# US 2024/0197641 A1 · Compositions and methods for targeted systemic delivery to cells

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- Number: US 2024/0197641 A1
- Document ID: US20240197641A1
- Status: Published application
- Kind: A1
- Application number: 18/283,615
- Filed: 2022-03-23
- Published: 2024-06-20
- Earliest claimed: 2021-03-23
- Assignees: ReCode Therapeutics, Inc.; Board of Regents, The University of Texas System
- Applicants: ReCode Therapeutics, Inc.; The Board of Regents of the University of Texas System
- Inventors: David J. Lockhart; Vladimir Kharitonov; Brandon Wustman; Daniel Siegwart; Xueliang Yu; Jackson Eby
- Web page: https://patentgrep.com/patent/US20240197641A1

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- 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 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 48/0041: {the non-active part being polymeric}
- C12N 15/88: using microencapsulation, e.g. using {amphiphile} liposome vesicle
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Described herein are compositions, kits, and methods for potent systemic delivery to a cell of a subject. Also described herein are pharmaceutical compositions comprising a therapeutic or prophylactic agent assembled to a lipid composition. The lipid composition can comprise an ionizable cationic lipid, a phospholipid, and a selective organ targeting lipid. Further described herein are high-potency dosage forms of a therapeutic or prophylactic agent formulated with a lipid composition.

## Claims

### Claim 1

A composition formulated for systemic (e.g., intravenous) administration, the composition comprising a therapeutic agent assembled with a lipid composition that comprises:
(i) an ionizable cationic lipid;
(ii) a polymer-conjugated lipid; and
(iii) a selective organ targeting (SORT) lipid has the structure of Formula (IA), or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein:
R1 and R2 are each independently alkyl(C8-C24), alkenyl(C8-C24), or a substituted version of either group;
R3, R3′, and R3″ are each independently alkyl(C≤6) or substituted alkyl(C≤6); and
X− is a monovalent anion.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the SORT lipid having the structure of Formula (IA) is selected from the group consisting of:
and a combination thereof.

### Claim 3

A composition formulated for systemic (e.g., intravenous) administration, the composition comprising a therapeutic agent assembled with a lipid composition that comprises:
(i) an ionizable cationic lipid;
(ii) a polymer-conjugated lipid; and
(iii) a selective organ targeting (SORT) lipid has the structure of Formula (S-III), or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein:
R1 and R2 are each independently alkyl(C8-C24), alkenyl(C8-C24), or a substituted version of either group;
R3, R3′, and R3″ are each independently alkyl(C≤6) or substituted alkyl(C≤6); and
X− is a monovalent anion.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the SORT lipid having the structure of Formula (S-III) is

