Immunomodulatory minicells and methods of use
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Publication Number
US-10039817-B2
Publication Date
2018-08-07
Expiration Date
Abstract
The present disclosure is related to immunomodulatory bacterial minicells and methods of using the minicells.
Core Innovation
Immunomodulatory non-living bacterial minicells are used to treat cancer by delivering cholesterol-dependent cytolysin proteins, including perfringolysin O. The minicells are described as engineered immune modulation vehicles with reduced toxicity compared with viable parental cells, and are non-infectious.
The disclosure further defines targeting of bacterial minicells to eukaryotic cells by contacting the cells with minicells that include perfringolysin O. Targeting is described for beta1-integrin-high cells, including cells with increased beta1-integrin expression and/or increased beta1-integrin activity, and invasin is described as a component enabling targeting to beta1-integrins.
The document also states that the minicells can include additional immunomodulatory components, including Th1 and Th2 cytokines, phospholipases, and toxin-related payloads such as catalytic diphtheria toxin fragment A or other protein toxins. It additionally describes safety features intended to eliminate viable parental cells, including inducible genetic suicide endonucleases, defined auxotrophy such as dapA, and detoxified lipopolysaccharide via lpxM/msbB deletion.
In vivo and in vitro examples are described for perfringolysin O delivered by minicells, including cytotoxicity and anti-tumor effects in tumor models such as subcutaneous xenografts and metastasis models. The document also describes an intravesical dosing approach in a murine non-muscle invasive bladder cancer model, and includes assays and measurements such as LDH release, MTT viability, hemolysis, and a Western blot for invasin.
Claims Coverage
The provided claims list includes one independent claim. The dependent claims refine targeting to beta1-integrin expression/activity and specific integrin subunits, and add Th1 immunomodulatory minicells and additional payload categories.
Targeting eukaryotic cells using perfringolysin o minicells by contacting
A method of targeting a bacterial minicell to a eukaryotic cell, comprising contacting the bacterial minicell with the eukaryotic cell, wherein the bacterial minicell comprises perfringolysin O.
Targeting cells with increased beta1-integrin expression and/or activity
The eukaryotic cell exhibits increased beta1-integrin expression and/or increased beta1-integrin activity.
Using specified integrin subtypes on the eukaryotic cell
The eukaryotic cell includes one or more specified integrins, such as integrin α3β1, α4β1, α5β1, α6β1, αvβ1, β21, and/or a combination thereof.
Employing a th1 immunomodulatory minicell
The bacterial minicell is a Th1 immunomodulatory minicell.
Including th1 cytokines and additional immunomodulatory or pore-forming components
The bacterial minicell includes one or more Th1 cytokines, pore forming cytolysin proteins, phospholipases, or immunomodulatory nucleic acids.
Using a catalytic fragment protein toxin payload
The method is performed using a protein toxin that is a catalytic fragment of diphtheria toxin, gelonin, Pseudomonas exotoxin A, or ricin A.
The claim coverage centers on contacting a eukaryotic cell with bacterial minicells comprising perfringolysin O, with refinement focused on beta1-integrin expression/activity and specified integrin subtypes, and further narrowing based on Th1 immunomodulatory minicells and additional payload categories including cytokines, cytolysin proteins, phospholipases, immunomodulatory nucleic acids, and specific catalytic protein toxin fragments.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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