This disclosure provides improved RNA molecules, including mRNA molecules that can be produced by in vitro transcription and are suitable for in vivo transfection using an appropriate delivery vehicle, such as a lipid nanoparticle (LNP) or targeted lipid nanoparticle (tLNP). The improved RNA include particular combinations of 5' untranslated region (UTR) and 3' UTR, particular 3' UTRs, or particular open reading frame sequences. Also provided herein are compositions of the LNP, or tLNP with an antibody as a targeting moiety, such as anti-CD8 antibodies that are used as targeting moiety.
This disclosure provides improved RNA molecules, including mRNA molecules that can be produced by in vitro transcription and are suitable for in vivo transfection using an appropriate delivery vehicle, such as a lipid nanoparticle (LNP) or targeted lipid nanoparticle (tLNP). The improved RNA include particular combinations of 5′ untranslated region (UTR) and 3′ UTR, particular 3′ UTRs, or particular open reading frame sequences. Also provided herein are compositions of the LNP, or tLNP with an antibody as a targeting moiety, such as anti-CD8 antibodies that are used as targeting moiety.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
C07K 16/40 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against enzymes
3.
Constrained Ionizable Cationic Lipids and Lipid Nanoparticles
Ionizable cationic lipids, methods for synthesizing the same, intermediates useful in synthesis of the ionizable cationic lipids and methods of synthesizing the intermediates are disclosed. The ionizable cationic lipids are useful as a component of lipid nanoparticles (LNP), which in turn can be used for the delivery of nucleic acids into cells in vivo or ex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is an LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
Ionizable cationic lipids, methods for synthesizing the same, intermediates useful in synthesis of the ionizable cationic lipids and methods of synthesizing the intermediates are disclosed. The ionizable cationic lipids are useful as a component of lipid nanoparticles (LNP), which in turn can be used for the delivery of nucleic acids into cells in vivo or ex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is an LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
C07D 205/06 - Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
in vivoex vivoex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is a LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
C07C 219/06 - Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
C07C 229/12 - Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
C07C 237/08 - Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
C07C 271/16 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
C07C 333/04 - Monothiocarbamic acidsDerivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
6.
EXTRACORPOREAL AND EX VIVO ENGINEERING OF SELECT CELL POPULATIONS FROM PERIPHERAL BLOOD
Disclosed are methods for producing a population of autologous engineered cells to be reinfused into a subject comprising extracorporeally transfecting an internal payload into a population of target cells from a sample obtained from the subject by incubating the population of cells with a lipid nanoparticle (LNP) and/or targeting lipid nanoparticle (tLNP) in an incubation component of an extracorporeal system for no more than 6 hours.
C12N 5/0783 - T cellsNK cellsProgenitors of T or NK cells
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61K 35/12 - Materials from mammalsCompositions comprising non-specified tissues or cellsCompositions comprising non-embryonic stem cellsGenetically modified cells
Disclosed are compositions of lipid nanoparticles (LNP) comprising an ionizable cationic lipid, a phospholipid, a sterol, and a PEG-lipid (non-functionalized and optionally functionalized). The functionalized PEG-lipid can be conjugated with a binding moiety to create a targeted LNP (tLNP). The disclosed tLNP preferentially deliver a nucleic acid molecule or other negatively charged payload to cells expressing a cell surface antigen recognized by the binding moiety of the tLNP, and are better tolerated, as compared to LNPs and tLNPs comprising ionizable cationic lipids found in marketed pharmaceuticals comprising LNPs.
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
A61K 47/18 - AminesAmidesUreasQuaternary ammonium compoundsAmino acidsOligopeptides having up to five amino acids
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
C12N 15/88 - Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using liposome vesicle
Disclosed are compositions of lipid nanoparticles (LNP) comprising an ionizable cationic lipid, a phospholipid, a sterol, and a PEG-lipid (non-functionalized and optionally functionalized). The functionalized PEG-lipid can be conjugated with a binding moiety to create a targeted LNP (tLNP). The disclosed tLNP preferentially deliver a nucleic acid molecule or other negatively charged payload to cells expressing a cell surface antigen recognized by the binding moiety of the tLNP, and are better tolerated, as compared to LNPs and tLNPs comprising ionizable cationic lipids found in marketed pharmaceuticals comprising LNPs.
