T cell responses in animals and in vitro stimulation of immature human and murine dendritic cells. The mechanism involved is the activation of the APCs by the signals induced by MHC class II molecules bound by their ligand (i.e., sLAG-3 molecules): the induction of dendritic cell maturation and activation favours the initiation of the cascade of events resulting in the generation of cytotoxic T lymphocytes able to clear the body from chronically infected cells or tumour cells.
IMP321 has two intended clinical settings:
– low dose (e.g. 250 µg) as adjuvant to cancer antigens
– high dose (e.g. repeated >5 mg s.c.) combined with standard chemotherapy.
ImmuCcine®: Vectorisation of T-Cell Antigens: "one molecule, two functions"
Covalently linking an antigen to IMP321 in a fusion protein results in both vectorisation of the antigen to dendritic cells as well as the immunostimulatory effect described above. Vectorised therapeutic vaccines have been obtained recently by Immutep’s researchers by genetically coupling antigens to IMP321 leading to rapid capture and internalisation of the antigen into dendritic cells with increased efficacy and lower dose of vaccine to be used per injection. This second technology thereby combines the T-cell immunostimulatory effect with a powerful vectorisation effect (i.e. one molecule, two functions).
Therapeutic Antibodies:
ImmuTune®: Fine Tuning of the Immune Response
This technology comprises antibodies against LAG-3 in its natural membrane-bound form on the surface of T cells:
- ImmuTune antagonist antibodies which inhibit the role of LAG-3 as a down-regulator of the T cell response. LAG-3 down-regulates the T cell response either directly by inhibiting effector T cells or indirectly through the suppressive activity of the LAG-3+ Tregs. Thus antagonist antibodies lead to enhanced T cell proliferation. Such antibodies can be used alone or in combination with therapeutic vaccines.
- ImmuTune depleting antibodies. This application is based on the fact that LAG-3 is, by definition, a marker of activated T cells enabling depleting antibodies to suppress unwanted T cell activity in autoimmune diseases or transplantation.
