Photoconjugation Reactions for Modification of Specific Proteins on Live Cells: A Promising Approach for the Selective Treatment of Solid Tumors

Background

A significant challenge for solid tumor treatment is ensuring that a sufficient concentration of therapeutic agent is delivered to the tumor site at doses that can be tolerated by the patient. Antibody-targeted enzyme prodrug therapy can bias accumulation in tumors by taking advantage of specific interactions with receptors overexpressed on cancerous cells. Although antibody-based immunoconjugates show high binding to specific cells, their low dissociation constants (KD) and large Stokes radii hinder their ability to penetrate deep into tumor tissue, leading to incomplete cell killing and tumor recurrence.

Technology

To address the limitations of antibody-targeted enzyme prodrug therapy, the researchers at CU Boulder (Jennifer Cha and Andrew Goodwin) developed a method to modify potentially any specific cell receptor with a unique biological tag without genetic engineering. Solid tumors can be selectively targeted by administering photocrosslinkable affibody-prodrug enzyme fusion proteins that form irreversible bonds to receptors expressed on the surface of cancer cells under long UV or NIR light in the presence of upconverting nanoparticles.

In one embodiment of the invention, a fusion protein was designed with both anti-epidermal growth factor receptor (EGFR) affibody and the prodrug enzyme cytosine deaminase, which can convert prodrug 5-fluorocytosine and to the anticancer drug 5-fluorouracil. When this affibody fusion protein was crosslinked to EGFR overexpressed on MDA-MB-468 breast cancer cells, prodrug conversion was found even 48-hours post-incubation without any apparent decrease in cell killing.

The photoactive affibody-prodrug enzyme fusion proteins developed here may be utilized as a platform technology for engineering new therapy conjugates that can penetrate deep into tumor tissue and be retained long enough for effective tumor therapy.

Advantages

• Can convert multiple prodrug doses into toxic drugs without the need for additional enzyme administrations
• Survives endosomal proteolysis

What's Next?

This technology is available for exclusive licensing, non-exclusive licensing or commercial partnerships.