Nanoparticle vaccine adjuvant and methods of use thereof
Inventors
Irvine, Darrell J. • Silva, Murillo • Crotty, Shane • Kato, Yu
Assignees
La Jolla Institute for Allergy and Immunology • Massachusetts Institute of Technology
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Publication Number
US-11547672-B2
Publication Date
2023-01-10
Expiration Date
Abstract
Non-liposome, non-micelle particles formed of a lipid, an additional adjuvant such as a TLR4 agonist, a sterol, and a saponin are provided. The particles are porous, cage-like nanoparticles, also referred to as nanocages, and are typically between about 30 nm and about 60 nm. In some embodiments, the nanocages include or are administered in combination with an antigen. The particles can increase immune responses and are particularly useful as adjuvants in vaccine applications and related methods of treatment. Preferred lipids, additional adjuvants including TLR4 agonists, sterols, and saponins, methods of making the nanocages, and method of using them are also provided.
Core Innovation
The invention is directed to porous, perforated cage-like nanocage vaccine adjuvant nanoparticles that are non-liposome and non-micelle. The particles comprise a phospholipid, a sterol, a saponin, and a pattern recognition receptor (PRR) ligand comprising a lipid, and the nanocage morphology is described as similar to ISCOMATRIX® adjuvant.
The particle population is described as monodisperse with a size range of about 30 nm to about 60 nm, with about 40 nm preferred. The PRR ligand is described as being a lipid that can be provided as a natural or synthetic monophosphoryl lipid A (MPLA) or a derivative thereof, including 3-O-deacylated monophosphoryl lipid A (3D-MPLA).
The nanoparticle formulation is described using detergent-assisted self-assembly to form the porous cage-like structure, followed by detergent removal to enable formation and purification of monodisperse particles. Antigen can be incorporated into the nanocage or co-formulated separately with the nanocage, and the formulations are reported to address immune activation via TLR4 activation through incorporation of MPLA-containing PRR ligand.
Claims Coverage
The partial claim set includes two independent claims. Across these independent claims, the core inventive subject matter is a porous cage-like particle built from a phospholipid, sterol, saponin, and a PRR ligand that includes a lipid, with an ISCOMATRIX®-like morphology requirement and an MPLA-based PRR ligand option in the second independent claim.
Porous cage-like non-liposome, non-micelle particle with phospholipid, sterol, saponin, and lipid PRR ligand
A non-liposome, non-micelle, porous, cage-like particle comprising a phospholipid, a sterol, a saponin, and a pattern recognition receptor (PRR) ligand comprising a lipid.
MPLA-containing porous cage-like nanoparticle with ISCOMATRIX-like morphology
A porous, cage-like nanoparticle comprising a phospholipid, a sterol, a saponin, a natural or synthetic monophosphoryl lipid A (MPLA) or a derivative thereof, and a morphology similar to that of ISCOMATRIX adjuvant.
Overall, the independent claims focus on porous, cage-like nanocage particles built from phospholipid, sterol, and saponin with a lipid PRR ligand, including MPLA or MPLA derivatives, and an ISCOMATRIX®-like morphology requirement; the first independent claim additionally specifies the particles are non-liposome and non-micelle.
Stated Advantages
Enhanced TLR4 activation with MPLA incorporation.
Increased antigen-specific IgG titers.
Strengthened germinal center and Tfh responses.
Increased plasmablast frequency and dendritic cell recruitment.
Increased pro-inflammatory cytokines.
Improved antigen drainage to lymph nodes and increased lymph node permeability.
Enhanced antigen uptake and activation of antigen-specific B cells.
Enhanced antigen-specific CD4 Tfh and dendritic cell activation in vivo.
Documented Applications
Prophylactic and therapeutic vaccine uses, including for cancer and infectious disease.
Tolerance induction with tolerogenic antigens.
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