### Claim 5 (depends on 1, 2)

The composition of claim 1 or 2, wherein the ionizable cationic lipid is a dendrimer or dendron of a generation (g) having a structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
(a) the core comprises a structural formula (XCore):
wherein:
Q is independently at each occurrence a covalent bond, —O—, —S—, —NR2—, or —CR3aR3b—;
R2 is independently at each occurrence R1g or -L2-NR1eR1f;
R3a and R3b are each independently at each occurrence hydrogen or an optionally substituted (e.g., C1-C6, such as C1-C3) alkyl;
R1a, R1b, R1c, R1d, R1e, R1f, and R1g (if present) are each independently at each occurrence a point of connection to a branch, hydrogen, or an optionally substituted (e.g., C1-C12) alkyl;
L0, L1, and L2 are each independently at each occurrence selected from a covalent bond, (e.g., C1-C12, such as C1-C6 or C1-C3) alkylene, (e.g., C1-C12, such as C1-C8 or C1-C6) heteroalkylene (e.g., C2-C8 alkyleneoxide, such as oligo(ethyleneoxide)), [(e.g., C1-C6) alkylene]-[(e.g., C4-C6) heterocycloalkyl]-[(e.g., C1-C6) alkylene], [(e.g., C1-C6) alkylene]-(arylene)-[(e.g., C1-C6) alkylene] (e.g., [(e.g., C1-C6) alkylene]-phenylene-[(e.g., C1-C6) alkylene]), (e.g., C4-C6) heterocycloalkyl, and arylene (e.g., phenylene); or,
alternatively, part of L1 form a (e.g., C4-C6) heterocycloalkyl (e.g., containing one or two nitrogen atoms and, optionally, an additional heteroatom selected from oxygen and sulfur) with one of R1c and R1d; and
x1 is 0, 1, 2, 3, 4, 5, or 6; and
(b) each branch of the plurality (N) of branches independently comprises a structural formula (XBranch):
wherein:
* indicates a point of attachment of the branch to the core;
g is 1, 2, 3, or 4;
Z=2(g-1);
G=0, when g=1; or G=Σi=0i=g-2, when g≠1;
(c) each diacyl group independently comprises a structural formula
wherein:
* indicates a point of attachment of the diacyl group at the proximal end thereof,
** indicates a point of attachment of the diacyl group at the distal end thereof,
Y3 is independently at each occurrence an optionally substituted (e.g., C1-C12);
alkylene, an optionally substituted (e.g., C1-C12) alkenylene, or an optionally substituted (e.g., C1-C12) arenylene;
A1 and A2 are each independently at each occurrence —O—, —S—, or —NR4—, wherein:
R4 is hydrogen or optionally substituted (e.g., C1-C6) alkyl;
m1 and m2 are each independently at each occurrence 1, 2, or 3; and
R3c, R3d, R3e, and R3f are each independently at each occurrence hydrogen or an optionally substituted (e.g., C1-C8) alkyl; and
(d) each linker group independently comprises a structural formula
wherein:
** indicates a point of attachment of the linker to a proximal diacyl group;
*** indicates a point of attachment of the linker to a distal diacyl group; and
Y1 is independently at each occurrence an optionally substituted (e.g., C1-C12) alkylene, an optionally substituted (e.g., C1-C12) alkenylene, or an optionally substituted (e.g., C1-C12) arenylene; and
(e) each terminating group is independently selected from optionally substituted (e.g., C1-C18, such as C4-C18) alkylthiol, and optionally substituted (e.g., C1-C18, such as C4-C18) alkenylthiol.

### Claim 6 (depends on 5)

The composition of claim 5, wherein x1 is 0, 1, 2, or 3.

### Claim 7 (depends on 5)

The composition of claim 5, wherein R1a, R1b, R1c, R1d, R1e, R1f, and R1g (if present) are each independently at each occurrence a point of connection to a branch (e.g., as indicated by *), hydrogen, or C1-C12 alkyl (e.g., C1-C8 alkyl, such as C1-C6 alkyl or C1-C3 alkyl), wherein the alkyl moiety is optionally substituted with one or more substituents each independently selected from —OH, C4-C8 (e.g., C4-C6) heterocycloalkyl (e.g., piperidinyl
N—(C1-C3 alkyl)-piperidinyl
piperazinyl
N—(C1-C3 alkyl)-piperadizinyl
morpholinyl
N-pyrrolidinyl
pyrrolidinyl
or N—(C1-C3 alkyl)-pyrrolidinyl
(e.g., C6-C10) aryl, and C3-C5 heteroaryl (e.g., imidazolyl
or pyridinyl

### Claim 8 (depends on 7)

The method of claim 7, wherein R1a, R1b, R1c, R1d, R1e, R1f, and R1g (if present) are each independently at each occurrence a point of connection to a branch (e.g., as indicated by *), hydrogen, or C1-C12 alkyl (e.g., C1-C8 alkyl, such as C1-C6 alkyl or C1-C3 alkyl), wherein the alkyl moiety is optionally substituted with one substituent —OH.

### Claim 9 (depends on 5)

The composition of claim 5, wherein R3a and R3b are each independently at each occurrence hydrogen.

### Claim 10 (depends on 5)

The composition of claim 5, wherein the plurality (N) of branches comprises at least 3 (e.g., at least 4, or at least 5) branches.

### Claim 11 (depends on 5)

The composition of claim 5, wherein g=1; G=0; and Z=1.

