Project: Innovative Liposomes for Vaccines and Adjuvants Efficient Delivery

LIPODEL project aims at developing technologies capable to improve human immune functions for both curative and preventive purposes. These technologies based on functionalized liposomes will target two of the most potent immune cells, monocytes and dendritic cells._x000D_The project intends:_x000D_ _x000D_1) To design and implement immune stimulating liposomes supporting co-delivery of Toll Like Receptor 7 (TLR7) agonists towards monocytes and pDCs suitable for immunotherapy in infectious diseases and cancer; _x000D__x000D_2) To develop a candidate liposomal vaccine co-delivering TLR7 ligands as adjuvant and a Group B streptococcus (GBS) antigen to monocytes and plasmacytoid Dendritic Cells (pDCs). The consortium expects to achieve a vaccine capable to raise a potent and durable antigenic specific response towards GBS infections and to prevent GBS’s vagina and rectum colonization in women._x000D__x000D_Background: A majority of vaccines used today are based on traditional technologies using classical adjuvants developed more than 40 years ago, e.g. Alum and Squalene. There is a strong need for novel vaccine technologies that build on the large amount of knowledge emerged during the last decade in immunological research (Steinman R. Nature, 2007, 449, p419). _x000D_TLRs in immune activation: A major advance for the understanding of the mechanisms of protective immunity, relevant for future vaccine development, is the identification of TLRs, which recognize pathogens that attempt to infect the host. TLR activation is essential for boosting an adaptive immune response, which is important for both vaccine development and immunotherapy. TLR7 is one of such receptors, expressed in pDCs, B-cells and monocytes only. TLR7 is localized in the endosomes inside the cell, where it is activated during viral infections (Kanzler H., et al., 2007, 13, 5, 552-559). TLR7 responses are often impaired in both infectious diseases and cancer. _x000D_TLR7 activation has been suggested as an important target for future vaccine and cancer immunotherapy (Hirsch I, et al, Trends Immunol, 2010, 391-7). The TLR7 mediated response is strongly dependent on the production of type I interferons from pDCs, which activates cellular and humoral responses, both essential for an efficient vaccine response (Douagi I et al., J Immunol, 2009, 182, 1991-2001)._x000D__x000D_TLR7 agonists: Several TLR7 agonists are known today and a number of them are in clinical use for cancer therapy. Two TLR7 agonists developed by Telormedix, TMX 201/202, have proven to be more potent than currently known TLR7 agonists in stimulating human immune cells. They are promising candidates for boosting the immune system, in cancer immunotherapy and in the development of new vaccines against infections, e.g. HIV, hepatitis B and C and human papilloma virus as well as group B streptococcus infections (Hirsch I, et al.). _x000D_Due to their unique chemical structure (TLR7 small molecule ligand conjugated to phospholipid moieties), TMX201 and TMX202 are suitable for liposomal formulation, where these TLR7 agonists can be released upon contact with and uptake into the endosome compartment, with subsequent activation of TLR7, which is located in the endosome membrane. _x000D__x000D_Immune cell targeting: Specific liposomal targeting to monocytes has been studied by DTU Nanotech and Bioneer, where a given liposomal composition has shown to target monocytes 100 times more efficiently than other cell types in whole blood assays (confidential and unpublished data). Targeting pDCs has been explored by other researchers, and it will be further investigated in this project, by using specific peptides and antibodies targeting pDCs receptors. Known pDCs receptors like DEC-205, DC-SIGN, CD11c/CD18, CLEC9A and CLEC12A have been studied, and at present it seems that targeting CLEC9A (Camingchi I et al., Blood, 2008, 112, 3264) and CLEC12A (Lahoud, MH. Et al., J Immunol, 2009, 182, 7587.) could be a promising approach to raise a potent antigen specific response._x000D__x000D_Antigen specific response towards Strep B:_x000D_A novel antigen candidate for Group B Streptococcus has been developed by Minervax ApS. Many previous attempts to produce a successful GBS vaccine have been hampered by genetic variation between strains and immune-evasion mechanisms employed by the bacteria. One such immune-evasion mechanism involves attracting the host immune response to highly immunodominant epitopes on the bacteria, which are non-essential to its life-support. _x000D_Minervax has identified novel protein epitopes which attracts hardly any immune response in the infected host due to immunodominant repeats present in the native proteins. Removing these immunodonimant repeats from the native proteins and fusing the protein epitopes together results in a new vaccine candidate highly neutralizing immune response against these otherwise immunosilent epitopes. The achieved vaccine candidate is capable of protecting against the clinically most relevant strains of GBS._x000D_

Acronym	LIPODEL (Reference Number: 6459)
Duration	01/01/2012 - 31/12/2013
Project Topic	LIPODEL aims at enhancing technologies improving immune response for preventive and curative purposes. The project will develop liposomes targeting monocytes and pDCs co-delivering TLR7 agonists for immunotherapy. LIPODEL liposomes will be used to implement a Group B Streptococcus vaccine candidate.
Project Results (after finalisation)	Bioneer initiated and obtained its part of the results. Upon completion of the project Simon S. Jensen, Ph.D. established the company MonTa Biosciences at The Technical University of Denmark in collaboration with professor Thomas Andresen (The Technical University of Denmark and also LIPODEL project participant). _x000D__x000D_At The Technical University a range of liposomes was developed and tested at Bioneer (drug formulation agents for transporting drugs in blood to the site of disease). _x000D__x000D_-The novel liposomes (liposomal formulation) proved to be efficient for delivering an antitumor agent as documented by animal experiments._x000D_-The novel liposomes proved to efficient for targeting specific subtypes of dendritic cells._x000D__x000D__x000D__x000D__x000D_
Network	Eurostars
Call	Eurostars Cut-Off 6

Project partner

Number	Name	Role	Country
4	Bioneer A/S	Partner	Denmark
4	Minervax ApS	Partner	Denmark
4	Technical University of Denmark - Department of Micro and Nanotechnology	Partner	Denmark
4	Telormedix SA	Coordinator	Switzerland