Immunomodulatory minicells and methods of use
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Publication Number
US-9566321-B2
Publication Date
2017-02-14
Expiration Date
Abstract
The present disclosure is related to immunomodulatory bacterial minicells and methods of using the minicells.
Core Innovation
The invention relates to immunomodulatory bacterial minicells engineered for cancer therapy as non-viable, non-infectious achromosomal nanoparticles. The bacterial minicells comprise perfringolysin O together with invasin, and the invasin is displayed on the surface of the bacterial minicell. The document further describes therapeutic formulations that combine a cholesterol-dependent pore-forming cytolysin, including perfringolysin O, with targeting via surface-displayed invasin.
The bacterial minicells are described as carriers for immunomodulatory molecules intended to induce Th1- or Th2-dominated immune responses in the context of cancer. Th1 cytokines mentioned include IFN-b3, IL-2, GMCSF, IL-12 subunits, IL-18, and TNF-b1, and Th2 cytokines are also discussed as optional. The document additionally describes inclusion of immunomodulatory components such as phospholipases and protein toxins, with examples including diphtheria toxin fragment A/B, anthrax LF/EF, Pseudomonas exotoxin A, and ricin A.
The document frames a rationale for using bacterial minicells rather than live bacteria and single cytokines, and it discusses safety-oriented features such as inducible genetic suicide via homing endonucleases and defined auxotrophy including dapA/DAP. Detoxified LPS via lpxM/MSB B deletion is also described. Subclasses including VAX-P, VAX-IP, and VAX-IPD are defined in the document, and the document reports observations linking perfringolysin O delivered by minicells to cytotoxicity and anti-tumor activity that depends on immune competence.
The document reports anti-tumor activity in cancer models using minicells with the perfringolysin O and invasin configuration, including targeting of non-muscle invasive bladder cancer. It also describes efficacy observations in in vivo xenograft and metastasis studies and associated readouts such as tumor metastases and cytotoxicity-related assays. The document further reports that removal of the targeting moiety can have little effect in some settings, while immune competence affects observed anti-tumor activity.
Claims Coverage
The partial content identifies two independent claims: one directed to a bacterial minicell comprising perfringolysin O and surface-displayed invasin, and one directed to treating bladder cancer by administering that minicell. Across these independent claims, the main inventive features are the specific minicell composition, the surface display of invasin, and the use of the minicell for bladder cancer treatment.
Perfringolysin O and surface-displayed invasin on a bacterial minicell
A bacterial minicell comprising perfringolysin O and invasin, wherein the invasin is displayed on the surface of the bacterial minicell.
Administering a perfringolysin O and surface-displayed invasin bacterial minicell to treat bladder cancer
A method of treating bladder cancer, comprising administering to a patient in need thereof a bacterial minicell, wherein the bacterial minicell comprises perfringolysin O and invasin, wherein the invasin is displayed on the surface of the bacterial minicell.
Claim scope is centered on bacterial minicells that combine perfringolysin O with invasin presented on the minicell surface, with independent claim coverage extending to a bladder-cancer treatment method based on administering that minicell.
Stated Advantages
Induces cytotoxicity via perfringolysin O delivered by the minicells.
Provides anti-tumor activity that depends on immune competence.
Documented Applications
Treating bladder cancer by administering the described bacterial minicell, including non-muscle invasive bladder cancer as a dependent narrowing.
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