Genome wide expression profiling of human peripheral blood mononuclear cells stimulated with BAY 50-4798, a novel T cell selective interleukin-2 analog.
BAY 50-4798, a novel, engineered form of interleukin (IL)-2, is a selective agonist for the high-affinity IL-2 receptor and induces the proliferation of activated human T cells with potency similar to recombinant IL-2 (rIL-2), but has reduced proliferative activity on natural killer cells and is associated with a diminished secondary cytokine cascade. In the current study, the transcriptional profiles of human peripheral blood mononuclear cells (PBMCs) stimulated in vitro with BAY 50-4798 and rIL-2 were compared using Affymetrix microarray technology in combination with Ingenuity Pathway Analysis (IPA) to determine whether there are quantitative or qualitative differences in the molecular networks activated by these IL-2 analogs. A total of 299 genes were differentially expressed in response to the two IL-2 analogs, with an increase in the number of differences over time. Consistent with the fact that BAY 50-4798 interacts with fewer forms of the IL-2 receptor than rIL-2 to activate fewer cell types, 169 genes were expressed at lower levels in PBMCs cultured with BAY 50-4798 compared with IL-2. These genes were mainly categorized as cytokines and chemokines, and were used to build multiple molecular interaction networks, the most significant of which centered around a subunit of NF-kappaB, which is known to play a pivotal role in inflammation, and was associated with cell death. Of the genes induced in response to BAY 50-4798, only 25% were expressed at lower levels than those induced by rIL-2. Moreover, despite its more selective receptor targeting compared with rIL-2, BAY 50-4798 caused higher levels of expression of 130 genes, which predominantly fell into categories associated with metabolism and transcription. We interpret these results as consistent with the expected transcriptional profile of a mutein engineered and demonstrated to have diminished inflammatory effects yet fully retain selected features of IL-2 activity. In addition to demonstrating that the responses to BAY 50-4798 are characterized by differential expression of genes known to be induced by IL-2, we report for the first time the induction of a significant number of genes not previously reported in the context of IL-2 biology.
Steppan
Sonja
S
Biotechnology Research Division, Bayer Corporation, Berkeley, CA, USA. sonja.steppan@gmail.com
Kupfer
Kenneth
K
Mayer
Anja
A
Evans
Mark
M
Yamasaki
Glenn
G
Greve
Jeffrey M
JM
Eckart
Michael R
MR
Cassell
Delanie J
DJ
D002478:Cells, Cultured; D015870:Gene Expression; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D007376:Interleukin-2; D011994:Recombinant Proteins; C082598:aldesleukin