title: Interleukin-15:Interleukin-15 receptor α scaffold for creation of multivalent targeted immune molecules.
abstract: Human interleukin-15 (hIL-15) and its receptor α (hIL-15Rα) are co-expressed in antigen presenting cells allowing trans-presentation of the cytokine to immune effector cells. We exploited the high-affinity interactions between hIL-15 and the extracellular hIL-15Rα sushi domain (hIL-15RαSu) to create a functional scaffold for the design of multispecific fusion protein complexes. Using single-chain T cell receptors (scTCRs) as recognition domains linked to the IL-15:IL-15Rα scaffold, we generated both bivalent and bispecific complexes. In these fusions, the scTCR domains retain the antigen-binding activity and the hIL-15 domain exhibits receptor binding and biological activity. As expected, bivalent scTCR fusions exhibited improved antigen binding due to increased avidity, whereas fusions comprising two different scTCR domains were capable of binding two cognate peptide/MHC complexes. Bispecific molecules containing scTCR and scCD8αβ domains also exhibit enhanced binding to peptide/MHC complexes, demonstrating that the IL-15:IL-15Rα scaffold displays flexibility necessary to support multi-domain interactions with a given target. Surprisingly, functional heterodimeric molecules could be formed by co-expressing the TCR α and β chains separately as fusions to the hIL-15 and hIL-15RαSu domains. Together, these properties indicate that the hIL-15 and hIL-15RαSu domains can be used as versatile, functional scaffold for generating novel targeted immune molecules.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14850, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wong
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhu
authors.forename: Lijing
authors.initials: L
authors.lastname: You
authors.forename: Lin
authors.initials: L
authors.lastname: Kong
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Han
authors.forename: Hyung-Il
authors.initials: HI
authors.lastname: Lee
authors.forename: Pierre-Andre
authors.initials: PA
authors.lastname: Chavaillaz
authors.forename: Moonsoo
authors.initials: M
authors.lastname: Jin
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D019409:Interleukin-15 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D053647:Receptors, Interleukin-15 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D011993:Recombinant Fusion Proteins