Christopher Mehlin

Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation

The efficacy of early bispecific antibodies redirecting T-cells to eradicate cancer cells was partly limited because of suboptimal effector cell engagement.1 More efficient T-cell activation has been obtained with single-chain variable fragment (scFv) antibodies, notably Bispecific T-cell Engagers (BiTEs).2 Activity of the CD19/CD3 BiTE blinatumomab in adults and children with chemotherapy-resistant CD19+ B-cell acute lymphoblastic leukemia (B-ALL) led to regulatory drug approval in Europe and the United States. Many other BiTEs, all relying on CD3 signaling without providing co-stimulation, are in clinical testing in several solid tumors and hematologic malignancies.2,3

Abstract 2443: Optides (optimized peptides), a new knottin-based cancer drug discovery platform

Some of the highest value targets in cancer therapeutics involve protein:protein interactions that are difficult to inhibit with small molecule therapeutics. Peptide drug candidates offer an alternative, but many peptide drugs have poor pharmacokinetic properties and some are immunogenic. Knottin peptides have long been promoted as scaffolds for human drug discovery efforts because the exquisitely tight knot formed by disulfide bridges creates resistance to proteolytic and other forms of degradation. Furthermore, some knottins cross the blood brain barrier, the gut wall, or cell membranes which is ideal for certain targets. Unfortunately, creating knottins synthetically or in bacteria results in a large number of disulfide isomers, which has hampered research. We have created a mammalian expression system that enables production of most knottin scaffolds and variants of native knottins encoded in plant and animal genomes. The platform routinely produces approximately 10 mg/liter of near pure naked peptide, which is sufficient to conduct in vivo studies without major scale-up. The system is endotoxin free. In addition to building the platform, we identified over 200,000 new potential knottin peptides in various genomes, creating a rich collection of scaffolds from which to establish diversity libraries of native and optimized variants. These candidates have potential for targeting therapeutics to cancer cells as a solid tumor penetrating alternative to antibody drug conjugates. Optides also have potential to be developed as anti-cancer drugs themselves. The fact that knottin peptides are not substrates for resistance mechanisms such as p-glycoprotein pumps underscores the potential importance of this class of drugs for those with previously treated cancer. Citation Format: James M. Olson, Roland Strong, Christopher Mehlin, Colin Correnti. Optides (optimized peptides), a new knottin-based cancer drug discovery platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2443. doi:10.1158/1538-7445.AM2015-2443