Platform technology aimed at increasing the half–life of small biologics by conjugating FcRn-binding molecules.
Protein-based therapeutics, also called biologics, have recently made significant inroads into the pharmaceutical market, and are being used to treat chronic diseases and cancer. In addition to acting potently and specifically on their molecular targets, efficacious biologics should be both long lasting in the blood circulation and penetrate well into the disease tissue. This poses a challenge because of the opposing dependencies of these two properties on molecular weight: relatively small proteins are rapidly excreted through the kidney, giving them a short circulating half-life, while larger proteins penetrate poorly into tissues. We propose to address this duality by focusing on improving the circulation levels of smaller proteins, which inherently exhibit good tissue penetrations. Our RecyTag technology will take advantage of the recycling mechanism of a receptor, FcRn, which is responsible for the long circulation times of antibodies. Related strategies have been applied; however, generally they focus on fusing large protein fragments to biologics, which unfortunately increases protein size thereby reducing tissue penetration. In our RecyTag approach, we instead propose to increase circulation times by identifying small molecules that bind to the FcRn receptor, and linking them to small biologics. In this ways, the biologic will remain small, and should retain good tissue penetration. We will employ an interdisciplinary approach to validate RecyTag, including in silico and in vitro screening of compound libraries, chemical conjugation of the small-molecule hits to different short half-life biologics, and testing these RecyTag conjugates in cellular models and finally in animals to demonstrate their improved circulation times.