Compositions and methods for delivery of agents

Patent metadata

Field	Value
Publication number	US-2018147298-A1
Application number	US-201715674107-A
Country	US
Kind code	A1
Filing date	Aug 10, 2017
Priority date	Dec 10, 2015
Publication date	May 31, 2018
Grant date	—

Abstract

This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering agents in vivo including nucleic acids and proteins. These compositions are not subject to accelerated blood clearance and they have an improved toxicity profile in vivo.

First claim

1 . A lipid nanoparticle (LNP) comprising a therapeutic agent, a fast diffusing PEG-lipid, an ionizable lipid, and a helper lipid, wherein the therapeutic agent is a mRNA coding for a protein and, wherein the LNP is insensitive to accelerated blood clearance upon in vivo administration of a second LNP to a subject within 10 days.

2 . The LNP of claim 1 , wherein the fast diffusing PEG-lipid is a hydroxy-PEGylated lipid.

3 . The LNP of claim 2 , wherein the hydroxy group of the hydroxy-PEGylated lipid is at the terminus of the PEG chain.

4 . The LNP of claim 1 , wherein the lipid of the fast diffusing PEG-lipid is a short lipid tail that is a fatty acid.

5 . The LNP of claim 4 , wherein the fatty acid is stearic acid.

6 . (canceled)

7 . The LNP of claim 6 , wherein the LNP further comprises a structural lipid and comprises a molar ratio of about 20-60% ionizable lipid: 5-25% helper lipid: 25-55% structural lipid; and 0.5-15% fast diffusing PEG-lipid.

8 . (canceled)

9 . The LNP of claim 8 , wherein the subject has no or reduced production of natural IgM capable of binding to the LNPs, relative to a subject receiving an LNP comprised of a methoxy-PEGylated lipid or MC3.

10 . The LNP of claim 9 , wherein a level of natural IgM capable of binding to the LNPs is measured within 2-96 hours following a first administration of the LNP.

11 .- 15 . (canceled)

16 . The LNP of claim 9 , wherein reduced production of natural IgM capable of binding to the LNPs is a reduction of at least 30% to 95%.

17 .- 19 . (canceled)

20 . The LNP of claim 1 , wherein the helper lipid comprises at least one carbon containing fatty acid chain of at least 8 carbons in length and at least one polar headgroup moiety, and wherein the helper lipid does not comprise a phosphatidyl choline (PC) and is a zwitterionic non-cationic helper lipid, a DSPC analog, oleic acid, an oleic acid analog, or a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) substitute.

21 . The LNP of claim 20 , wherein the DSPC analog has at least one of a (i) modified head group that is a modified quaternary amine head group, (ii) a modified core group, and (iii) a modified lipid tail group.

22 .- 23 . (canceled)

24 . The LNP of claim 1 , wherein the helper lipid competitively reduces or inhibits phosphocholine from binding to CD36.

25 . (canceled)

26 . The LNP of claim 1 , wherein the LNP comprises oleic acid or an oleic acid analog.

27 . The LNP of claim 1 , wherein the LNP has no or reduced B1a cell stimulating activity compared to an LNP comprising phosphatidyl choline.

28 .- 31 . (canceled)

32 . The LNP of claim 1 , wherein the LNP further comprises an agent that inhibits immune responses in the subject.

33 . The LNP of claim 32 , wherein the agent that inhibits immune responses in the subject is a miR binding site.

34 . The LNP of claim 33 , wherein the miR binding site is selected from miR 126, miR 155, and miR 142 3p.

35 . The LNP of claim 33 , wherein the miR binding site is incorporated into the mRNA.

36 . The LNP of claim 33 , wherein the miR binding site is separate from the mRNA.

37 . The LNP of claim 1 , wherein the PEG-lipid comprises a compound of Formula (III):

or salts thereof, wherein:
R 3 is —OR O ;
R O is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
r is an integer between 1 and 100, inclusive;
L 1 is optionally substituted C 1-10 alkylene, wherein at least one methylene of the optionally substituted C 1-10 alkylene is independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, —O—, —N(R N )—, —S—, —C(O)—, —C(O)N(R N )—, —NR N C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(R N )—, —NR N C(O)O—, or —NR N C(O)N(R N )—;
D is a moiety obtained by click chemistry or a moiety cleavable under physiological conditions;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
A is of the formula:

each instance of L 2 is independently a bond or optionally substituted C 1-6 alkylene, wherein one methylene unit of the optionally substituted C 1-6 alkylene is optionally replaced with —O—, —N(R N )—, —S—, —C(O)—, —C(O)N(R N )—, —NR N C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(R N )—, —NR N C(O)O—, or —NR N C(O)N(R N )—;
each instance of R 2 is independently optionally substituted C 1-30 alkyl, optionally substituted C 1-30 alkenyl, or optionally substituted C 1-30 alkynyl; optionally wherein one or more methylene units of R 2 are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, —N(R N )—, —O—, —S—, —C(O)—, —C(O)N(R N )—, —NR N C(O)—, —NR N C(O)N(R N )—, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(R N )—, —NR N C(O)O—, —C(O)S—, —SC(O)—, —C(═NR N )—, —C(═NR N )N(R N )—, —NR N C(═NR N )—, —NR N C(═NR N )N(R N )—, —C(S)—, —C(S)N(R N )—, —NR N C(S)—, —NR N C(S)N(R N )—, —S(O)—, —OS(O)—, —S(O)O—, —OS(O)O—, —OS(O) 2 —, —S(O) 2 O—, —OS(O) 2 O—, —N(R N )S(O)—, —S(O)N(R N )—, —N(R N )S(O)N(R N )—, —OS(O)N(R N )—, —N(R N )S(O)O—, —S(O) 2 —, —N(R N )S(O) 2 —, —S(O) 2 N(R N )—, —N(R N )S(O)N(R N )—, —OS(O) 2 N(R N )—, or —N(R N )S(O) 2 O—;
each instance of R N is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
p is 1 or 2.

38 . The LNP of claim 37 , wherein the compound of Formula (III) is of Formula (III-OH):

or a salt thereof.

39 . The LNP of claim 37 , wherein the compound of Formula (III) is of Formula (V-OH):

or salts thereof, wherein:
r is an integer between 1 and 100, inclusive; and R 5 is optionally substituted C 10-40 alkyl.

40 . The LNP of claim 39 , wherein the compound of Formula (V-OH) is:

or a salt thereof.

41 . The LNP of claim 37 , wherein the compound of Formula (III) is of one of the following formulae:

or a salt thereof.

42 . The LNP of claim 1 , wherein the ionizable lipid is a compound of Formula (X):

or a salt or isomer thereof, wherein:
R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, —R*YR″, —YR″, and —R″M′R′;
R 2 and R 3 are independently selected from the group

Assignees

• Modernatx Inc

Inventors

• Besin Gilles
• Hoge Stephen
• Senn Joseph
• Benenato Kerry
• Sabnis Staci

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title