Calcium-dependent affinity domains as therapeutics

Protein regulation by metal ion interaction has been utilized for many different purposes, covering biological therapies.

In this project application, we aim at designing binders that capture their target proteins in serum where the calcium concentration is high and release them in the endosome, where the calcium concentration is about 1000 times lower. We suggest two different therapeutic areas where this concept could be utilized.

For targeted treatment in cancer medicine today the key-players are Antibody Drug Conjugates (ADC) but these drugs often suffer from low internalization.

By utilizing calcium dependent binding, the drug conjugate will be released in the endosome while the receptor is recycled to the cell surface capable of binding the next drug molecule enabling a more efficient treatment.The other therapeutic area where calcium-dependent binding could be beneficial is for neutralization of over-expressed disease-causing proteins.

Currently specific antibodies that inhibit the disease-causing protein are used for treatment, with the drawback that the disease-causing protein stays in the circulation, although inhibited.

To bring the target protein to the endosomes, an FcRn-binding protein domain will be fused to the binder, enable transport to the endosome where degradation will be accomplished.

If this project is funded it will lead to the development of a novel platform for calcium-dependent therapy that possibly will require lower doses for therapeutic effect.