Cell-selective, intracellular delivery of macromolecular therapeutics
THE PROBLEM
Large-molecule biotherapeutics such as antibodies and proteins have traditionally been restricted to targeting extracellular molecules and cell-surface receptors. Intracellular targets have essentially been “undruggable” for biotherapeutics programs, primarily due to the inability of macromolecules to penetrate cellular barriers.
THE SOLUTION
SRI’s Biosciences division has developed the FOX Three Molecular Guidance System platform to deliver any cargo to selected cell types, then internalize into those cells to targeted subcellular locations. FOX Three is a novel, proprietary platform that can deliver a wide variety of “payloads/cargo” that have been unable to successfully reach their targets intracellularly. The FOX Three platform solves the challenge of delivering therapeutics to the correct cell and the correct cellular location.
How it works
FOX Three Molecular Guidance System uses proprietary procedures to identify unique peptide delivery agents called “MGS”. The identified MGSs are delivered systemically but hone in on the desired cell type and deliver the payload in a cell-specific way. Importantly, when a MGS binds to its correct target, the event triggers rapid cellular uptake of the attached cargo and delivers it to a specific part of the cell called a subcellular organelle. Our current library of more than 40 MGSs target close to 20 cell types and more than a dozen cellular locations. We have demonstrated delivery of a wide range of payloads from protein-based toxins, antibodies and nucleic acids, to liposomes and nanoparticles. What is important here is that the cargos do not alter MGS cellular binding, uptake or trafficking which allows for a fast translation of a fully functional, targeted therapy.
The project was initially focused in oncology for molecules targeting a variety of solid tumors, however we have expanded into liquid tumors, cardiovascular uses, metabolic applications, and vaccine targets. We continue to expand our library of targeted cell types. The FOX Three MGS platform has demonstrated the ability to internalize a variety of cargos without altering cellular binding, uptake or trafficking. MGSs identified by the FOX Three selection platform have been validated to deliver a variety of cargos to a targeted cell yet not be internalized with non-targeted cells. The MGSs have the ability to transport cell impermeable biotherapeutics inside the cell, where they can complete the required task. This opens up the opportunity to utilize biologic therapeutics to control the inner workings of the cell.
Validation
Examples of these therapeutics include:
- Nucleic acids such as siRNA and ASO
- Antibodies: An anti-RAS antibody that blocks the RAS–Raf protein-protein interaction with demonstrated tumor reduction
- Enzymes: MGS allowed for the delivery of the ribosomal inactivating protein (RIP) saporin to targeted tumor cells which led to to anti-tumor efficacy and a broad therapeutic window
- Antigens: Targeted delivery of memory antigens to tumor cells, leading to cytotoxic T-cell activation and tumor-cell death.
Partner with us
SRI Biosciences partners with commercial companies through research collaborations that lead to options and license agreements for further commercialization. The FOX Three platform is designed to be combined with a “cargo” that is targeted for intracellular-based therapies. We are looking for commercial partners who meet the following criteria:
- Are interested in SRI’s pipeline of MGS-drug candidates
- Have cargo compounds and/or platforms that align well with our current MGS library; or
- Are interested in co-discovering new MGSs for new target cells/ intracellular locations using partner-defined cargo compounds or targets of interest.
Contact biosciences@sri.com to explore partnership opportunities.
FOX Three presented by Kathlynn Brown at BIO 2020
In this presentation from the BIO Digital International Convention 2020, SRI International’s Senior Director of Macromolecular Bioscience and Cancer Biology, Kathlynn Brown, provides a high-level overview of the FOX Three Molecular Guidance System™ intracellular drug delivery technology platform
