Technologies
PDF


WARF: P150370US02

Enhanced Drug Delivery Across the Blood-Brain Barrier: pH-Dependent Antibodies Targeting the Transferrin Receptor


INVENTORS -

Eric Shusta, Benjamin Tillotson

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing targeting antibodies for cancer or brain delivery, with significantly increased intracellular accumulation.
OVERVIEWDrug delivery to the brain is hampered by the presence of the blood-brain barrier (BBB), which excludes more than 98 percent of small molecule pharmaceuticals and nearly 100 percent of all protein and gene therapeutics.

One promising delivery method involves antibodies that target receptor-mediated systems at the BBB. Drug molecules can be attached to the antibodies and transported into brain tissue. Antibodies that target the transferrin and insulin receptor systems currently are available, but these systems are expressed throughout the body, leading to the mistargeting of expensive pharmaceuticals.

Nevertheless, the transferrin receptor (TfR) presents a valuable therapeutic target both on normal and cancerous cells, and can be antagonized directly or exploited indirectly as an intracellular drug delivery vector. Needed in the field is an antibody with pH-sensitive binding capability; this would enable the antibodies to bind TfR at physiological pH and release rapidly at endosomal pH.
THE INVENTIONUW–Madison researchers have developed several new single-chain antibody fragments to the transferrin receptor which exhibit increased dissociation at pH 5.5. Such targeting antibodies could have immense potential for drug delivery into and across target cells including cancer cells and the BBB.

Unlike other anti-TfR antibodies in development for cancer or brain delivery, the new antibodies have been endowed with pH-sensitivity resulting in differential trafficking and increased intracellular accumulation up to 2.6 times their wild-type parent.
APPLICATIONS
  • Drug delivery to the brain
  • Treating cancer
  • May enable new methods of treating disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, autism, multiple sclerosis, brain cancer and stroke
KEY BENEFITS
  • Non-invasive delivery
  • Potentially selective and efficient
  • May minimize side effects that can result when drugs are mistargeted
  • Antibody fragments are fully human, lowering the risk of immunogenic reactions that can result when non-human antibodies are used.
STAGE OF DEVELOPMENTThe researchers subjected an anti-TfR single-chain antibody to histidine saturation mutagenesis at a single CDR (CDR1) known to participate in TfR binding. The resulting library was screened and eight antibodies with increased dissociation at pH 5.5 were identified. One of these (M16) was dosed onto live cancer cells in vitro and exhibited intracellular accumulation 2.6 times greater than its parent antibody.
Contact Information
For current licensing status, please contact Jennifer Gottwald at jennifer@warf.org or 608-960-9854.
The WARF Advantage

WARF: A Leader in Technology Transfer Since 1925
Since its founding as a private, nonprofit affiliate of the University of Wisconsin–Madison, WARF has provided patent and licensing services to UW–Madison and worked with commercial partners to transform university research into products that benefit society. WARF intellectual property managers and licensing staff members are leaders in the field of university-based technology transfer. They are familiar with the intricacies of patenting, have worked with researchers in relevant disciplines, understand industries and markets, and have negotiated innovative licensing strategies to meet the individual needs of business clients.

The University of Wisconsin and WARF –
A Single Location to Accelerate Translational Development of New Drugs

UW–Madison has the integrative capabilities to complete many key components of the drug development cycle, from discovery through clinical trials. As one of the top research universities in the world, and one of the two best-funded universities for research in the country, UW–Madison offers state-of-the-art facilities unmatched by most public universities.

These include the Small Molecule Screening Facility at the UW Comprehensive Cancer Center; the Zeeh Pharmaceutical Experiment Station, which provides consulting and laboratory services for developing formulations and studying solubility, stability and more; the Waisman Clinical Biomanufacturing Facility; the Wisconsin Institute for Medical Research, which provides UW–Madison with a complete translational research facility; and the innovative, interdisciplinary Wisconsin Institutes for Discovery, home to the private, nonprofit Morgridge Institute for Research and its public twin, WID, part of the university's graduate school. The highly qualified experts at these facilities are ready to work with you to create a library of candidates for drug development.