Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2
| Autor: | Michael Michalik, Elena Izquierdo, Tamina Seeger-Nukpezah, Indra Moellenkotte, Verena Barbarino, Stuart Blakemore, Reinhild Brinker, Oleg Fedorchenko, Sinika Henschke, Daniela Vorholt, Nadine Nickel, Christian P. Pallasch, Michael Hallek, Nelly Mikhael |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Janus kinase 2
biology medicine.drug_class Chemistry Chronic lymphocytic leukemia Monoclonal antibody medicine.disease chemistry.chemical_compound hemic and lymphatic diseases Ibrutinib biology.protein medicine Cancer research Bruton's tyrosine kinase Kinase activity Tyrosine kinase Monoclonal antibody therapy |
| DOI: | 10.1101/2020.06.10.135632 |
| Popis: | Targeted inhibition of Bruton’s Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström’s Macroglobulinemia, Mantle cell lymphoma and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibitionin vitroas well as with CRISPR/Cas9 JAK2−/−experimentsin vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage mediated immune responses. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|