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EP-4735454-A1 - HELPER LIPIDS FOR NUCLEIC ACID DELIVERY

EP4735454A1EP 4735454 A1EP4735454 A1EP 4735454A1EP-4735454-A1

Abstract

Provided herein are a class of helper lipid compounds of use in the in vivo delivery of therapeutic agents, such as nucleic acids.

Inventors

  • DENG, HONGFENG
  • DEROSA, FRANK
  • KARVE, Shrirang
  • KAUSHAL, Neha

Assignees

  • Sanofi Pasteur Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1. A compound having a structure according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is selected from optionally substituted C 2 -C 6 alkylene or optionally substituted C 4 .C 6 alkenylene; R a is absent, or R a is optionally substituted C 1 -C 10 alkyl, wherein, when R a is present, the nitrogen to which R a is bonded bears a positive charge; each R 1 is independently selected from hydrogen or optionally substituted C 1 -C 10 alkyl; each R 2 is independently selected from: (i) optionally substituted C 4 -C 24 alkyl, optionally substituted C 4 -C 24 alkenyl, and optionally substituted C 4 -C 24 alkynyl; (ii) wherein each R A is independently selected from optionally substituted C 1 -C 31 alkyl, optionally substituted C 2 -C 31 alkenyl, and optionally substituted C 2 -C 31 alkynyl; and wherein each Z A is independently selected from optionally substituted C 1 -C 10 alkylene and optionally substituted C 2 -C 10 alkenylene; (iii) wherein each R B is independently selected from optionally substituted C 1 -C 31 alkyl, optionally substituted C 2 -C 31 alkenyl, and optionally substituted C 2 -C 31 alkynyl; and wherein each Z B is independently selected from optionally substituted C 1 -C 10 alkylene and optionally substituted C 2 -C 10 alkenylene.
  2. 2. The compound of claim 1, wherein the compound has a structure according to Formula (II), (Ila), (IIb), (IIc), (IId) or (III):
  3. 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is selected from (i) optionally substituted C 2-6 alkylene or (ii) optionally substituted C 4-6 alkenylene, for example wherein Y is -CH 2 CH 2 -.
  4. 4. The compound of claim 1, wherein the compound has a structure according to Formula (IV), (V), (Va), (Vb), (Vc), or (Vd): (Va) (Vb) (Vc) (Vd), or a pharmaceutically acceptable salt thereof.
  5. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein (i) the stereochemistry of the carbon atom situated between R 2 C(=O)O-CH 2 - and -CH 2 -OP(=O)(OH)- O- is as depicted in the following structure: (ii) the stereochemistry of the carbon atom situated between R 2 C(=O)O-CH 2 - and -CH 2 -OP(=O)(OH)- O- is as depicted in the following structure:
  6. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from , wherein each n is independently selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, and 23,
  7. 7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R A or R B , if present, is independently selected from: , wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, and 30,
  8. 8. The compound of any one of the preceding claims wherein: (i) each R A , if present, is and each Z A is then C 7 alkylene; (ii) each R A , if present, is and each Z A is then C 6 alkylene; (iii) each R A , if present, is and each Z A is then C 2 alkylene; (iv) each R A , if present, is and each Z A is then independently selected from C5-C 7 alkylene, for example wherein each Z A is C 6 alkylene; (v) each R A , if present, is and each Z A is then C 6 alkylene; (vi) each R A , if present, is and each Z A is then C 6 alkenylene; (vii) each R A , if present, is and each Z A is then C 6 alkylene; (viii) each R A , if present, is and each Z A is then C 6 alkylene; (ix) each R B , if present, is and each Z B is then C 5 alkylene; or (x) each R B , if present, is and each Z B is then C 6 alkylene.
  9. 9. A compound selected from those listed in Table A, or a pharmaceutically acceptable salt thereof.
  10. 10. A composition comprising one or more lipid(s) of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and further comprising: (i) one or more cationic lipids, (ii) one or more sterol-based lipids, and (iii) one or more PEG-modified lipids, optionally wherein the one or more sterol-based lipids is a cholesterol-based lipid, for example cholesterol.
  11. 11. The composition of claim 10, wherein the composition is a lipid nanoparticle, optionally wherein: (i) the one or more cationic lipid(s) constitute(s) about 20 mol% to about 60 mol% of the lipid nanoparticle; (ii) the one or more lipid(s) of any one of claims 1-9 constitute(s) about 10 mol% to about 50 mol% of the lipid nanoparticle; (iii) the one or more PEG-modified lipid(s) constitute(s) about 1 mol% to about 4 mol% of the lipid nanoparticle; and/or (iv) the one or more sterol-based lipids constitute(s) about 10 mol% to about 50 mol% of the lipid nanoparticle.
  12. 12. The composition of claim 11, wherein the lipid nanoparticle encapsulates an mRNA encoding a peptide or protein, optionally for use in a vaccine.
  13. 13. The composition of claim 12 for use in therapy.
  14. 14. The composition of claim 12 for use in a method of treating or preventing a disease amenable to treatment or prevention by the peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen and/or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer, optionally wherein the composition is administered intravenously, intrathecally, or intramuscularly, or by pulmonary delivery, optionally through nebulization.
  15. 15. A method for treating or preventing a disease wherein said method comprises administering to a subject in need thereof the composition of claim 12 and wherein the disease is amenable to treatment or prevention by the peptide or protein encoded by the mRNA, optionally wherein the mRNA encodes an antigen and/or the disease is (a) a protein deficiency, optionally wherein the protein deficiency affects the liver, lung, brain or muscle, (b) an autoimmune disease, (c) an infectious disease, or (d) cancer, optionally wherein the composition is administered intravenously, intrathecally, or intramuscularly, or by pulmonary delivery, optionally through nebulization.

