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[ CAS No. 162635-04-3 ] {[proInfo.proName]}

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Chemical Structure| 162635-04-3
Chemical Structure| 162635-04-3
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Leclercq, Gabrielle ; Haegel, Hélène ; Toso, Alberto , et al. DOI: PubMed ID:

Abstract: Background: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. Methods: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. Results: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. Conclusions: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

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Leclercq, Gabrielle ;

Abstract: T cell bispecific antibodies (TCBs) are a novel class of T cell engagers redirecting T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in tumor celllysis. On-target activity of TCBs may come with a risk of Cytokine Release Syndrome (CRS), characterized by elevated levels of pro-inflammatory cytokines in the serum, such as IL-6, IL-1β, TNF-α or IFN-γ and over activation of immune cells. Besides, the expression of the tumorassociated antigen on healthy cells may induce off-tumor activity of the TCB and contribute to inflammation. Despite the use of step-up dosing, glucocorticoids, or tocilizumab to manage or prevent these safety liabilities, they remain the major dose-limiting toxicities associated with the treatment of T cell engagers, highlighting the need to develop preventive mitigation treatments. To this aim, we investigated the biological mechanisms and the chronology of events involved in TCB-mediated cytokine release and explored mitigation strategies that might retain profound treatment efficacy while reducing cytokine release. Using an in vitro co-culture of peripheral blood mononuclear cells (PBMCs) or total leukocytes(PBMCs + neutrophils) and target cells with the respective TCBs, or whole blood treated with a B cell depleting TCB, we confirmed the contribution of T cell and myeloid cells and revealed the role of neutrophils in the TCB-mediated cytokine release. In the same model, the use of anticytokine neutralizing antibodies provided insights into the chronology of events triggering the cascade of cytokines after TCB stimulation. Ultimately this work guided the evaluation of mitigation strategies directed against T-cell derived cytokine release by targeting kinases involved in signaling pathways downstream of the T cell receptor (TCR) after stimulation with TCBs. A novel small molecule-kinase inhibitors screen identified mTOR, JAK and Src inhibitors as candidates to switch-off T-cell derived cytokine release. We validated the effects of these kinase inhibitors and fine-tuned their effective doses in in vitro co-cultures of peripheral blood mononuclear cells (PBMCs) and tumor cells with the respective TCBs. In vivo, we used nontumor or tumor-bearing-humanized NSG mice to assess the effect of mTOR, JAK and Srcinhibitors on CD19-TCB-mediated cytokine release and anti-tumor efficacy. Altogether, we confirmed the biological mechanisms of the TCB-mediated cytokine cascade and revealed the contribution of neutrophils. Our work on kinase inhibitors highlights their differential activities on the inhibition of cytokine release and/or T cell cytotoxicity and demonstrates the decoupling between both mechanisms. Our data open new horizons for the prophylactic mitigation of CRS with the use of FDA approved mTOR and JAK inhibitors or the transient use of the Src inhibitor dasatinib. Finally, our results also indicate that dasatinib may serve as an “antidote” against adverse events related to the treatment with TCBs such as high grade CRS or unpredictable off-tumor activity of TCBs, a strategy which is now implemented the clinic.

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Product Details of [ 162635-04-3 ]

CAS No. :162635-04-3 MDL No. :MFCD00934421
Formula : C56H87NO16 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 1030.29 Pubchem ID :-
Synonyms :
CCI-779;Torisel;US brand name: Torisel.;Torisel?
Chemical Name :(1R,2R,4R)-4-((R)-2-((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-Dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1]oxa[4]azacyclohentriacontin-3-yl)propyl)-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

Safety of [ 162635-04-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:
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