Lipid Nanoparticle LNP Systems for RNA Delivery Lipid Nanoparticle LNP System Nucleic Acid Delivery by LNP Photo from Precision Nanosystems Lipid Nanoparticle LNP System General Properties ID: 930373
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Slide1
Photo by Kyriakos
Kaziras
Lipid Nanoparticle (LNP)
Systems for RNA Delivery
Slide2Lipid Nanoparticle (LNP) SystemNucleic Acid Delivery by LNP
Photo from Precision
Nanosystems
Slide3Lipid Nanoparticle (LNP) SystemGeneral Properties
Size: diameters less than 100 nm Basic constituents
Structural lipidIonizable amino lipidPEG-lipid conjugate
CholesterolNucleic acid (siRNA, mRNA,
etc
)
pKa
of
ionizable amino lipid less than pH 7 Prepared using microfluidics (ethanol/water mixing in flow system) AdvantagesIncreased half lifeProtection from nucleasesAids in endocytosis and endosomal escapeDisadvantagesElevated risk of toxicity with introducing excipient materials
Slide4Lipid Nanoparticle (LNP) System
Basic Constituents & Structural ElementsPhoto from Arbutus Biopharm
Slide5Lipid Nanoparticle (LNP) SystemBasic Constituents: Cationic Lipid
Pros
Efficient delivery
Condense plasmidCons
Toxicity
Dissociation from DNA
Pros
Lower toxicity
Cons
Dissociation from DNAPros Low/no toxicity Dissociates from DNACons Low efficiency
Slide6Lipid Nanoparticle (LNP) SystemBasic Constituents: Cationic Lipid
Cullis
PR, Hope MJ. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther. 2017 Jul 5;25(7):1467-1475.
Slide7Lipid Nanoparticle (LNP) SystemEffect of Cationic Lipid Structure on
pKa
Jayaraman et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl. 2012 Aug 20;51(34):8529-33.
Slide8Lipid Nanoparticle (LNP) SystemEffect of
pKa on LNP Delivery
Wan C, Allen TM, Cullis PR. Lipid nanoparticle delivery systems for siRNA-based therapeutics. Drug Deliv Transl Res. 2014 Feb;4(1):74-83.
One of the key findings from these studies was the optimum lipid pKa value of 6.2–6.5 as a dominating factor in determining hepatic gene-silencing activity in vivo.
Slide9Photo by Kyriakos
Kaziras
Slide10cGMP manufacturing initiated in 1985
Supplied the first semi-synthetic phospholipid for an approved drug product in 1990
Dipalmitoyl phosphatidylcholine (DPPC)
Exosurf
®
Neonatal, synthetic lung surfactant replacement for neonates with
respiratory distress syndrome
Currently support ~25 active drug master files for clinical trials and commercial products
Manufacture cGMP quality materials from 50g to 25kg batches
Maximum annual capacity: 2 MT per shift
Manufacturing suites available for production:
General lipid production 10
Small scale lipid production 1
Adjuvant production 2
Formulations 1
cGMP Manufacturing
API, Excipient, & Contract Manufacturing
Slide11In general, lipids are non-toxic, flexible, biocompatible, completely biodegradable, and
non-immunogenic for systemic and non-systemic administrations.
Classical drug delivery systems (drug depot) Encapsulation of hydrophilic drugs (passive and remote loading)
Sequestration and dispersion of hydrophobic drugs
Targeted drug delivery systems via coupling with site-specific ligands
Delivery of genetic material (cationic lipids)
Plasmid
siRNA
mRNA
Liposomal adjuvant systems for vaccine development and immunotherapy Contrast agents for MRI (targeted and untargeted)
Nasal and pulmonary delivery of drugs
Topical delivery of drugs (enhanced penetration)
Opthalmic
delivery of drugs
Lipid-coated microbubbles for ultrasound imaging or treatment
Applications
Slide12Drug Product Patent Expires Active Drug Lipid Components
DaunoXome® 2009
Daunorubicin
DSPC, Cholesterol
Doxil
®
2010 Doxorubicin HSPC, Cholesterol, DSPE-
mPEG(2000)
Epaxal
® 2012 Inactivated hepatitis A virus DOPC:DOPE
Inflexal
® V 2012 Inactivated hemagglutinin of
DOPC:DOPE
influenza virus strains A and B
Depocyt® 2015
Cytarabin
/Ara-C DOPC, DPPG, Triolein
, Cholesterol
Ambisome®
2016 Amphotericin B HSPC, DSPG, Cholesterol
Amphotec
® 2016 Amphotericin B Cholesteryl
sulphate
Visudyne
®
2016
Verteporphin
DMPC, EPG
DepoDur
™ 2017 Morphine sulfate DOPC, DPPG,
Triolein
, Cholesterol
Mepact
®
2019
Mifamurtide
DOPS, POPC
Abelcet
®
2019 Amphotericin B DMPC, DMPG
Marqibo
®
2020 Vincristine SM, Cholesterol
Exparel
®
2021 Bupivacaine DEPC, DPPG,
Tricaprylin
, Cholesterol
Onivyde
™ 2028 Irinotecan DSPC, DSPE-
mPEG
(2000), Cholesterol
Myocet
®
N/A Doxorubicin EPC, Cholesterol
Approved Liposomal Drug Products
Slide13Phospholipids (Semi-synthetic, plant-derived) Phospholipids (Natural)
DMPC DLPE DMPG Egg PC (>95%) DPPC DMPE DPPG
DSPC DPPE DSPG
DEPC DSPE POPG
DOPC DOPE
POPC
Adjuvants (Synthetic MPLA)
PHAD
®
3D-PHAD
®
3D(6-acyl)-PHAD
®
Other
Tricaprylin
Semi-synthetic Cholesterol (plant-derived)
Triolein
DSPE-
mPEG
(2000)-
Maleimide
DOTAP
cGMP Lipids Currently Available
Slide14Synthetic Monophosphoryl Lipid A (MPLA)
PHAD® 3D-PHAD®
3D(6-acyl)-PHAD®
Equivalent to bacterial-derived MPLA (native)
Toll-like receptor 4 (TLR4) agonist
Elicits a strong T
H
1 immune response
Used in multiple clinical trials
Adjuvant system formulations available (research & cGMP)
Available in gram to kilogram scale
Adjuvants
Vaccine Development & Immunotherapy
Slide15From research to early phase clinical Products Liposomes
Emulsion Lyophilized lipid formulations Scaled from milliliters to > 100L
Most Avanti lipids can be incorporated into liposomal formulations Custom synthesis lipids can also be
used in formulations
Formulations
Liposomes & Nanoparticles
Contract Manufacturing
Proven Partner for Development to Commercialization
Over 150 combined years of lipid synthesis experience Route scouting and process development for proprietary lipids
Small-scale batches available (<100g) Scale-up support for multi-kilo production
Custom packaging options
Full analytical support with
method
development and validation Regulatory support for clinical trial
and commercial filings
Slide17People do
amazing
things with our lipids!
What will you
do?