Description

Helper lipids for nucleic acid delivery RELATED APPLICATIONS This application claims priority to European application no. EP23306048.2 filed on 28th June 2023, the entire disclosure of which is hereby incorporated by reference. BACKGROUND [001] Delivery of nucleic acids has been explored extensively as a potential therapeutic option for certain disease states. In particular, messenger RNA (mRNA) therapy has become an increasingly important option for the prevention and treatment of various diseases (e.g., in the use of vaccines). [002] Efficient delivery of liposome-encapsulated nucleic acids remains an active area of research. Liposome-encapsulated nucleic acids can be administered intramuscularly (IM). [003] The helper lipid component of a liposome plays an important role in improving the efficacy of nucleic acid transfection. Various helper lipids suitable for in vivo use have been discovered. However, there remains a need to identify helper lipids that are effective for intramuscular delivery of mRNA (e.g., in vaccines, such as for Flu or Respiratory Syncytial virus (RSV)). There also remains a need to identify helper lipids that can be synthesized efficiently and cheaply without the formation of potentially toxic by-products. SUMMARY OF THE INVENTION [004] The present invention provides, among other things, a novel class of helper lipid compounds for improved in vivo delivery of therapeutic agents, such as nucleic acids. Helper lipids may add stability, rigidity, and/or fluidity within lipid bilayers/nanoparticles and facilitate cell fusion and endosomal escape. The inventors of the present invention have surprisingly found that lipid nanoparticles comprising helper lipids of the present invention are very effective for the intramuscular delivery of mRNA encapsulated in said lipid nanoparticles. Indeed, lipid nanoparticles comprising the helper lipids of the present invention have demonstrated high levels of peptide or protein expression when delivering mRNA encoding for said peptide or protein by intramuscular delivery. [005] It is contemplated that lipid nanoparticles comprising these helper lipid compounds are capable of highly effective in vivo intramuscular delivery of therapeutic agents and vaccines (e.g., for Flu or Respiratory Syncytial virus (RSV)). [006] In an aspect, provided herein are helper lipids having a structure according to Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from C2-6 alkylene or C4-6 alkenylene; Ra is absent, or Ra is optionally substituted C1-C10 alkyl, wherein, when Ra is present, the nitrogen to which Ra is bonded bears a positive charge; each R1 is independently selected from hydrogen or optionally substituted C1-C10 alkyl; each R2 is independently selected from: (i) optionally substituted C4-C24 alkyl, optionally substituted C4-C24 alkenyl, and optionally substituted C4-C24 alkynyl; (ii) wherein each RA is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and wherein each ZA is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene; (iii) wherein each RB is independently selected from optionally substituted C1-C31 alkyl, optionally substituted C2-C31 alkenyl, and optionally substituted C2-C31 alkynyl; and wherein each ZB is independently selected from optionally substituted C1-C10 alkylene and optionally substituted C2-C10 alkenylene. [007] In an aspect, provided herein are helper lipids that are pharmaceutically acceptable salts of Formula (I). [008] In an aspect, provided herein are compositions comprising one or more helper lipids of the present invention or a pharmaceutically acceptable salt thereof, and further comprising: one or more cationic lipids; (ii) one or more sterol-based lipids; and (iii) one or more PEG-modified lipid. [009] In an aspect, the composition is a lipid nanoparticle, optionally a liposome. [010] In an aspect, the compositions comprising a cationic lipid and one or more helper lipids of the present invention may be used in therapy, for example, to treat, prevent or ameliorate Flu or Respiratory Syncytial virus (RSV). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions [Oil] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. [012] Amino acid: As used herein, the term "amino acid," in its broadest sense, refers to any compound and/or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some em