Anticancer trail-targeted plant virus particles
Inventors
Assignees
Case Western Reserve University
Publication Number
US-12251410-B2
Publication Date
2025-03-18
Expiration Date
2038-05-17
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Abstract
An agent is described that includes a plant virus particle or VLP conjugate to TRAIL. Associating TRAIL with the plant virus particle or VLP serves to both target cancer cells and induce their apoptosis. The agent can therefore be used for a method of treating cancer in a subject.
Core Innovation
The invention provides agents comprising a plant virus particle or virus-like particle (VLP), specifically including potato virus X (PVX), conjugated to at least one tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The conjugation is achieved non-covalently via coordination bonds between nickel-coordinated nitrilotriacetic acid (Ni-NTA) modules displayed on the PVX surface and a histidine-tag on TRAIL. This design enables multivalent and surface-bound presentation of TRAIL, which mimics the membrane-bound state of TRAIL and facilitates efficient targeting and apoptosis induction in cancer cells.
The background identifies the problem that soluble TRAIL, although safe, has poor physiochemical properties and does not effectively trigger apoptosis in cancer cells, leading to limited efficacy in clinical trials. There remains the need for a delivery platform that presents multivalent TRAIL in a surface-bound state to better activate apoptosis in target cancer cells, particularly through more effective engagement of cell surface death receptors DR4 and DR5, which are overexpressed in many cancer cells but not healthy cells.
The innovation is further extended to methods for treating cancer in a subject by administering a therapeutically effective amount of the described agent. The agent can include additional conjugated molecules such as imaging agents (e.g., fluorescent molecules for imaging), anticancer agents (e.g., platinum-based drugs such as phenanthriplatin, or doxorubicin), or targeting agents (e.g., tumor-associated receptor ligands such as EGFR ligands). The plant virus particle or VLP can also be PEGylated to improve bioavailability and reduce immune response. This agent is intended for various administration regimens and the treatment of multiple cancer types, including particularly aggressive cancers such as triple negative breast cancer.
Claims Coverage
The patent includes one independent claim with several dependent claims, covering multiple inventive features related to PVX-TRAIL conjugates, additional loadable agents, conjugation specifics, and treatment methods.
Non-covalent conjugation of TRAIL to PVX via Ni-NTA/His-tag interaction
An agent and method comprising a potato virus X (PVX) plant virus particle or virus-like particle (VLP) which is non-covalently conjugated to at least one tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) via coordination bonds between nickel-coordinated nitrilotriacetic acid (Ni-NTA) modules displayed on the outer surface of the PVX particle or VLP and a histidine-tag on TRAIL.
Loading of additional agents onto PVX-TRAIL conjugate
The PVX plant virus particle or VLP can be further loaded with or conjugated to one or more of: an imaging agent, an anticancer agent, or a targeting agent. The targeting agent can be a ligand for a tumor-associated receptor, such as an epidermal growth factor receptor (EGFR) ligand. The anticancer agent can be a platinum-based anticancer agent (including phenanthriplatin) or doxorubicin. The imaging agent can include a fluorescent molecule for fluorescent imaging.
PEGylation of plant virus particles or VLPs
The plant virus particle or virus-like particle (VLP) can be PEGylated to modify its properties, including decreasing immunogenicity and altering pharmacokinetic behavior.
Imaging cancer tissue post administration
When the PVX plant virus particle or VLP is loaded with or conjugated to an imaging agent, the method further comprises the step of imaging cancer tissue in the subject using an imaging device subsequent to administration.
Treatment of specific cancer types including triple negative breast cancer
The method is applicable to the treatment of specific cancers selected from the group consisting of breast cancer, ovarian cancer, soft-tissue sarcoma, pancreatic cancer, colorectal cancer, non-small cell lung cancer, lymphoma, non-Hodgkins lymphoma, and hepatocarcinoma, specifically including triple negative breast cancer.
Therapeutically effective amount for caspase-dependent apoptosis
The therapeutically effective amount of the agent comprising the PVX plant virus particle or VLP is defined as the amount required to activate caspase-dependent apoptosis via TRAIL-DR4/5 receptor binding in cancer cells of the subject.
N-terminal binding and display of TRAIL molecules
TRAIL is bound to the plant virus particle or VLP via the N-terminus region of the ligand, providing display of the C-terminus region for binding with death receptors on cancer cells.
Multivalent display of TRAIL ligands
At least 100 TRAIL ligands are conjugated to the plant virus particle or VLP.
Use of trimeric TRAIL
TRAIL comprises trimers of TRAIL monomers when conjugated to the plant virus particle or VLP.
The inventive features collectively establish a multifunctional cancer therapeutic comprising non-covalently assembled PVX-TRAIL conjugates, with options to enhance functionality through loading of imaging, targeting, or additional therapeutic agents, multivalent and specific trimeric presentation of TRAIL, PEGylation, and methods of use for both treatment and imaging in a range of cancers.
Stated Advantages
PVX-mediated, multivalent, and surface-bound presentation of TRAIL mimics the membrane-bound state and increases efficacy in triggering apoptosis in cancer cells relative to soluble TRAIL.
Plant virus particles are biocompatible, biodegradable, non-infectious to mammals, and scalable for production, with stable and monodisperse quality.
The conjugation method provides high yield and orientation-controlled display of TRAIL, ensuring bioactive trimer exposure for effective receptor engagement.
The PVX-TRAIL conjugate platform can be further customized with imaging, targeting, and additional anticancer agents, enabling multifunctionality for both therapeutic and diagnostic (theranostic) uses.
PEGylation reduces immunogenicity and allows tuning of circulation time in vivo.
PVX-HisTRAIL demonstrates enhanced cell-killing efficacy and tumor growth inhibition in vitro and in vivo compared to free TRAIL in triple negative breast cancer models.
Documented Applications
Treatment of cancers sensitive to TRAIL-induced apoptosis, including breast cancer, ovarian cancer, soft-tissue sarcoma, pancreatic cancer, colorectal cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, and hepatocarcinoma.
Specific application to the treatment of triple negative breast cancer with enhanced efficacy demonstrated in preclinical models.
Combination with additional anticancer agents (e.g., phenanthriplatin, doxorubicin) for treating aggressive and drug-resistant cancers (e.g., ovarian cancer).
Use in conjunction with imaging agents to image and track cancer tissues in vivo.
Use of EGFR-targeted PVX-TRAIL conjugates to increase tumor specificity and delivery efficiency in EGFR-expressing tumors.
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