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(12) Patent Application Publication (10) Pub. No.: US 2017/0173128A1 Hoge Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0173128A1 Hoge Et Al US 20170173128A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0173128A1 Hoge et al. (43) Pub. Date: Jun. 22, 2017 (54) TARGETED ADAPTIVE VACCINES Related U.S. Application Data (60) Provisional application No. 61/912,635, filed on Dec. (71) Applicant: Moderna TX, Inc., Cambridge, MA 6, 2013. (US) Publication Classification (72) Inventors: Stephen G. Hoge, Cambridge, MA (51) Int. Cl. (US); Eric Yi-Chun Huang, A6139/00 (2006.01) Cambridge, MA (US) A 6LX 39/39 (2006.01) (52) U.S. Cl. (21) Appl. No.: 15/102,230 CPC .......... A61K 39/0008 (2013.01); A61K 39/39 (2013.01); A61 K 2039/53 (2013.01); A61 K (22) PCT Filed: Dec. 8, 2014 2039/57 (2013.01) (86). PCT No.: PCT/US1.4f6915S (57) ABSTRACT The invention relates to compositions and methods for the S 371 (c)(1), preparation, manufacture and therapeutic use of polynucle (2) Date: Jun. 6, 2016 otide molecules for targeted adaptive vaccines (TAVs). Patent Application Publication Jun. 22, 2017 Sheet 1 of 14 US 2017/0173128A1 FIGURE 1 a seese we 'a' . a as 8, & sys w.x sex sexese 8, 8 & 'wise. w x x s we w, a & sy, six xxx x we we we & A Patent Application Publication Jun. 22, 2017 Sheet 2 of 14 US 2017/0173128A1 FIGURE 2 Chimeric Polynucleotides 5'Cap s S is Codig or Nor-Coig Regia cre or intere or consistics RayA ir Regies t" ars Batterred; Synthetit Open; Erzyatisfy: chirnsit stairegion iterriter Regist Patent Application Publication Jun. 22, 2017 Sheet 3 of 14 US 2017/0173128A1 FIGURE 3 Patterns of positional modification polypeptide encoding S Cag SUTR R 38 polyA 3’ iiker regions Synthetic Enzyraticfy Patent Application Publication Jun. 22, 2017 Sheet 4 of 14 US 2017/0173128A1 FIGURE 4 Patterns of positional modification 5' NNNNN, ... NNNNNNNNNNNN.), 2 XXXXXXXXXXXX), .33' 5'ENNNNN, XXXXXXXXXXXXXXX., 2 (XXXXXXXXXXXX, 33 5' XXXXXX, i.1 (XXXXXXXXXXXXXXX.), 2 XXXXXXXXXXXX., 33 5INNNNN,), L1, NNNNNNNNNNNN.), 2 XXXXXXXXXXXX), 1.33 A, B, C- Regioi or Part of chimeric polynucleotide N-nucleoside , o, p-number of aucieosides x, y, 2-timber of regions X-selective piacement nucleoside -inker optional Patent Application Publication Jun. 22, 2017 Sheet 5 of 14 US 2017/0173128A1 FIGURES Backed of strictured 3' terrini A ) - 3. - (...) - C - (1) 5' NNNN, ii. NNNNNNNNNNNN, 12 XXXXXXXXXXXX), .33 5'ENNNN, a NNNNNNNNNNNN., 2 XXXXXXXXXXXX, K3 5' NNNN, L1 NNNNNNNNNNNN, 12 XXXXXXXXXXXXXXXX XX 3XXXXXXXXXXXXX 5'ENNNNN,. NNNNNNNNNNNN, 12 XXXXXXXXXXXXXXX t 3'XXXXXXXXXXX. 5' NNNNN, 1NNNNNNNNNNNN), 2 (XXXXXXXXXXXXXXX 3. X X XXXXXXXXXXXLt A, B, C- Region or Part of chieric polynucleotide XX XXXXXXXXXXX3 N-nucleoside in, o, p-number of Rucieosides x, y, z-number of regions X-seective pacement nucleoside K-to-nucleosidicciety of conjugate -inker (optionai) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Patent Application Publication Jun. 22, 2017 Sheet 6 of 14 US 2017/0173128A1 FIGURE 6 SS Patent Application Publication Jun. 22, 2017 Sheet 7 of 14 US 2017/0173128A1 FIGURE 7 E3 was 83 Patent Application Publication Jun. 22, 2017 Sheet 8 of 14 US 2017/0173128A1 FIGURE 8 S: 3. Patent Application Publication Jun. 22, 2017 Sheet 9 of 14 US 2017/0173128A1 FIGURE 9 Patent Application Publication Jun. 22, 2017. Sheet 10 of 14 US 2017/0173128A1 FIGURE 10 8. Patent Application Publication Jun. 22, 2017. Sheet 11 of 14 US 2017/0173128A1 FIGURE 11 Patent Application Publication Jun. 22, 2017. Sheet 12 of 14 US 2017/0173128A1 FIGURE 12 3888 ~.“s 3 & Y Patent Application Publication Jun. 22, 2017. Sheet 13 of 14 US 2017/0173128A1 FIGURE 13 Nassawa-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-axaawasa'anaananasawa-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-a-assass' -out is&se: issssssssssssssssswww.sssssssssssssssssssssswissssswww.swisssssssswssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssw bei rites Yi 2x .*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*)*%&zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Patent Application Publication Jun. 22, 2017. Sheet 14 of 14 US 2017/0173128A1 FIGURE 14 Targeted Adaptive Vaccine Composition Antigen, protein or fragment thereof (encoded on polynucleotide) Dendritic Cell Targeting Agent or Moiety; (optional) to enhance immune Stimulation (polynucleotide, polypeptide or combination; may be fused or associated with antibodies or fragments Immunomodulatory Agent or Moiety; (optional) to enhance immune Stimulation or response (polynucleotide, polypeptide or combination; may be fused or associated with antibodies or fragments thereof, may be polycistronic) Tolerizing Agent or Composition (optional) co administered with TAV to induce antigen specific