BPS 2015
A Chemical Approach to Half-life Extension of Peptides and Proteins
Daniel Santi
President, ProLynx
ABSTRACT
We have reported an approach for half-life extension of peptidic drugs that uses sets of self-cleaving linkers to tether the drugs to macromolecular carriers. The linkers undergo β-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over a year. Initially, we used polyethylene glycol as a circulating carrier, but half-life extension becomes limited by the renal elimination rate of the carrier. More recently, we used biodegradable hydrogels as non-circulating drug carriers. By using one β-eliminative linker to tether a peptidic drug to the hydrogel, and incorporating another β-eliminative linker with a longer half-life in crosslinks to control polymer degradation, the system can be coordinated to release the drug before the gel dissipates. Practical utilities are illustrated by PEG- and PEG hydrogel–peptide conjugates that allow infrequent administration, and results indicate that the technology may serve as a generic platform for tunable half-life extension of potent therapeutics.
BIO
Dr. Santi received a Ph.D. in Medicinal Chemistry from SUNY in 1967 and a M.D. from UCSF in 1981. He was Assistant Professor of Chemistry at UCSB from 1968 to 1974. He joined the UCSF faculty in 1974 and was Professor of Biochemistry and Biophysics, and of Pharmaceutical Chemistry at UCSF until 2000 when he became CEO of Kosan Biosciences. He returned to UCSF in 2007 where he served as interim Director of the Clinical and Translational Science Institute and then Director of Translational Research at QB3. He became an Associate Dean of External Relationships in 2009, and has managed a successful Industry Outreach Program since that time. Dr. Santi has published over 300 scientific papers and is co-inventor on over 40 US patents.
Dan Santi was a member of the original Scientific Advisory Board of Chiron Corp. and has co-founded five biotechnology companies. In 1988, he founded and was Chairman of the peptide-combinatorial chemistry company Protos Corp., which merged with Chiron in 1992. He was also a co-founder of Parnassus Pharmaceuticals, and of Prospect Genomics that merged with Structural Genomix in 2001. In 1996, he co-founded Kosan Biosciences where he served as CEO and Chairman until 2006; Kosan was acquired by Bristol Myers Squibb. During his tenure as CEO the company went public (NASDAQ), and four oncology compounds were brought into clinical trials. He co-founded the platform technology company ProLynx LLC in 2010, where he currently serves as President.