Interleukin-15:Interleukin-15 receptor α scaffold for creation of multivalent targeted immune molecules.

TitleInterleukin-15:Interleukin-15 receptor α scaffold for creation of multivalent targeted immune molecules.
Publication TypeJournal Article
Year of Publication2011
AuthorsWong RL, Liu B, Zhu X, You L, Kong L, Han K-P, Lee H-I, Chavaillaz P-A, Jin M, Wang Y, Rhode PR, Wong HC
JournalProtein Eng Des Sel
Volume24
Issue4
Pagination373-83
Date Published2011 Apr
ISSN1741-0134
KeywordsCells, Cultured, Humans, Interleukin-15, Protein Multimerization, Protein Structure, Tertiary, Receptors, Interleukin-15, Recombinant Fusion Proteins
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.

DOI10.1093/protein/gzq116
Alternate JournalProtein Eng Des Sel
PubMed ID21177283
PubMed Central IDPMC3049345
Grant ListR43 CA139810 / CA / NCI NIH HHS / United States
Related Institute: 
MRI Research Institute (MRIRI) Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065