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EP-4735417-A1 - IONIZABLE CATIONIC LIPID COMPOUNDS FOR DELIVERY OF BIOLOGICALLY ACTIVE AGENTS

EP4735417A1EP 4735417 A1EP4735417 A1EP 4735417A1EP-4735417-A1

Abstract

The present disclosure relates to novel lipid compounds for delivering one or more biologically active molecules to a subject. The present application also relates to a composition or a nanoparticle comprising said lipid compounds, methods of preparing said lipid compounds, method of using said lipid compounds and use of said lipid compounds.

Inventors

  • ZHU, XI
  • CHEN, HONG
  • HOU, Chenxi
  • LI, Dalang
  • TIAN, SHIN-SHAY
  • Zhao, Xiaoping

Assignees

  • Shanghai Vitalgen Biopharma Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. An ionizable lipid having formula (I) , or a salt, tautomer, or stereoisomer thereof, wherein: 1) m and p are independently selected from any integer ranging from 3 to 8; 2) n is selected from any integer ranging from 2 to 4; 3) X is a bond, -C (O) O-, or a biodegradable group; 4) R 1 is a hydrogen bond donor-containing group or hydrogen bond acceptor-containing group; 5) both of R 2 are same and selected from C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl and substituted C 3 -C 12 cycloalkyl and combinations of thereof; 6) R 3 is: (a) selected from C 4 -C 22 alkyl, substituted C 4 -C 22 alkyl, C 4 -C 22 alkenyl, substituted C 4 -C 22 alkenyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl and combinations of thereof; or (b) an acetal group of wherein both of R 4 are same and selected from C 1 -C 16 alkyl, substituted C 1 -C 16 alkyl, C 2 -C 16 alkenyl, substituted C 2 -C 16 alkenyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl and combinations of thereof.
  2. The ionizable lipid according to claim 1, wherein having formula (II) , or a salt, tautomer, or stereoisomer thereof, wherein q is selected from any integer ranging from 2 to 4.
  3. The ionizable lipid according to claim 1 or 2, wherein R 2 is C 7 -C 12 alkyl.
  4. The ionizable lipid according to any one of claims 1-3, wherein each R 2 has at least one carbon atom with hydrogen atom (s) substituted by one or two side chains.
  5. The ionizable lipid according to any one of claims 1, 3 and 4, wherein R 3 of said formula (I) is selected from C 6 -C 12 alkyl, substituted C 6 -C 12 alkyl, C 6 -C 12 cycloalkyl, substituted C 6 -C 12 cycloalkyl, C 6 -C 12 alkenyl, substituted C 6 -C 12 alkenyl and combinations of thereof.
  6. The ionizable lipid according to claim 5, wherein R 3 is C 7 -C 12 alkyl.
  7. The ionizable lipid according to any one of claims 1 and 3-6, wherein R 3 has at least one carbon atom with hydrogen atom (s) substituted by one or two side chains.
  8. The ionizable lipid according to any one of claims 3-7, wherein R 3 is the same with R 2 .
  9. The ionizable lipid according to any one of claims 2-4, R 4 of said formula (II) are independently selected from C 2 -C 12 alkyl, substituted C 2 -C 12 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl and combinations of thereof.
  10. The ionizable lipid according to any one of claims 2-4 and 9, wherein R 4 is C 7 -C 12 alkyl.
  11. The ionizable lipid according to any one of claims 2-4, 9 and 10, wherein each R 4 has at least one carbon atom with hydrogen atom (s) substituted by one or two side chains.
  12. The ionizable lipid according to any one of claims 2-4 and 9-11, wherein R 4 is the same with R 2 .
  13. The ionizable lipid according to any one of claims 4, 7 and 11, wherein said carbon atom with hydrogen atom (s) substituted by one or two side chains is the second or more distant carbon atom counting from the junction.
  14. The ionizable lipid according to any one of claims 4, 7, 11 and 13, wherein said one or two side chains are C 1 -C 4 alkyls.
  15. The ionizable lipid according to any one of claims 1-14, wherein each R 2 , R 3 and/or each R 4 is independently selected from one of the following formulas:
  16. The ionizable lipid according to any one of claims 1-15, wherein R 1 is selected from hydroxyalkyl group having 1 to 5 carbon atoms, or optionally substituted amino alkylenyl group having 1 to 6 carbon atoms.
  17. The ionizable lipid according to any one of claims 1-16, wherein R 1 is selected from one of the following formulae: wherein o is selected from 1, 2, 3, 4, and 5.
  18. The ionizable lipid according to any one of claims 1-17, wherein said ionizable lipid is selected from a group consisting of Compound No: 002-011 and 013-103 as shown in Table 1.
  19. The lipid according to any one of claims 1-18, wherein the lipid is an ionizable cationic lipid.
  20. A lipid nanoparticle (LNP) comprising an ionizable cationic lipid of claim 19, a neutral lipid, a PEG lipid and a steroid.

