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  • Finally the effects of In NLS

    2019-05-15

    Finally, the effects of 111In-NLS-CSL360 on hematopoietic function in healthy Balb/c mice was studied. Groups of 2–4 mice were injected i.v. with 6.1±1.4MBq, 18.8±1.5MBq or 35.8±0.9MBq of 111In-NLS-CSL360 or an equivalent mass (70μg) of unlabeled CSL360 or received normal saline. At two weeks post-treatment, a complete blood cell count (CBC) was obtained and EZ Cap Reagent AG (Hb) levels were measured. Significant differences (P<0.05) for all studies were tested using an unpaired, two-sided Student\'s t-test, 1-way ANOVA followed by a Bonferroni multiple comparisons post-test, or log-rank test.
    Results and discussion
    Conflict of interest
    Authorship contributions
    Acknowledgments The authors thank Drs. Gino Vairo and Samantha Busfeld, CSL Limited, for helpful advice. This research was supported by a grant from the Canadian Institutes of Health Research (Grant no. MOP111118).
    Introduction B cell receptor (BCR) activation and subsequent downstream signalling is pivotal for maintenance and proliferation of chronic lymphocytic leukaemia (CLL) leading to tumour progression [1]. Therefore targeting the BCR and associated pathways is attractive for CLL and other BCR driven B cell malignancies. These BCR signals are mediated via a series of key kinases including SYK, BTK and PI3K, and inhibitors such as entospletinib (SYK inhibitor), ibrutinib (BTK inhibitor) and idelalisib (PI3Kδ inhibitor) are showing clinical efficacy, and are likely to replace standard chemotherapy regimens for the treatment of CLL. So far, with limited follow up, ibrutinib and idelalisib have shown clear efficacy in suppressing tumour progression but have not been curative. A minority of treated patients who go on to develop resistance to ibrutinib have extremely poor outcomes with a median survival of 3.1 months after discontinuation [2]. However once resistance to ibrutinib occurs, PI3K inhibitors may still be therapeutically effective [3]. This review will therefore focus on PI3K inhibitors in CLL. PI3K, via phosphorylation of the inositol lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), forms the second messenger molecule phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) which recruits and activates pleckstrin homology domain containing proteins, leading to downstream signalling events crucial for proliferation, survival and migration. Class I PI3K enzymes consist of four distinct catalytic isoforms, PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. The PI3Kδ and PI3Kγ isoforms are expressed predominantly in leucocytes, whereas the PI3Kα and PI3Kβ isoforms are ubiquitously expressed [4]. PI3K becomes activated upon ligation of a number of chemokine and cytokine receptors expressed by CLL cells and following BCR ligation [5,6]. PI3K mediated signalling is known to be constitutively activated in CLL [6] and patients with more progressive disease [IGHV unmutated (U-CLL)] show significantly greater PI3K expression compared to less progressive disease [IGHV mutated (M-CLL)] [7].
    Pharmacological inhibition of PI3Kδ in CLL The crucial role of PI3Kδ in normal B cell biology was identified using genetic and pharmacological studies [4] and its haematopoietic restricted expression has made it an attractive target for therapeutic intervention in haematological malignancies (Fig. 1A). Idelalisib preferentially inhibits PI3Kδ and has recently gained approval for the treatment of relapsed/refractory CLL. It has been evaluated in a phase I clinical trial in 54 CLL patients with relapsed/refractory disease; nodal shrinkage and overall survival were obtained in 81% and 72% patients respectively [8]. In a phase III clinical trial, idelalisib combined with the anti-CD20 antibody rituximab significantly improved progression free survival (81%) and overall survival (91%) in relapsed CLL patients (n=220) compared to placebo plus rituximab [9]. Commonly observed adverse events in patients taking idelalisib included pneumonia, rash and diarrhoea [8], however idelalisib and rituximab demonstrated an acceptable safety profile with no significant increase overall in adverse events compared to placebo plus rituximab [9].