Anti-CD20 treatment for B-cell malignancies: current status and future directions

Klein, Christian; Jamois, Candice; Nielsen, Tina

doi:10.1080/14712598.2020.1822318

Cited by 37 publications

(16 citation statements)

References 182 publications

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“…2C ), indicating that the fadraciclib-induced cell death was selective to B cells. However, B cell toxicity may not pose a problem of using fadraciclib in the clinic as the B cell-targeting antibodies such as rituximab, ofatumumab and obinutuzumab were proven to be safe in CLL patients [ 32 ]. In addition, fadraciclib was well tolerated in clinical trials in solid tumors either with a 1 h or 4 h infusion [ 33 , 34 ].…”

Section: Resultsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

Chen

Xiong

et al. 2022

Leukemia

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Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.

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Section: Resultsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

Chen

Xiong

et al. 2022

Leukemia

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“…OFA is a fully human IgG1 mab binding both the large and small CD20 extracellular loop with a high binding affinity and slow off-rate [46]. It was first developed by Genmab and approved by the FDA under the name Arzerra for refractory CLL in October 2009, however in significantly higher doses [47].…”

Section: Ofatumumabmentioning

confidence: 99%

“…This may be of specific interest when considering key effector mechanisms in the CNS where the complement system plays an important role in immunity [65,66]. Furthermore, OFA is thought to dissolve more slowly from the CD20 antigen, also resulting in a stronger efficacy [67]. Another interesting feature of OFA, in contrast to RTX, is the maintenance of high CDC in the presence of low CD20 expression [64].…”

Section: Mode Of Actionmentioning

confidence: 99%

“…UB was manufactured with a low fucose content in order to enhance ADCC/ADCP. This enhancement is facilitated through a strong affinity of the antibody to the FcγRIIIa and results in a high NK cell-mediated ADCC regardless of CD20 surface expression [67]. UB possesses the highest efficacy regarding ADCC within the current anti-CD20 mabs [60].…”

Section: Mode Of Actionmentioning

confidence: 99%

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A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

2021

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Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies.

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“…However, disease resistance or relapse after successful initial therapy and declining efficacy of subsequent rounds occurs. Thus, a number of second and third generation anti-CD20 antibodies have been developed, such as ofatumumab, ublituximab, and obinutuzumab with specific mechanisms of action [ 6 ]. So far, obinutuzumab-based immunochemotherapy has demonstrated superiority over rituximab-based immunochemotherapy for first-line treatment (GALLIUM study) [ 7 ].…”

mentioning

confidence: 99%

Immunotherapies in Non-Hodgkin’s Lymphoma

Bezombes

Pérez-Galán

2021

Cancers

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Anti-CD20 treatment for B-cell malignancies: current status and future directions

Cited by 37 publications

References 182 publications

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

Immunotherapies in Non-Hodgkin’s Lymphoma

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