A61K 38/17 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
A61K 47/60 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C12N 15/11 - DNA or RNA fragmentsModified forms thereof
C12N 15/88 - Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using liposome vesicle
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceuticals; pharmaceutical preparations; pharmaceutical substances; therapeutics; therapeutic agents; biopharmaceuticals; medicines; drugs; vaccines; in vivo cell therapies; cells for medical or clinical use; stem cells for medical purposes; cells for medical use; genetically engineered cells; systems to express therapeutic proteins in vivo; gene therapy products; gene therapy preparations; gene therapy products, namely, genetically engineered cells for transplant purposes; in vivo nucleic acid, DNA, RNA, and mRNA technologies; targeted in vivo RNA technologies; lipid nanoparticles for medicinal use; binding moiety decorated lipid nanoparticles for medicinal use; lipid nanoparticles for durable cell reprogramming or cell engineering; binding moiety decorated lipid nanoparticles for durable cell reprogramming or cell engineering; targeted lipid nanoparticles for medicinal use; targeted lipid nanoparticles for durable cell reprogramming or cell engineering; targeted lipid nanoparticles for transient cell reprogramming or cell engineering; cell engineering platforms; cell engineering platforms for treatment of human diseases, disorders and conditions; technology platforms for developing and engineering therapeutic cells; in vivo cell engineering platforms; transient in vivo cell engineering platforms for durable gene therapy; technology platforms for transfection, namely, binding moiety decorated lipid nanoparticles for genetic engineering; reagents for transfection; reagents for transfection in vivo; reagents for transfection, namely, binding moiety decorated lipid nanoparticles; technology platforms for delivery of a payload by binding moiety decorated lipid nanoparticles including antibody decorated lipid nanoparticles; technology platforms for delivery of a nucleic acid payload; technology platforms for delivery of a negatively charged payload; biologics delivery systems; biologics delivery platforms; reagents for delivery of a payload by binding moiety decorated lipid nanoparticles including antibody decorated lipid nanoparticles; cell engineering platforms consisting of reagents, lipid nanoparticles, cell receptors, proteins, recombinant protein binders, mRNA, and antibodies or antigen binding portions thereof; biological technology platforms consisting of reagents, lipid nanoparticles, cell receptors, proteins, recombinant protein binders, nucleic acid, DNA, RNA, mRNA, and antibodies or antigen binding portions thereof, for the treatment and prevention of treatment of human diseases, disorders and conditions; chemical reagents for medical uses; clinical medical reagents; reagents for medical use; biological reagents for medical use; binding moiety decorated lipid nanoparticles;
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceuticals; pharmaceutical preparations; pharmaceutical substances; therapeutics; therapeutic agents; biopharmaceuticals; medicines; drugs; vaccines; systems to express therapeutic proteins in vivo; gene therapy products; gene therapy preparations; in vivo nucleic acid, DNA, RNA, and mRNA technologies; lipid nanoparticles for medicinal use; binding moiety decorated lipid nanoparticles for medicinal use; lipid nanoparticles for durable cell reprogramming or cell engineering; binding moiety decorated lipid nanoparticles for durable cell reprogramming or cell engineering; cell engineering platforms; cell engineering platforms for treatment of human diseases, disorders and conditions; technology platforms for developing and engineering therapeutic cells; in vivo cell engineering platforms; transient in vivo cell engineering platforms for durable gene therapy; technology platforms for transfection, namely, binding moiety decorated lipid nanoparticles for genetic engineering; reagents for transfection; reagents for transfection in vivo; reagents for transfection, namely, binding moiety decorated lipid nanoparticles; technology platforms for delivery of a payload by binding moiety decorated lipid nanoparticles including antibody decorated lipid nanoparticles; technology platforms for delivery of a nucleic acid payload; technology platforms for delivery of a negatively charged payload; biologics delivery systems; biologics delivery platforms; reagents for delivery of a payload by binding moiety decorated lipid nanoparticles including antibody decorated lipid nanoparticles; cell engineering platforms consisting of reagents, lipid nanoparticles, cell receptors, proteins, recombinant protein binders, mRNA, and antibodies or antigen binding portions thereof; biological technology platforms consisting of reagents, lipid nanoparticles, cell receptors, proteins, recombinant protein binders, nucleic acid, DNA, RNA, mRNA, and antibodies or antigen binding portions thereof, for the treatment and prevention of treatment of human diseases, disorders and conditions; chemical reagents for medical uses; clinical medical reagents; reagents for medical use; biological reagents for medical use; binding moiety decorated lipid nanoparticles;
