RNActive® Vaccines Complexed to Protamine

Dear all,
numerous research activities with a strong focus on nucleic acid chemistry-based therapeutics have to face the same problem: how to transport these poly-anionic compounds into the cell? The most applied technology is the complexation of siRNA (1), microRNA (2), antagomirs (3), antisense (4), or mRNA vaccines (5) with cationic lipids. In fact, a once promising approach has turned into a disillusioning obstacle.
The first mRNA transcript vaccine ever studied in a human clinical trial was CV9103 (6), a transcript encoding for four proteins in a row, and complexed with the cationic peptide protamine (7). The idea behind was to produce an intracellular shuttle for antigen expression encoded by the transcript, and also to generate an immunostimulatory agent. The most preferred and also effective ratio in either case was uncovered to be mRNA:protamine = 2:1 (8), resulting in a component containing both complexed and free (=naked) transcripts.
In another very recent clinical trial the mRNA vaccines were electroporated into autologous dendritic cells, and reinjected into 34 cancer patients (9), an innovative approach which could reduce GMP production and packaging costs. Interestingly, the same four therapeutic proteins were included as for CV9103.
And finally, there are an increasing number of publications dealing with the injection of just naked, but chemically stabilized transcript vaccines, so simple (10). Strong immune response can also be stimulated by simply changing the route of administration for naked mRNA vaccines (11).

Enjoy your weekend,
Your binding-assay.com team

References:
(1) Adami RC et al (2011), Mol Ther 19(6): 1141-51 (a Marina Biotech DiLA2 publication).
(2) Wu Y et al (2011), Mol Pharm doi:10.1021/mp2002076
(3) Liu XQ et al (2011), Mol Pharm 8(1): 250-9.
(4) Chiu SJ et al (2006), J Control Release 112(2): 199-207 (a Genasence® paper)
(5) Perche F et al (2011), Nanomedicine doi:10.1016/j.nano.2010.12.010
(6) Weide B et al (2009), J Immunother 32(5): 498-507.
(7) Fotin-Mleczek and Voss S (2010), Patent WO 2010/037408 A1.
(8) Fotin-Mleczek M et al (2011), J Immunother 34(1), 1-15.
(9) Wilgenhof S et al (2011), J Immunother 34(5): 448-56.
(10) Kormann MSD et al (2011), Nature Biotech 29: 154-157 (an Ethris publication)
(11) Lorenzi JCC et al (2010), BMC Biotechnol 10: 77

RNActive® is a trademark of CureVac GmbH.
Genasence® is a trademark owned by Genta Inc.

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