### Claim 12 (depends on 11)

The composition of claim 11, wherein each branch of the plurality of branches comprises a structural formula

### Claim 13 (depends on 5)

The composition of claim 5, wherein g=2; G=1; and Z=2.

### Claim 14 (depends on 13)

The composition of claim 13, wherein each branch of the plurality of branches comprises a structural formula

### Claim 15 (depends on 5)

The composition of claim 5, wherein the core is selected from those set forth in Table 1 or a subset thereof.

### Claim 16 (depends on 5)

The composition of claim 5, wherein the core comprises a structural formula selected from the group consisting of:
and pharmaceutically acceptable salts thereof, wherein * indicates a point of attachment of the core to a branch of the plurality of branches.

### Claim 17 (depends on 5)

The composition of claim 5, wherein the core has the structure
wherein * indicates a point of attachment of the core to a branch of the plurality of branches or H.

### Claim 18 (depends on 17)

The composition of claim 17, wherein at least 2 branches are attached to the core.

### Claim 19 (depends on 17)

The composition of claim 17, wherein at least 3 branches are attached to the core.

### Claim 20 (depends on 17)

The composition of claim 17, wherein at least 4 branches are attached to the core.

### Claim 21 (depends on 5)

The composition of claim 5, wherein the core has the structure
wherein * indicates a point of attachment of the core to a branch of the plurality of branches or H.

### Claim 22 (depends on 21)

The composition of claim 21, wherein at least 4 branches are attached to the core.

### Claim 23 (depends on 21)

The composition of claim 21, wherein at least 5 branches are attached to the core.

### Claim 24 (depends on 21)

The composition of claim 21, wherein at least 6 branches are attached to the core.

### Claim 25 (depends on 5)

The composition of claim 5, wherein A1 is —O— or —NH—.

### Claim 26 (depends on 25)

The composition of claim 25, wherein A1 is —O—.

### Claim 27 (depends on 5)

The composition of claim 5, wherein A2 is —O— or —NH—.

### Claim 28 (depends on 27)

The composition of claim 27, wherein A2 is —O—.

### Claim 29 (depends on 5)

The composition of claim 5, wherein Y3 is C1-C12 (e.g., C1-C6, such as C1-C3) alkylene.

### Claim 30 (depends on 5)

The composition of claim 5, wherein the diacyl group independently at each occurrence comprises a structural formula
such as
optionally wherein R3c, R3d, R3e, and R3f are each independently at each occurrence hydrogen or C1-C3 alkyl.

### Claim 31 (depends on 5)

The composition of claim 5, wherein each terminating group is independently C1-C18 (e.g., C4-C18) alkenylthiol or C1-C18 (e.g., C4-C18) alkylthiol.

### Claim 32 (depends on 5)

The composition of claim 5, wherein each terminating group is independently selected from those set forth in Table 3 or a subset thereof.

### Claim 33 (depends on 1, 2)

The composition of claim 1 or 2, wherein the ionizable cationic lipid is selected from those set forth in Table 4, or pharmaceutically acceptable salts thereof, or a subset of the lipids and the pharmaceutically acceptable salts thereof.

### Claim 34 (depends on 1, 2)

The composition of claim 1 or 2, wherein the ionizable cationic lipid is selected from those set forth in Table 4 or Table 5, or pharmaceutically acceptable salts thereof, or a subset of the lipids and the pharmaceutically acceptable salts thereof.

### Claim 35 (depends on 1, 2)

The composition of claim 1 or 2, wherein the lipid composition further comprises a phospholipid.

### Claim 36 (depends on 35)

The composition of claim 35, wherein the phospholipid is at a molar percentage from about 8% to about 23%.

### Claim 37 (depends on 1, 2)

The composition of claim 1 or 2, wherein the lipid composition further comprises a steroid or steroid derivative.

### Claim 38 (depends on 37)

The composition of claim 37, wherein the steroid or steroid derivative is at a molar percentage from about 15% to about 46%.

### Claim 39 (depends on 1, 2)

The composition of claim 1 or 2, wherein the ionizable cationic lipid is at a molar percentage from about 5% to about 30%.