Ionizable cationic lipids, methods for synthesizing them, as well as intermediates useful in synthesis of these lipids and methods of synthesizing the intermediates are disclosed. The ionizable cationic lipids are useful as a component of lipid nanoparticles (LNP), which in turn can be used for the delivery of nucleic acids into cells in vivo or ex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is a LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
C07C 271/16 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
C07C 275/14 - Derivatives of urea, i.e. compounds containing any of the groups the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
C07D 211/46 - Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
C07D 295/088 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Disclosed are methods of conditioning subjects who receive, are receiving, or have received an agent for in vivo reprogramming of immune cells in order to improve the efficiency of the in vivo reprogramming and/or the overall therapeutic effect of the treatment. Also disclosed are nanoparticle compositions for providing the conditioning agent(s). The conditioning agent can be provided prior to, concurrently with, or after administration of the in vivo reprogramming agent depending on the conditioning agent. The conditioning regimens are useful in combination with in vivo reprogramming of immune cells to treat hematologic cancers and solid tumor, fibrotic disorders, and B cell or T cell mediated autoimmunity, chronic infection. Some conditioning regimens are also useful in combination with other cancer treatments.
THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA (USA)
Inventor
Aghajanian, Haig
Albelda, Steven
Bot, Adrian Ion
Abstract
in vivoin vivoin vivoin vivoin vivo reprogramming of immune cells to treat hematologic cancers and solid tumor, fibrotic disorders, and B cell or T cell mediated autoimmunity, chronic infection. Some conditioning regimens are also useful in combination with other cancer treatments.
Ionizable cationic lipids, methods for synthesizing them, as well as intermediates useful in synthesis of these lipids and methods of synthesizing the intermediates are disclosed. The ionizable cationic lipids are useful as a component of lipid nanoparticles (LNP), which in turn can be used for the delivery of nucleic acids into cells in vivo or ex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is a LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
C07D 295/088 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
C07D 211/46 - Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
C07C 271/16 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
C07C 275/14 - Derivatives of urea, i.e. compounds containing any of the groups the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
Ionizable cationic lipids, methods for synthesizing them, as well as intermediates useful in synthesis of these lipids and methods of synthesizing the intermediates are disclosed. The ionizable cationic lipids are useful as a component of lipid nanoparticles (LNP), which in turn can be used for the delivery of nucleic acids into cells in vivo or ex vivo. LNP compositions are also disclosed, including LNP comprising a functionalized lipid to enable conjugation of a binding moiety, and targeted LNP (tLNP), that is a LNP in which a binding moiety has been conjugated to the functionalized lipid and can serve as a targeting moiety to direct the tLNP to a desired tissue or cell type.
C07C 275/16 - Derivatives of urea, i.e. compounds containing any of the groups the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
C07C 271/22 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
Disclosed herein are polyethylene glycol (PEG)-lipids, functionalized PEG-lipids, and functionalized PEG-lipids that are conjugated to a binding moiety which can comprise an antibody antigen binding domain. Also disclosed are methods for synthesizing and functionalizing the PEG-lipids. The PEG-lipids are useful components lipid nanoparticles (LNP) used for the delivery of nucleic acids into living cells, in vivo or ex vivo. LNP comprising functionalized PEG-lipids that are conjugated to a binding moiety are useful as targeted LNP for delivering nucleic acids into cells or tissues expressing the ligand of the binding moiety.
A61K 47/14 - Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
A61K 47/54 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
A61K 47/60 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
C07C 69/67 - Esters of carboxylic acids having esterified carboxyl groups bound to acyclic carbon atoms and having any of the groups OH, O-metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
C07C 69/73 - Esters of carboxylic acids having esterified carboxyl groups bound to acyclic carbon atoms and having any of the groups OH, O-metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
C07C 271/22 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
C07C 275/16 - Derivatives of urea, i.e. compounds containing any of the groups the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
