Therapeutic constructs for co-delivery of mitotic kinase inhibitor and immune checkpoint inhibitor
Inventors
Yantasee, Wassana • REDA, Moataz • NGAMCHERDTRAKUL, Worapol
Assignees
Oregon Health and Science University • PDX Pharmaceuticals Inc
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Publication Number
US-12059500-B2
Publication Date
2024-08-13
Expiration Date
Abstract
Disclosed herein are therapeutic constructs including a delivery particle, at least one mitotic kinase inhibitor, and at least one immune checkpoint inhibitor. Also disclosed are therapeutic constructs including a mitotic kinase inhibitor, an immune checkpoint inhibitor, and a chemical linker. These therapeutic constructs cause cancer death by both therapeutic and immune effects and promote targeted delivery of more therapeutics to the surviving cancer cells in a positive feed-back loop. They enhance therapeutic index of free drugs and can be used intratumorally or systemically. This strategy can treat broad cancer types and is particular useful for cancer without obvious receptors for cancer-targeted delivery of otherwise toxic therapeutics.
Core Innovation
The disclosure provides therapeutic constructs comprising a mesoporous silica nanoparticle (MSNP) platform loaded with an anti-cancer agent and a Programmed Death-Ligand 1 (PD-L1) antibody conjugated onto the MSNP platform. The construct is presented as a carrier for both the anti-cancer agent and the PD-L1 antibody conjugate, and as an engineered delivery system for cancer treatment.
The approach addresses delivery to the tumor microenvironment (TME), including enhanced permeability and retention (EPR) effect, and positions the construct to localize to the TME. The disclosure states that the construct combines anti-cancer payload activity with PD-L1 targeting and immune checkpoint blockade to promote adaptive antitumor immunity.
The engineered delivery systems described include particles and therapeutic construct formats such as mesoporous silica nanoparticles, liposomes, polymeric nanoparticles, and hybrid vehicles. The disclosure further describes core-shell, nanolipogel-like or polymeric/lipid particle structures, including a biodegradable hydrogel core and a liposomal shell, with PEGylation, surface charge, tunable release, and local stimuli-responsive linkers.
Claims Coverage
The independent claim family centers on a therapeutic construct comprising an MSNP platform loaded with an anti-cancer agent and a PD-L1 antibody conjugated onto the MSNP platform. The provided claim coverage identifies five inventive features.
MSNP platform loaded with anti-cancer agent and PD-L1 antibody conjugate
A therapeutic construct comprising a mesoporous silica nanoparticle (MSNP) platform loaded with an anti-cancer agent in an amount 0.1% to 20% by weight of the therapeutic construct, and a Programmed Death-Ligand 1 (PD-L1) antibody conjugated onto the MSNP platform.
PD-L1 antibody weight constraint
The PD-L1 antibody is present in an amount 0.1% to 20% by weight of the therapeutic construct.
MSNP mean particle size range
The MSNP has a mean particle size of about 30 nm to about 80 nm.
Cross-linked PEI and PEG coating on MSNP
The MSNP is coated with cross-linked polyethylenimine (PEI) and polyethylene glycol.
Anti-cancer agent selected from specified inhibitor categories
The anti-cancer agent includes at least one specified inhibitor type including PARP inhibitor, MEK inhibitor, CDK4/6 inhibitor, EGFR inhibitor, HER2 inhibitor, VEGF inhibitor, BRAF inhibitor, PI3K inhibitor, mTOR inhibitor, or ras inhibitor.
The inventive core is an MSNP platform that simultaneously carries an anti-cancer agent and a PD-L1 antibody conjugated onto the MSNP platform, with refinements including weight limits, particle size, coating, and specified inhibitor categories.
Stated Advantages
Improves therapeutic index by localizing checkpoint blockade to surviving cancer cells.
Enhances anti-tumor immunity through mitotic inhibition-induced PD-L1 upregulation and antigen release.
Documented Applications
No documented applications found
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