Description

IONIZABLE CATIONIC LIPID COMPOUNDS FOR DELIVERY OF BIOLOGICALLY ACTIVE AGENTS FIELD OF THE INVENTION The present disclosure belongs to the field of drug delivery. Specifically, the present application relates to novel lipid compounds and nanoparticles comprising said lipid compounds for delivering one or more biologically active agents to a subject. Also provided are methods of preparing and using said lipid compounds and nanoparticles, as well as use of said lipid compounds and nanoparticles. BACKGROUND Nucleic acid-based therapeutics have enormous potential therapeutical application. These therapeutic nucleic acids include messenger RNA (mRNA) , antisense oligonucleotides, siRNA, miRNA, ribozymes, guide RNA, DNAzymes, plasmids, plasmids-based interfering nucleic acids, closed-end DNA, and aptamers. Different types of nucleic acids are currently being developed as therapeutics for the treatment of a number of diseases. Some nucleic acids, such as mRNA, plasmids, closed-end DNA, can be used to express specific protein or enzyme, as would be useful in the treatment of, for example, single gene diseases related to deficiency or misfunction of such protein or enzyme. Nucleic acids encoding an antigen of a pathogen, including mRNA and DNA, could be used as vaccine for the prophylaxis of infectious diseases, such as COVID-19. Nucleic acids encoding one or more neoantigens could be used as tumor vaccines, which can effectively activate the body’s immune system to kill tumor cells, making individualized immunotherapy based on tumor neoantigens a new direction for the development of personalized immunotherapy for treating tumors. Other nucleic acids can down-regulate or up-regulate intracellular levels of specific mRNA, which subsequently affect expression of specific cellular proteins. These nucleic acids, such as siRNAs and miRNAs, have extremely broad therapeutic applications. Targets may include mRNAs associated with disease-states, such as tumor suppressor, and mRNAs of infectious agents. Antisense oligonucleotide constructs have shown the ability to specifically down-regulate target proteins through degradation of the cognate mRNA. Nucleic acids such as miRNA inhibitors would be useful in the treatment of diseases related to deficiency of protein or enzyme. Although nucleic acid-based therapeutics have enormous potential, effective delivery of these molecules to appropriate sites within a cell or organism are prerequisite to realize this potential. There are many challenges associated with the delivery of nucleic acids to achieve a desired response in a biological system. RNA molecules are susceptible to nuclease digestion in  plasma and have extremely short half-life. Furthermore, nucleic acids are impermeable to cell membrane due to its unique molecular characteristics. Thus, these molecules can hardly gain access to the intracellular compartment where the relevant translation machinery resides. Therefore, nucleic acids are usually considered have no druggability in its naked form. Improvement of delivery vehicle for nucleic acid is crucial for these molecules to fulfill their therapeutic potentials. Nanoscale delivery vehicles, including lipid and polymeric nanoparticles have been used to facilitate the cellular uptake of the nucleotides and prevent their degradation in biological environment. Lipid nanoparticles formed from ionizable cationic lipids with other lipid components, such as neutral lipids, cholesterol, PEGylated lipids (PEG lipids) , and oligonucleotides have been proved to be one of the most potent delivery systems. Cationic lipids are critical for protecting the nucleic acid payload from degradation and facilitating intracellular delivery of the nucleic acid. The cationic lipids should be biodegradable, well-tolerated and provide an adequate therapeutic index. In 2010, Semple et al. hypothesized that after endocytosis, the cationic lipid interacts with naturally occurring anionic phospholipids in the endosomal membrane, forming ion pairs that adopt non-bilayer structures and disrupt membranes. In isolation, cationic lipids and endosomal membrane anionic lipids such as phosphatidylserine adopt a cylindrical molecular shape, which is compatible with packing in a bilayer configuration. However, when cationic and anionic lipids are mixed together, they combine to form ion pairs where the cross-sectional area of the combined headgroup becomes smaller than that of the sum of individual headgroup areas in isolation. The ion pair therefore adopts a molecular ‘cone’s hape, which promotes the formation of inverted, non-bilayer phases such as the hexagonal HII phase. Such inverted phases do not support bilayer structure and are associated with membrane fusion and membrane disruption. As a result, the membrane of endosome can be lysed to allow the release of the payload, e.g. nucleic acids, into the cytoplasm. By using a rational lipid design strategy, the same group reported DLin-MC3-DMA (MC3)