### Claim 40 (depends on 1, 2)

The composition of claim 1 or 2, wherein the polymer-conjugated lipid is at a molar percentage from about 0.5% to about 10%.

### Claim 41 (depends on 1, 2)

The composition of claim 1 or 2, wherein the polymer-conjugated lipid is at a molar percentage from about 1% to about 10%.

### Claim 42 (depends on 1, 2)

The composition of claim 1 or 2, wherein the polymer-conjugated lipid is at a molar percentage from about 2% to about 10%.

### Claim 43 (depends on 1, 2)

The composition of claim 1 or 2, wherein the SORT lipid is at a molar percentage from about 20% to about 65%.

### Claim 44 (depends on 1, 2)

The composition of claim 1 or 2, wherein the therapeutic agent is a polynucleotide; and wherein a molar ratio of nitrogen in the lipid composition to phosphate in the polynucleotide (N/P ratio) is no more than about 20:1.

### Claim 45 (depends on 44)

The composition of claim 44, wherein the N/P ratio is from about 5:1 to about 20:1.

### Claim 46 (depends on 1, 2)

The composition of claim 1 or 2, wherein a molar ratio of the therapeutic agent to total lipids of said lipid composition is no more than about 1:1, 1:10, 1:50, or 1:100.

### Claim 47 (depends on 1, 2)

The composition of claim 1 or 2, wherein at least about 85% of said therapeutic agent is encapsulated in particles of said lipid compositions.

### Claim 48 (depends on 1, 2)

The composition of claim 1 or 2, wherein said lipid composition comprises a plurality of particles characterized by one or more characteristics of the following:
(1) a (e.g., average) size of 100 nanometers (nm) or less;
(2) a polydispersity index (PDI) of no more than about 0.2; and
(3) a negative zeta potential of −10 millivolts (mV) to 10 mV.

### Claim 49 (depends on 1, 2)

The composition of claim 1 or 2, wherein said lipid composition has an apparent ionization constant (pKa) outside a range of 6 to 7.

### Claim 50 (depends on 49)

The composition of claim 49, wherein said apparent pKa of said lipid composition is of about 7 or higher.

### Claim 51 (depends on 49)

The composition of claim 49, wherein said apparent pKa of said lipid composition is of about 8 or higher.

### Claim 52 (depends on 49)

The composition of claim 49, wherein said apparent pKa of said lipid composition is from about 8 to about 13.

### Claim 53 (depends on 1, 2)

A method for targeted delivery of a therapeutic agent to a spleen cell, the method comprising (e.g., systemically) administering a composition according to claim 1 or 2, thereby providing an effective amount or activity of said therapeutic agent in said spleen cell of said subject that is at least 1.1-fold greater than a corresponding amount or activity of said therapeutic agent achieved in a lung cell of said subject.

### Claim 54 (depends on 53)

The method of claim 53, wherein the effective amount or activity of said therapeutic agent in said spleen cell of said subject that is at least 1.1-fold greater, at least 2.5-fold greater, at least 3.5-fold greater, at least 10-fold greater, at least 5.5-fold greater, at least 10-fold greater, at least 15-fold greater, at least 20-fold greater, or at least 50-fold greater than a corresponding amount or activity of said therapeutic agent achieved in a lung cell of said subject.

### Claim 55 (depends on 1, 2)

A method for targeted delivery of a therapeutic agent to a lung cell, the method comprising (e.g., systemically) administering a composition according to claim 1 or 2, thereby providing an effective amount or activity of said therapeutic agent in said lung cell of said subject that is at least 1.1-fold greater than a corresponding amount or activity of said therapeutic agent achieved in a spleen cell of said subject.

### Claim 56 (depends on 55)

The method of claim 55, wherein said effective amount or activity of said therapeutic agent in said lung cell of said subject is at least 1.1-fold greater, at least 5-fold greater, at least 10-fold greater, at least 15-fold greater, at least 18-fold greater, at least 20-fold greater, or at least about 50-fold greater than a corresponding amount or activity of said therapeutic agent achieved in a liver cell of said subject.