MOMP telonanoparticles, and related compositions, methods and systems

Patent metadata

Field	Value
Publication number	US-11207422-B2
Application number	US-201816609420-A
Country	US
Kind code	B2
Filing date	May 1, 2018
Priority date	May 2, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

A telodendrimer-nanolipoprotein particle (t-NLP), comprising one or more membrane forming lipids, one or more telodendrimers, and a scaffold protein and a Chlamydia major outer membrane protein (MOMP) comprising a MOMP hydrophobic region, and related compositions methods and systems.

First claim

The invention claimed is:

1. A telodendrimer-nanolipoprotein particle (t-NLP), comprising
one or more membrane forming lipids,
one or more telodendrimers, and
a scaffold protein and a Chlamydia major outer membrane protein (MOMP) and/or a fragment thereof comprising a MOMP hydrophobic region,

wherein the one or more membrane forming lipids are arranged in a discoidal membrane lipid bilayer stabilized by the scaffold protein and the one or more telodendrimers, with the membrane lipid bilayer attaching the MOMP and/or the fragment thereof through interaction of the MOMP hydrophobic region with the membrane lipid bilayer.

2. The telodendrimer-nanolipoprotein particle of claim 1 , having a size between 5 nm to 100 nm in diameter and comprising a telodendrimer to lipid ratio of 1:10 to 1:1000 a ratio of scaffold protein to lipid of 1:30 to 1:100 and a ratio of MOMP to scaffold protein of 20:1 to 1:4.

3. The telodendrimer-nanolipoprotein particle of claim 1 , having a size between 10 nm to 70 nm in diameter and comprising a telodendrimer to lipid ratio of 1:50 and 1:500 a ratio of scaffold protein to lipid of 1:30 to 1:100, and a ratio of MOMP to scaffold protein of 5:1 to 1:2.

4. The telodendrimer-nanolipoprotein particle of claim 1 , having a size between 25 nm to 50 nm in diameter and comprising a telodendrimer to lipid ratio of 1:100 to 1:200, a ratio of scaffold protein to lipid of 1:30 to 1:100 and a ratio of MOMP to scaffold protein of 3:1 to 1:1.

5. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the telodendrimer is a compound of formula (I):
( T ) m -( A ) p - L - D -(R) n   (I)

wherein
D is a dendrimer
T is a tail group;
A is a spacer moiety configured to be directly covalently connected to each T and to a linker moiety L, and comprises a polymer of 1 to m number of spacer A monomers, wherein the spacer A monomer comprises a substituted or unsubstituted linear C1-C15 alkyl; branched C3-C15 alkyl; cyclic C3-C15 alkyl; linear, cyclic, or branched C2-C15 alkenyl; linear, cyclic, or branched C2-C15 alkynyl; C6-C20 substituted or unsubstituted aryl; and C6-C20 substituted or unsubstituted heteroaryl,
R can be a detergent moiety, a lipid and/or an amino acid
m is 0-20 and p is 0-1, and
wherein m is 0 or 1 when p is 0; or m is 2-20 when p is 1.

6. The telodendrimer-nanolipoprotein particle of claim 5 , wherein the D is lysine, L is a bond, R is cholic acid or cholate, m is 1, and/or n is 2, 4 or 8.

7. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the telodendrimer comprises one or more compounds of formulas (II)-(III):
PEG - D -(R) n   (II)

PEG - L - D -(R) n   (III)

( PEG ) m′ - A - L - D -(R) n   (IV)

wherein
D is a dendrimer;
L is a linker moiety;
R is a detergent moiety, a lipid and/or an amino acid;
n is an integer from 2 to 128;
and subscript m′ of formula (IV) is 2-20.

8. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the MOMP is a MOMP of Chlamydia species Chlamydia trachomatis, Chlamydia pneumoniae , and Chlamydia psittaci (human pathogens), Chlamydia suis (affects only swine), Chlamydia pecorum (affects cows/swine/koala) and Chlamydia pneumonia (affects koala) and Chlamydia muridarum (affects only mice and hamsters) or a variant thereof or a fragment thereof, and wherein the variant maintains a beta barrel structure with 18 transmembrane regions separated by loops of the MOMP.

9. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the MOMP is a MOMP immunogenic fragment.

10. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the membrane forming lipid comprises at least one phospholipid, selected from soy phosphatidylcholine, egg phosphatidylcholine, soy phosphatidylglycerol, egg phosphatidylglycerol, palmitoyl-oleoyl-phosphatidylcholine distearoylphosphatidylcholine, distearoylphosphatidylglycerol phosphatidylcholine, phosphatidylglycerol, sphingomyelin, phosphatidylserine, phosphatidic acid, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylinositol, cephalin, cardiolipin, cerebrosides, dicetylphosphate, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, stearoyl-palmitoyl-phosphatidylcholine, di-palmitoyl-phosphatidylethanolamine, distearoyl-phosphatidylethanolamine, di-myrstoyl-phosphatidylserine, di-myrstoyl-phosphatidylcholine and dioleyl-phosphatidylcholine.

11. The telodendrimer-nanolipoprotein particle of claim 1 , wherein the scaffold protein is one or more of a human derived apoE4, a truncated version of human derived apoE4, a human derived apoE3, a truncated version of human derived apoE3, a human derived apoE2, a truncated version of human derived apoE2, a human derived apoA1, a truncated version of human derived apoA1, a mouse derived apoE4, a truncated version of mouse derived apoE4, mouse derived apoE3, truncated versions of mouse derived apoE3, a mouse derived apoE2, a truncated version of mouse derived apoE2, a mouse derived apoA1, a truncated version of mouse derived apoA1, a rat derived apoE4, a truncated version of rat derived apoE4, a rat derived apoE3, a truncated version of rat derived apoE3, a rat derived apoE2, a truncated version of rat derived apoE2, a rat derived apoA1, a truncated version of rat derived apoA1, a lipophorin, a synthetic cyclic peptide mimicking an apolipoprotein function.

12. The telodendrimer-nanolipoprotein particle of claim 1 , further comprising one or more lysolipids selected from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-didecanoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, egg phosphatidylcholine extracts, soy phosphatidylcholine extracts, heart phosphatidylcholine extracts, brain phosphatidylcholine extracts, liver phosphatidylcholine extracts, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-dilauroyl-sn-glycero-3-phosphate, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine, Egg phosphatidylethanolamine extract, soy phosphatidylethanolamine extract, heart phosphatidylethanolamine extract, brain phosphatidylethanolamine extract, 1,2-distearoyl-sn-glycero-3-phospho-(1 ‘-rac-glycerol), 1,2-dioleoyl-sn-glycero-3-phospho-(1’-rac-glycerol), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol), 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol), 1,2-dilauroyl-sn-glycero-3-phospho-(1′-rac-glycerol), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), egg phosphatidylglycerol extract, soy phosphatidylglycerol extract, 1,2-distearoyl-sn-glycero-3-phospho-L-serine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine, 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine, 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine, 1,2-dilauroyl-sn-glycero-3-phospho-L-serine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine, soy phosphatidylserine extract, brain phosphatidylserine extract, 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl hydrogen phospha

Assignees

• L Livermore Nat Security Llc

Inventors

• Coleman Matthew A
• Fischer Nicholas O
• Rasley Amy
• Blanchette Craig D
• Peterson Todd

Classifications

• A61K39/39

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61K9/1273

  Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61K2039/543

  intranasal · CPC title

• A61K9/513

  Organic macromolecular compounds; Dendrimers · CPC title