Personalized medicine therapeutic MiniCircle
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Publication Number
US-11583594-B2
Publication Date
2023-02-21
Expiration Date
Abstract
Bispecific antibodies (bsAbs) have emerged as a class of promising anti-cancer and anti-infection biological drugs. They are capable of killing target cells, either cancer cells or microbe-infected cells, at levels of nanograms per milliliter serum in vivo, about 1e+5 folds more powerful than regular antibodies. To bypass the problems of high cost in production and inconvenience in administration, a logical solution is to use gene therapy vectors to produce them in vivo. In a series of preclinical studies, we have demonstrated that DNA MiniCircle was able to express far above therapeutic levels of bsAB persistently both in the presence as well as the absence of transfection co-factors. As a specific and intended improvement of the claimed invention, an enhanced form of bispecific antibodies incorporating a target cell-effector cell bridging device (BTEC) is additionally disclosed.
Core Innovation
The invention provides a therapeutic MiniCircle circular DNA vector for in vivo gene delivery in a patient. The MiniCircle DNA vector encodes a bispecific antibody, and bacterial backbone plasmid sequences are absent from the vector. This configuration addresses plasmid backbone-mediated silencing observed with plasmid backbone DNA in skeletal muscle delivery, enabling improved and persistent expression.
The invention further describes combining the bispecific antibody MiniCircle DNA vector with a co-transfection aid selected from glycyrrhizin (GL) and Ginseng Rh1 (GS). The combination is used with local delivery to skeletal muscle in the patient for treatment of disease.
Additionally, the invention describes engineered protein bridge constructs referred to as BTEC (bridge between target and effector cells) protein formats for generating bispecific/trispecific-like constructs. The protein bridge formats include scTCR, scFv, VHH, ligand, and polypeptide arms targeting receptor pathways associated with T cells and NK cells.
Claims Coverage
The independent claim contains three principal inventive aspects: preparing and using a bispecific antibody MiniCircle DNA vector lacking bacterial backbone plasmid sequences, combining the vector with a co-transfection aid selected from glycyrrhizin (GL) and Ginseng Rh1 (GS), and administering the vector via local delivery to skeletal muscle using an effective dose to treat disease in a patient.
Bacterial-backbone-absent bispecific antibody MiniCircle DNA vector
Preparing a bispecific antibody MiniCircle DNA vector for therapeutic delivery, wherein bacterial backbone plasmid sequences are absent from the vector.
Co-transfection aid selection with GL or Ginseng Rh1
Combining the bispecific antibody MiniCircle DNA vector with a co-transfection aid selected from the group consisting of glycyrrhizin (GL) and Ginseng Rh1 (GS).
Local skeletal muscle administration of an effective dose
Administering by local delivery to skeletal muscle in said patient an effective dose of said bispecific antibody MiniCircle DNA vector for treatment of disease in said patient.
Tumor-specific antigen bispecific antibody encoding
Using a bispecific antibody MiniCircle DNA vector that encodes a bispecific antibody targeting a tumor-specific antigen.
Tumor-associated antigen bispecific antibody encoding
Using a Minicircle DNA vector encoding a bispecific antibody that targets a tumor-associated antigen.
Overall, the claim set covers treatment of disease in a patient using a bispecific antibody MiniCircle DNA vector that lacks bacterial backbone plasmid sequences, delivered locally to skeletal muscle at an effective dose, optionally combined with glycyrrhizin (GL) or Ginseng Rh1 (GS), and further specifies bispecific antibody target selection as either tumor-specific antigen or tumor-associated antigen.
Stated Advantages
Improved and persistent expression in muscle compared with plasmid backbone-mediated silencing.
Documented Applications
Treatment of disease in a patient by administering a bispecific antibody MiniCircle DNA vector by local delivery to skeletal muscle.
Treatment using a bispecific antibody MiniCircle DNA vector encoding a bispecific antibody targeting a tumor-specific antigen.
Treatment using a bispecific antibody MiniCircle DNA vector encoding a bispecific antibody targeting a tumor-associated antigen.
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