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-11679082-B2
Publication Date
2023-06-20
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 invention provides a therapeutic construct that combines a mesoporous silica nanoparticle (MSNP) platform with programmed delivery of a mitotic kinase modality and an immune checkpoint component. The MSNP platform is loaded with either a small molecule mitotic kinase inhibitor in an amount 0.01% to 5% by weight of the therapeutic construct or a mitotic kinase-specific siRNA, and is further functionalized with a Programmed Death-Ligand 1 (PD-L1) antibody conjugated onto the MSNP platform.
The therapeutic construct is framed for use in treating hyperproliferative diseases, including cancer. The disclosure states a strategy in which cancer cell death from mitotic inhibition is followed by checkpoint expression, including PD-L1 upregulation, in surviving cancer cells, enabling adaptive antitumor immunity with immune checkpoint blockade and targeted homing associated with upregulated checkpoint expression.
The therapeutic construct is further described as being administered intratumorally or systemically across broad cancer types. The document also discusses formulation and nanoparticle property considerations consistent with delivery via the enhanced permeability and retention (EPR) effect, and optional components described include delivery particles, including MSNPs and other nanoparticles or microparticles, and additional adjuvants such as CpG/CpG TLR agonists.
Claims Coverage
The provided claims identify one independent MSNP-based inventive construct with mitotic kinase targeting and PD-L1 antibody conjugation, together with additional quantitative and nanoparticle-related features. A method of treating hyperproliferative disease by administering the composition is also included.
Msnp platform loaded with mitotic kinase inhibitor or mitotic kinase-specific siRNA plus pd-l1 antibody conjugation
A therapeutic construct comprising a mesoporous silica nanoparticle (MSNP) platform loaded with a small molecule mitotic kinase inhibitor in an amount 0.01% to 5% by weight of the therapeutic construct, or a mitotic kinase-specific siRNA, and a Programmed Death-Ligand 1 (PD-L1) antibody conjugated onto the MSNP platform.
Mitotic kinase target coverage for inhibitor or siRNA
The therapeutic construct where either the small-molecule mitotic kinase inhibitor inhibits at least one specified mitotic kinase, or the mitotic kinase-specific siRNA is specific for at least one specified mitotic kinase.
Pd-l1 antibody weight-percentage constraint
The therapeutic construct where the PD-L1 antibody comprises 0.1% to 20% by weight of the therapeutic construct.
Nanoparticle surface coating with cross-linked pei and polyethylene glycol
A therapeutic construct in which a nanoparticle is coated with cross-linked polyethylenimine (PEI) and polyethylene glycol.
Nanoparticle mean particle size constraint
The therapeutic construct characterized by a nanoparticle with a mean particle size of about 30–80 nm.
The core inventive concept is an MSNP platform that simultaneously delivers a mitotic kinase modality and presents a PD-L1 antibody conjugate, with refinements including selected mitotic kinase targets, quantitative composition constraints for the PD-L1 antibody, and nanoparticle coating and size limitations. A therapeutic method of treating hyperproliferative disease by administering the composition is also included.
Stated Advantages
Improves tumor control and survival in the described preclinical example context.
Upregulates PD-L1 via mitotic kinase inhibition in the described preclinical context.
Demonstrates CD8+ T-cell dependence in the described preclinical context.
Improving therapeutic index.
Reducing dose-limiting toxicity.
Providing synergistic adaptive antitumor immunity.
Enabling targeted homing based on PD-L1 upregulation in surviving cancer cells.
Documented Applications
Treating a subject diagnosed with a hyperproliferative disease or condition by administering an effective amount of the claimed composition.
Use in cancer-related therapeutic contexts, including hyperproliferative diseases as framed in the provided content.
Administration described as intratumoral or systemic across broad cancer types for treating cancer via the therapeutic construct.
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