The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia

Dürig, Jan; Dührsen, Ulrich; Klein-Hitpaß, Ludger; Worm, Jesper; Hansen, Jakob Bondo; Ørum, Henrik; Wissenbach, Margit

doi:10.1038/leu.2010.322

Cited by 40 publications

(37 citation statements)

References 34 publications

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“…The authors did not find significant on-target effects of the drug, and a clinical response was only observed in a few patients. 36 Because gene expression analyses from oligonucleotide-treated patients indicated an activation of TLR in CLL cells, these data suggest that TLR signals may also engage a BCR response in vivo. (4) Although not systematically studied, published data suggest that bacterial infections can promote disease onset and progression, 37,38 which may be related to TLR9 activation by bacterial DNA.…”

Section: Discussionmentioning

confidence: 99%

Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

Wagner

Oelsner

Moore

et al. 2016

Blood

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Key Points• Activation of innate immune receptors induces an antiapoptotic signal and proliferation in ZAP-70-positive CLL dependent on Syk activation.• TLR9 activation autonomously induces BCR signaling in ZAP-70-positive CLL based on an auto/paracrine feedback loop involving immunoglobulin M.The crucial dependence of chronic lymphocytic leukemia (CLL) cells on signals derived from the B cell receptor (BCR) has encouraged the development of new inhibitors, which interfere with BCR signaling and demonstrate clinical benefits in nearly all patients. In addition, signaling through Toll-like receptor (TLR) 9 of the innate immune system has been shown to further contribute to the activation of CLL cells. However, responses to TLR9 engagement are not uniform, but diametrically opposed with cell death in some patients and cell proliferation in others. We now provide evidence that heterogeneous responses to TLR agonists are related to differences in the ability of CLL cells to activate the BCR-associated kinase Syk. Notably, expression of ZAP-70 appears to be of crucial importance for TLR9-mediated activation of Syk. We show that the activation of Syk provides an antiapoptotic signal, which is independent of Mcl-1, Bcl-2, and Bcl-X L , but related to the degradation of the proapoptotic Bim. Mechanistically, TLR9-mediated antiapoptotic signals in ZAP-70-positive CLL trigger secretion of immunoglobulin M, which then serves as (auto-) antigen for a prosurvival BCR signal. Thus, our data show that single activation of the innate immune receptor TLR9 is sufficient to fully engage BCR signaling in ZAP-70-positive CLL, protecting malignant cells from apoptosis. We conclude that the integration of TLR signaling into an adaptive immune response can further promote survival of CLL cells and may contribute to the unfavorable prognosis of ZAP-70-positive CLL. (Blood. 2016;127(4):436-448)

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Section: Discussionmentioning

confidence: 99%

Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

Wagner

Oelsner

Moore

et al. 2016

Blood

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“…We selected three different antisense LNA SSOs with a phosphorothioate backbone, previously characterized in NHPs and humans (Durig et al , 2011; Frieden and Orum, 2008; Lee et al , 2013; Lindholm et al , 2012; Straarup et al , 2010; van Poelgeest et al , 2013) and a LNA-based microRNA antagonist, with a phosphorothioate backbone (Gebert et al , 2014; Hildebrandt-Eriksen et al , 2012). …”

Section: Methodsmentioning

confidence: 99%

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

et al. 2017

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Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds. The studies included toxicokinetic investigations, in-life monitoring, clinical and anatomic pathology. In the minipig, we demonstrated target engagement by the SSOs where relevant, and a similar toxicokinetic behavior in plasma, kidney, and liver when compared with NHPs. Clinical tolerability was similar between minipig and NHPs. For the first time, we showed similar and dose-dependent effects on the coagulation and complement cascade after intravenous dosing similar to those observed in NHPs. Similar to NHPs, morphological changes were seen in proximal tubular epithelial cells of the kidney, Kupffer cells, hepatocytes, and lymph nodes. Minipigs appeared more sensitive to the high-dose kidney toxicity of most of the selected SSOs than NHPs. No new target organ or off-target toxicities were identified in the minipig. The minipig did not predict the clinical features of human injection site reactions better than the NHPs, but histopathological similarities were observed between minipigs and NHPs. We conclude that there is no impediment, as default, to the use of minipigs as the non-rodent species in SSO candidate non-clinical safety packages.

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“…Besides monogenic disorders, AON-based therapies have also been developed to treat several cancer and inflammation disorders, such as chronic lymphocytic leukemia (Durig et al 2011), acute myeloid leukemia (Erba et al 2013), or psoriasis (Colin et al 2014). All these studies denote the potential of AONs as a treatment strategy for a wide range of disorders, by showing beneficial effects in the patients with low toxicity and little inflammatory responses.…”

Section: Antisense Oligonucleotides: Structure Function and Clinicalmentioning

confidence: 98%

Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

Gérard

Garanto

Rozet

et al. 2015

Retinal Degenerative Diseases

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Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.

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The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia

Cited by 40 publications

References 34 publications

Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

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