Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

Bhatt, Shruti; Parvin, Salma; Cho, Hyun Mi; Kunkalla, Kranthi; Vega, Francisco; Timmerman, John M.; Shin, Seung Uon; Rosenblatt, Joseph D.

doi:10.1182/blood-2016-09-738211

Cited by 28 publications

(13 citation statements)

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“…We also tested the half-lives of Erb-IL21 and LA22-IL21. Similar to human IgG, the half-lives of both fusion proteins were about 24 hours (Supplemental Figure 2C), while the half-life of native IL-21 was less than half an hour (38). To evaluate whether the antitumor effect of Erb-IL21 is dose dependent, we treated tumor-bearing mice with various doses of Erb-IL21 (25 μg, 75 μg, and 225 μg).…”

Section: Resultsmentioning

confidence: 99%

“…Previous work of ours showed that intratumoral injection of IL-21 could shift tumor macrophages from an M2 to an M1 phenotype and that this resulted in tumor control (37). Unfortunately, the half-life of IL-21 is also very short (37,38), and the intratumoral administration of recombinant IL-21 is rather difficult to administer for most patients.…”

Section: Introductionmentioning

confidence: 92%

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Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

et al. 2020

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

et al. 2020

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“…All procedures performed in studies involving animals were in accordance with the ethical standards of the University of California Los Angeles (UCLA) Animal Research Committee. Murine A20 BALB/c B cell lymphoma line (ATCC) and A20 cells transduced with a lentivirus encoding the human CD20 gene (A20-hCD20, clone R2D2) [34] were cultured in RPMI1640 supplemented with 10% FBS and 50 μmol/L 2-mercaptoethanol (Life Technologies). Human CD20 transgenic mice (hCD20TM), a kind gift from Mark Shlomchik, Yale University, have been described previously [30,34] and were backcrossed onto BALB/c backgrounds and genotypes confirmed by PCR ( Fig.…”

Section: Syngeneic Disseminated B Cell Lymphoma Modelmentioning

confidence: 99%

18F-labeled anti-human CD20 cys-diabody for same-day immunoPET in a model of aggressive B cell lymphoma in human CD20 transgenic mice

Zettlitz

Tavaré

Tsai

et al. 2018

Eur J Nucl Med Mol Imaging

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Purpose Metabolic imaging using [ 18 F]FDG is the current standard for clinical PET; however, some malignancies (e.g., indolent lymphomas) show low avidity for FDG. The majority of B cell lymphomas express CD20, making it a valuable target both for antibody-based therapy and imaging. We previously developed PET tracers based on the humanised anti-CD20 antibody obinutuzumab (GA101). Preclinical studies showed that the smallest bivalent fragment, the cys-diabody (GAcDb, 54.5 kDa) with a peak uptake at 1-2 h post-injection and a biological half-life of 2-5 h, is compatible with short-lived positron emitters such as fluorine-18 (18 F, t 1/2 110 min), enabling same-day imaging. Methods GAcDb was radiolabeled using amine-reactive N-succinimidyl 4-[ 18 F]-fluorobenzoate ([ 18 F]SFB), or thiol-reactive N-[2-(4-[ 18 F]-fluorobenzamido)ethyl]maleimide ([ 18 F]FBEM) for site-specific conjugation to C-terminal cysteine residues. Both tracers were used for immunoPET imaging of the B cell compartment in human CD20 transgenic mice (hCD20TM). [ 18 F]FB-GAcDb immunoPET was further evaluated in a disseminated lymphoma (A20-hCD20) syngeneic for hCD20TM and compared to [ 18 F]FDG PET. Tracer uptake was confirmed by ex vivo biodistribution. Results The GAcDb was successfully 18 F-radiolabeled using two different conjugation methods resulting in similar specific activities and without impairing immunoreactivity. Both tracers ([ 18 F]FB-GAcDb and [ 18 F]FBEM-GAcDb) specifically target human CD20-expressing B cells in transgenic mice. Fast blood clearance results in high contrast PET images as early as 1 h post injection enabling same-day imaging. [ 18 F]FB-GAcDb immunoPET detects disseminated lymphoma disease in the context of normal tissue expression of hCD20, with comparable sensitivity as [ 18 F]FDG PET but with added specificity for the therapeutic target. Conclusions [ 18 F]FB-GAcDb and [ 18 F]FBEM-GAcDb could monitor normal B cells and B cell malignancies non-invasively and quantitatively in vivo. In contrast to [ 18 F]FDG PET, immunoPET provides not only information about the extent of disease but also about presence and localisation of the therapeutic target.

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“…Some strategies have been implemented to sensitize rituximab therapy by combining with other agents to increase the pro-apoptotic effect. These additional agents include macromolecules such as the humanized monoclonal mapatumumab targeting TRAIL-R1 49 , the genetically engineered fusion proteins scFvRit:sFasL 50 , Apo2 ligand (Apo2L)/TRAIL (dulanermin) 51,52 and anti-CD20-interleukin-21 53 , and small molecules, such as the selective NEDD8 activating enzyme inhibitor pevonedistat (MLN4924) 54 , the mTOR (mammalian target of rapamycin) inhibitor temsirolimus 55 , and the proteasome inhibitor bortezomib 56 . However, the efficacy of these agents requires further confirmation or has been suggested to be insufficient based on clinical trials 52 .…”

Section: Discussionmentioning

confidence: 99%

Midostaurin potentiates rituximab antitumor activity in Burkitt’s lymphoma by inducing apoptosis

Chen

et al. 2018

Cell Death Dis

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An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt’s lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-κB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo, midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments. Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.

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Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

Abstract: Key Points Delivering IL-21 to tumor B cells by fusion with anti-CD20 antibody (αCD20-IL-21 fusokine) is a potent antilymphoma therapeutic strategy. αCD20-IL-21 fusokine demonstrated superior antilymphoma activity compared with its individual components.

Cited by 28 publications

References 44 publications

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

18F-labeled anti-human CD20 cys-diabody for same-day immunoPET in a model of aggressive B cell lymphoma in human CD20 transgenic mice

Midostaurin potentiates rituximab antitumor activity in Burkitt’s lymphoma by inducing apoptosis

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