Antitumor Activity of the Novel BTK Inhibitor TG-1701 Is Associated with Disruption of Ikaros Signaling in Patients with B-cell Non–Hodgkin Lymphoma

Ribeiro, Marcelo Lima; Reyes-Garau, Diana; Vinyoles, Meritxell; Profitós-Pelejà, Núria; Santos, Juliana C.; Armengol, Marc; Fernández-Serrano, Miranda; Mor, Alícia Sedó; Bech-Serra, Joan Josep; Blecua, Pedro; Musulén, Eva; Gómez, Carolina; Miskin, Hari P.; Esteller, Manel; Bosch, Francesc; Menéndez, Pablo; Normant, Emmanuel; Roué, Gaël

doi:10.1158/1078-0432.ccr-21-1067

Cited by 10 publications

(11 citation statements)

References 31 publications

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“…To investigate how the upregulation of GPR183 in target cells could impact their recognition and phagocytosis by M1 macrophages, a single-clone derived Raji-GPR183 KO cell was generated by CRISPR/Cas9 gene editing (Figure 3A and source data 1), using previously described procedures (Ribeiro et al, 2021) and co-cultured for 24h with primary M1 macrophages and BMSCs under Nanoshuttle-driven magnetic levitation (Souza et al, 2010) in a conditioned medium to form functional 3D spheroids. Compared to the Raji-GPR183 wt , the Raji-GPR183 KO spheroids harboured a complete blockade of M1 cell infiltration within the multicellular aggregates, both at basal levels and upon treatment with the triplet (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Tumour volumes were measured each 2-3 days with external callipers. The number of animals used in each of the experimental groups is based on the literature and previous results from the group (Ribeiro et al, 2021). Immunohistochemical staining of representative tumour specimens (N=3) was performed using anti-CD20 (Sigma), anti-GPR183 (Santa Cruz), anti-F4/80 (Abcam), anti-Histone H3-pSer10 (Abcam) and anti-CD56/NCAM-1 (Abcam).…”

Section: Methodsmentioning

confidence: 99%

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GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

Ribeiro

Profitós-Pelejà

Santos

et al. 2022

Preprint

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Targeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most disease subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3Kδ/CK1e inhibitor, umbralisib ("U2"-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP) in vitro, leading to an additive antitumor effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93% tumor growth inhibition, with 40% of the animals remaining tumor-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodeling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3Kδ- and CD20-targeting agents in patients with B-NHL.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

Ribeiro

Profitós-Pelejà

Santos

et al. 2022

Preprint

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“…SHR1459 (TG 1701, EBI-1459; Reistone Biopharma, Jiangsu Hengrui Medicine Co., Lianyungang, China) is a second-generation, covalently bound, and irreversible secondgeneration BTKi currently under clinical development. This agent has been found to demonstrate superior selectivity to BTK compared to ibrutinib in in vitro kinase screening [80]. SHR1459 therapy, alone or in combination with ublituximab and umbralisib, is currently under clinical development in phase 1 trial in patients with R/R mature B cell neoplasms or CLL (NCT03671590; NCT04806035) [81].…”

Section: Shr1459mentioning

confidence: 99%

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Robak

Witkowska

Smolewski

2022

Cancers

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.

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“…Another more selective inhibitor is zanubrutinib, which also showed antitumor activity in the nanomolar range in MCL cell lines as well as in ABC-DLBCL cells, with a similar effect as ibrutinib but with less off-target effects and prolonged overall survival in a DLBCL xenograft model [ 66 , 67 ]. Alternative irreversible BTKi are M2951 and M7583, presenting an in vivo antitumor activity in preclinical models of ABC-DLBCL [ 68 ]; spebrutinib (CC-292), with high efficacy as a single agent as well as in synergistic combinations in ABC-DLBCL, but limited efficacy in GCB-DLBCL [ 69 ]; tirabrutinib (ONO/GS-4059), which is showing promising results in preclinical studies [ 70 , 71 ]; TG-1701, a more selective inhibitor, presenting Ikaros as an important biomarker for response and efficacy, both in vitro and in vivo [ 72 ]; and other compounds, currently under development with promising results in vitro, such as QL47 [ 73 ].…”

Section: Pharmacological Targeting Of Bcr Upstream Kinases and Its Li...mentioning

confidence: 99%

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

Profitós-Pelejà

Santos

Marín‐Niebla

et al. 2022

Cancers

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The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

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Antitumor Activity of the Novel BTK Inhibitor TG-1701 Is Associated with Disruption of Ikaros Signaling in Patients with B-cell Non–Hodgkin Lymphoma

Cited by 10 publications

References 31 publications

GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

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