tolerance US 2017/01731 28 A1 Jun. 22, 2017 TARGETED ADAPTIVE VACCNES proteins to generate new antigens which can help them skipping the active immune system that has been immunized CROSS-REFERENCE TO RELATED by vaccines containing the viruses. APPLICATIONS 0008 For example, influenza A, B and C viruses are the 0001. This application claims the benefit of Provisional etiological agents of influenza. Hemagglutinin (HA), the Application No. 61/912,635, filed Dec. 6, 2013, which is major envelop glycoprotein of influenza A and B viruses, or incorporated herein by reference in its entirety. its homologue, hemagglutinin-esterase (HE) in influenza C virus, is the natural reservoir of the viruses. The rapid FIELD OF THE INVENTION evolution of the hemagglutinin (HA) protein of the influenza virus results in the constant emergence of new strains, 0002 The invention relates to compositions, methods, rendering the adaptive immune response of the host only processes, kits and devices for the design, preparation, partially protective to new infections. The biggest challenge manufacture and/or formulation of targeted adaptive vac for therapy and prophylaxis against influenza and other cines (TAVs). infections using traditional vaccines is the limitation of vaccines in breadth, providing protection only against BACKGROUND OF THE INVENTION closely related subtypes. 0003 Vaccination is an effective way to provide phro 0009. It is of great interest to develop new approaches for phylactic protection against infectious diseases, such as developing new vaccines, not only for infectious agents and influenza, AIDS, hepatotisis virus infection, cholera, malaria cancer but for other therapeutic indications. One such and tuberculosis, and many other diseases. For example, approach recently developed is to make a vaccine available influenza infections are the seventh leading cause of death in that elicits a broad neutralizing response. However, the the United States with 200,000 hospitalizations and 40,000 production of a large amount of broadly neutralizing mono deaths seen in the United States per year and cause about 3-5 clonal antibodies against influenza viruses or other infec million hospitalizations and about 300,000 to 500,000 tious agents is currently not available. deaths worldwide per year (K. Stohr, 2002, Lancet Infect. 0010. The present invention which is directed to targeted Dis. 2,517, the contents of which are herein incorporated by adaptive vaccines (TAVs) provides compositions, methods, reference in its entirety). Millions of people receive flu devices and kits that may rapidly provide vaccines for vaccines to protect them from seasonal flu each year. Vac prophylactic protection and treatment by providing an “anti cination can also rapidly prevent the spread of an emerging gen-like character” (e.g., via chemical or structural modifi influenze pandemic. cation of the antigen or a polynucleotide encoding the 0004 Vaccines may also be used to treat diseases, such as antigen) to a normally non-antigenic molecule, for example cancers. For example, the first cancer treatment vaccine, an endogenous protein or fragment thereof. The TAVs may sipuleucel-T (Provenge(R), manufactured by Dendreon) is also increase or boost the immune response of antigenic used for certain men with metastatic prostate cancer. It is molecules, whether endogenous or not. designed to stimulate an immune response to prostatic acid 0011 To this end, TAVs may be utilized in any therapeu phosphatase (PAP), an antigen that is found on most prostate tic indication. One Such indication is hypercholesterolaemia. cancer cells. (Kantoff P W. et al., 2010, New England Familial hypercholesterolaemia (FH) is one of the common Journal of Medicine, 365, 411-422, which is incorporated est inherited disorders of human metabolism, affecting herein by reference in its entirety). approximately 1 in 500 individuals in most populations. The 0005. A typical vaccine contains an agent that resembles disorder is characterised by markedly increased low-density a weakened or dead form of the disease-causing agent, lipoprotein (LDL) cholesterol in serum, causing deposition which could be a microorganism, Such as bacteria, virus, of cholesterol in peripheral tissues to form tendon and skin fungi, parasite and prion, or the toxins and one or more Xanthomas. Accumulation of cholesterol in the arterial wall Surface proteins (often called antigens) of Such a microor results in accelerated atherosclerosis and premature coro ganism. The antigen or agent in the vaccine can stimulate the nary heart disease. FH is generally accepted to be an body's immune system to recognize the agent as a foreign autosomal dominant disorder with a gene dosage effect. invader, generate
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