title: A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.
abstract: Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.
authors.affiliation: Research, Biotechnology, Bayer Corporation, Pharmaceutical Division, 800 Dwight Way, Berkeley, CA 94701, USA. armen.shanafelt@roche.com
authors.forename: A B
authors.initials: AB
authors.lastname: Shanafelt
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: M C
authors.initials: MC
authors.lastname: Shanafelt
authors.forename: C P
authors.initials: CP
authors.lastname: Forte
authors.forename: N
authors.initials: N
authors.lastname: Dubois-Stringfellow
authors.forename: C
authors.initials: C
authors.lastname: Carter
authors.forename: J A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: S L
authors.initials: SL
authors.lastname: Cheng
authors.forename: K A
authors.initials: KA
authors.lastname: Delaria
authors.forename: R
authors.initials: R
authors.lastname: Fleischer
authors.forename: J M
authors.initials: JM
authors.lastname: Greve
authors.forename: R
authors.initials: R
authors.lastname: Gundel
authors.forename: K
authors.initials: K
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: Kelly
authors.forename: B
authors.initials: B
authors.lastname: Koh
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Lantz
authors.forename: P
authors.initials: P
authors.lastname: Mak
authors.forename: L
authors.initials: L
authors.lastname: Neyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Plym
authors.forename: S
authors.initials: S
authors.lastname: Roczniak
authors.forename: D
authors.initials: D
authors.lastname: Serban
authors.forename: J
authors.initials: J
authors.lastname: Thrift
authors.forename: L
authors.initials: L
authors.lastname: Tsuchiyama
authors.forename: M
authors.initials: M
authors.lastname: Wetzel
authors.forename: M
authors.initials: M
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Zolotorev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002455:Cell Division; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000031:analogs & derivatives / Q000235:genetics* / Q000627:therapeutic use* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D007694:Killer Cells, Natural / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009368:Neoplasm Transplantation; D002679:Pan troglodytes; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D011994:Recombinant Proteins; C082598:aldesleukin