title: Dual Agonist Surrobody Simultaneously Activates Death Receptors DR4 and DR5 to Induce Cancer Cell Death.
abstract: Death receptors of the TNF family are found on the surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors 4 and 5 (DR4 and DR5) is TNF-related apoptosis-inducing ligand, TRAIL (Apo2L). As most untransformed cells are not susceptible to TRAIL-induced apoptosis, death receptor activators have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients is to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. Another strategy that attempted to evade decoy receptor sequestration and to provide improved pharmacokinetic properties was to generate DR4 or DR5 agonist antibodies. The resulting monoclonal agonist antibodies overcame the limitations of short half-life and avoided decoy receptor sequestration, but are limited by activating only one of the two death receptors. Here, we describe a DR4 and DR5 dual agonist produced using Surrobody technology that activates both DR4 and DR5 to induce apoptotic death of cancer cells in vitro and in vivo and also avoids decoy receptor sequestration. This fully human anti-DR4/DR5 Surrobody displays superior potency to DR4- and DR5-specific antibodies, even when combined with TRAIL-sensitizing proapoptotic agents. Moreover, cancer cells were less likely to acquire resistance to Surrobody than either anti-DR4 or anti-DR5 monospecific antibodies. Taken together, Surrobody shows promising preclinical proapoptotic activity against cancer cells, meriting further exploration of its potential as a novel cancer therapeutic agent.
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Snezana
authors.initials: S
authors.lastname: Milutinovic
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kashyap
authors.affiliation: Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Yanagi
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Carina
authors.initials: C
authors.lastname: Wimer
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California. Sutro Biopharma, South San Francisco, California.
authors.forename: Sihong
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California. Novartis Institutes for Biomedical Research, Emeryville, California.
authors.forename: Ryann
authors.initials: R
authors.lastname: O'Neil
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California. Rigel Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Kurtzman
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California.
authors.forename: Alexsandr
authors.initials: A
authors.lastname: Faynboym
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California. Oxford BioTherapeutics, San Jose, California.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hannum
authors.affiliation: Biometrica, San Diego, California.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Diaz
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Horowitz
authors.affiliation: Sea Lane Biotechnologies, Mountain View, California. Rigel Pharmaceuticals, Inc., South San Francisco, California. John_C.reed@roche.com rbhatt@rigel.com.
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Bhatt
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. John_C.reed@roche.com rbhatt@rigel.com.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases