Injectable hydrogels for controlled release of immunomodulatory compounds
Inventors
ROTH, Gillie A. • Appel, Eric Andrew • Davis, Mark • GALE, Emily C. • CORREA, Santiago
Assignees
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Publication Number
US-12433959-B2
Publication Date
2025-10-07
Expiration Date
Abstract
An immunomodulatory delivery system includes a hydrogel, a first immunomodulatory cargo encapsulated in the cargo, and a second immunomodulatory cargo encapsulated in the hydrogel. The hydrogel includes a polymer non-covalently crossed-linked with a plurality of nanoparticles. The first immunomodulatory cargo is smaller than the second immunomodulatory cargo. A ratio of a diffusivity of the first immunomodulatory cargo through the hydrogel to a diffusivity of the second immunomodulatory cargo through the hydrogel is less than 3.
Core Innovation
The invention provides an injectable vaccine delivery system in the form of a hydrogel depot. The hydrogel comprises a hydrophobically-modified cellulose derivative non-covalently cross-linked with a plurality of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) nanoparticles, and it encapsulates a first immunomodulatory cargo comprising an immune-activating compound and a second immunomodulatory cargo comprising an antigen.
The hydrogel depot is configured to recruit antigen-presenting cells (APCs) to infiltrate into the depot. While the infiltrating APCs are present within the depot, the immune-activating compound and the antigen activate the infiltrating APCs, and after activation the hydrogel allows the activated infiltrating APCs to migrate out of the depot.
The system is engineered so that payload co-delivery is sustained and tuned by hydrogel-nanoparticle formulation and transport relationships. The diffusivity and release behavior are matched to enable substantially similar sustained co-release despite cargo size differences, and the polymer-nanoparticle hydrogel platform is described as shear-thinning and self-healing, supporting injectability while maintaining depot function.
Claims Coverage
The relevant independent claims are clm-00001 (method) and clm-00019 (vaccine delivery system). Each independent claim centers on a hydrogel depot that recruits APCs, activates them with an encapsulated immune-activating compound plus an encapsulated antigen, and then allows activated APCs to migrate out, using a hydrophobically-modified cellulose derivative non-covalently cross-linked with PEG-PLA nanoparticles.
Hydrogel depot with non-covalent PEG-PLA cross-linking
A hydrogel comprising a hydrophobically-modified cellulose derivative non-covalently cross-linked with a plurality of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) nanoparticles.
Co-encapsulation of immune-activating compound and antigen
A first immunomodulatory cargo encapsulated in the hydrogel, the first immunomodulatory cargo comprising an immune-activating compound; and a second immunomodulatory cargo encapsulated in the hydrogel, the second immunomodulatory cargo comprising an antigen.
APC recruiting, in-depot activation, and migration out
The hydrogel forms a depot that is configured to recruit antigen-presenting cells (APCs) to infiltrate into the depot, activate the infiltrating APCs with the immune-activating compound and the antigen while the infiltrating APCs are present within the depot, and allow the activated infiltrating APCs to migrate out of the depot.
Vaccine delivery system configured to form the functional depot in a subject
The hydrogel is configured to form a depot in a subject that recruits antigen-presenting cells (APCs), activates the infiltrating APCs with the immune-activating compound and the antigen, and allows the activated infiltrating APCs to migrate out of the depot.
Across the independent claims, the inventive core is a hydrophobically-modified cellulose derivative/PEG-PLA non-covalently cross-linked hydrogel encapsulating both an immune-activating compound and an antigen, configured to recruit APCs, activate them in situ, and permit activated APC migration out.
Stated Advantages
Sustains antigen/adjuvant availability for infiltrating APCs within the depot.
Increases magnitude, duration, and affinity of humoral immune responses after single subcutaneous administration.
Prolongs germinal center responses.
Improves antibody affinity.
Increases local inflammatory infiltrate, including monocytes/macrophages and dendritic cells.
Enhances germinal center metrics, including GCBC frequency, class switching, Tfh frequency, and LZ/DZ ratio.
Produces higher and longer-lasting serum IgG1 compared with PBS bolus.
Documented Applications
Influenza extension using influenza hemagglutinin (HA) with TLR agonist R848 via tethered nanoparticles.
Cancer immunotherapy examples including TRP1/Poly(I:C) + IL2 + anti-CD28, and R848 with anti-PD1 and anti-CD40, with reported tumor control/survival and altered biodistribution/off-target exposure.
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