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(Received for publication, May 24, 1996, and in revised form, September 13, 1996)
From the Departments of Interleukin (IL)-15 is a multifunctional cytokine
that shares many biological activities with IL-2. This functional
overlap, as well as receptor binding subunits shared by IL-15 and IL-2, suggests tertiary structural similarities between these two cytokines. In this study, recombinant human IL-15 was PEGylated via
lysine-specific conjugation chemistry in order to extend the
circulation half-life of this cytokine. Although PEGylation did extend
the
Volume 272, Number 4,
Issue of January 24, 1997
pp. 2312-2318
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
and
Analytical Chemistry and
Formulation, ¶ Protein Chemistry, 
Immunobiology, ** Product
Recovery, and Cellular Immunology, Immunex
Corporation, Seattle, Washington 98101
-elimination circulation half-life of IL-15 by greater than
50-fold, the biological activity of polyethylene glycol (PEG)-IL-15 was
significantly altered. Specifically, PEG-IL-15 lost its ability to
stimulate the proliferation of CTLL but took on the properties of a
specific IL-15 antagonist in vitro. In comparing sequence
alignments and molecular models for IL-2 and IL-15, it was noted that
lysine residues resided in regions of IL-15 that may have selectively disrupted receptor subunit binding. We hypothesized that PEGylation of
IL-15 interferes with but not 
receptor subunit binding, resulting in the IL-15 antagonist activity observed in
vitro. The validity of this hypothesis was tested by engineering
site-specific mutants of human IL-15 as suggested by the IL-15 model
(IL-15D8S and IL-15Q108S block and 
receptor subunit binding,
respectively). As with PEG-IL-15, these mutants were unable to
stimulate CTLL proliferation but were able to specifically inhibit the
proliferation of CTLL in response to unmodified IL-15. These results
supported our model of IL-15 and confirmed that interference of receptor subunit binding by adjacent PEGylation could be responsible
for the altered biological activity observed for PEG-IL-15.
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