The therapeutic objective enabled by Immune System Programming (ISP™) technology is to produce long-lived plasma cells from a patient’s B cells that replace missing or defective enzymes/proteins to cure serious disease.
The figure below shows the steps involved in using an ISP™-based therapeutic regimen:
- The initial step involves collecting a patient’s B cells from a simple blood draw using a well established laboratory.
- Once isolated, the patient’s B-cells are electroporated with DNA containing that encodes for a missing/defective protein responsible for the disease condition. The therapeutic gene is inserted into the patient’s cell(s) as a large plasmid, which includes the SB transposon system – the molecular machinery to integrate the gene into the cellular DNA.
- Selected ISP™ modified B cells are expanded ex vivo in our proprietary lymphophesis culture systems.
- The cell population is subsequently induced ex vivo in the culture system to differentiate into plasmablasts and plasma cells – termed ISP™ cells. The culture system yields a large population of ISP™ cells instructed to produce the desired therapeutic protein.
- Long-lived plasma cells provide a lifetime of immunity against pathogens, and have robust protein production capabilities. This cell type naturally homes to survival niches in the bone marrow where they become long-lived, and actively secrete protein for extended periods.
- Bellicum Pharmaceuticals have developed the iCasp9™ suicide gene system that can be added to ISP™ cells allowing for rapid in vivo elimination if the cell therapy should no longer be needed or desired.
Immusoft’s ISP technology offers several advantages over viral gene delivery approaches.
- The DNA plasmid construct can be readily optimized to contain the correct gene payload and produced in large quantities that are sufficient for therapeutic use. Viral transfection methods are not as efficient and require large quantities of purified virus which can be difficult to produce.
- In contrast to viral injections, ISP treatments are not subject to immune clearance, thus repeat ‘dosing’ can be contemplated.
- The proprietary ISP transposon-based gene delivery platform can be readily adapted to express any therapeutic protein and used directly to modify a patient’s B-cells via standard cell transfection methods like electroporation. There is no need to optimize a viral gene delivery vehicle though pseudotyping or other methodology to enhance its efficiency of infecting key cell types.
- Immusoft has conducted several proof-of-concept studies of the ISP system. In one of these studies, in collaboration with Seattle Biomedical Research Institute, B cells were isolated from the blood of a healthy human donor and successfully modified to produce the desired proteins – in this case, antibodies against HIV.
- Singh H, Huls H, Kebriaei P, Cooper LJN. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. [Internet]. Immunol. Rev. 2014 Jan;257(1):181–90. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109051/
- Tellier J, Kallies A. Finding a home for plasma cells–a niche to survive. [Internet]. Eur. J. Immunol. 2014 Aug;44(8):22 43–6. http://onlinelibrary.wiley.com/doi/10.1002/eji.201444871/full