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IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models

Ågerstam, Helena LU ; Hansen, Nils LU ; von Palffy, Sofia LU ; Sandén, Carl LU ; Reckzeh, Kristian LU ; Karlsson, Christine LU ; Lilljebjörn, Henrik LU ; Landberg, Niklas LU ; Askmyr, Maria LU and Högberg, Carl LU , et al. (2016) In Blood 128(23). p.2683-2693
Abstract

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that... (More)

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

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@article{6c5004c7-7e9c-4990-87e3-b5ba1032dafc,
  abstract     = {<p>Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.</p>},
  author       = {Ågerstam, Helena and Hansen, Nils and von Palffy, Sofia and Sandén, Carl and Reckzeh, Kristian and Karlsson, Christine and Lilljebjörn, Henrik and Landberg, Niklas and Askmyr, Maria and Högberg, Carl and Rissler, Marianne and Porkka, Kimmo and Wadenvik, Hans and Mustjoki, Satu and Richter, Johan and Järås, Marcus and Fioretos, Thoas},
  issn         = {1528-0020},
  language     = {eng},
  month        = {12},
  number       = {23},
  pages        = {2683--2693},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models},
  url          = {http://dx.doi.org/10.1182/blood-2015-11-679985},
  volume       = {128},
  year         = {2016},
}