Role of ofatumumab in treatment of chronic lymphocytic leukemia

Veliz, Marays; Pinilla‐Ibarz, Javier

doi:10.2147/jbm.s13063

Cited by 7 publications

(2 citation statements)

References 21 publications

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“…Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by an increase in the number of functionally deficient mature CD5+ B lymphocytes in the blood, bone marrow, lymph nodes, and spleen [ 1 , 2 ]. CLL is most commonly observed in Western countries and affects mainly older individuals [ 3 , 4 ]. The main purposes of CLL treatment are to reduce cancer progression and induce apoptosis while providing quality of life for patients.…”

Section: Introductionmentioning

confidence: 99%

“…The main purposes of CLL treatment are to reduce cancer progression and induce apoptosis while providing quality of life for patients. Treatment approaches for CLL include chemotherapy, radiotherapy, immunotherapy, and bone marrow transplantation (BMT) with high-dose chemotherapy [ 4 , 5 ]. Among these treatment options, purine analogs such as fludarabine and cladribine, alkylating agents like chlorambucil, and alkylating agent/anthracycline combinations are frequently used [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

Gökbulut¹,

Yaşar²,

Baran

2015

Tjh

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Objective:The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey), on 232B4 chronic lymphocytic leukemia (CLL) cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells.Materials and Methods:The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry.Results:We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase.Conclusion:KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

Gökbulut¹,

Yaşar²,

Baran

2015

Tjh

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Multiple Sclerosis

Pitts

Dyckman

2021

Burger's Medicinal Chemistry and Drug Discovery

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Several new medicines have been approved or entered development for the treatment of Multiple Sclerosis (MS) in the past few years. The sphingosine‐1‐phosphate (S1P) modulator fingolimod was the first FDA approved oral disease modifying therapy for MS, and it has inspired a number of additional agents directed at this clinically validated target. Fumarates (e.g. dimethyl fumarate), dihydroorotate dehydrogenase inhibitors (e.g. teriflunomide) and other agents which decrease lymphocyte proliferation (e.g. cladribine) represent additional clinically validated therapeutic approaches. While the mechanisms of action for these new agents may not be fully defined, they have demonstrated a good degree of efficacy in the treatment of relapsing forms of MS. It is of interest to note that biologic agents which target CD20 on B cells have also shown significant efficacy in the treatment of MS. This, in turn, has spurred MS clinical trials with Bruton's Tyrosine Kinase (BTK) inhibitors, which also act on B cell pathways. The introduction of each of these newer agents still requires careful consideration of the risk–benefit for individual patients, but has also set a higher bar in the treatment of MS for subsequent agents, as evidenced by the discontinuation of several agents in late stage clinical trials. This higher bar has also pushed some historic agents to second or third line agents. This speaks to an overall advancement in the treatment of MS, and provides hope for further advances in therapeutic options.

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Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin

Zhang

Wang

et al. 2013

Invest New Drugs

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Utilization of antibodies to deliver highly potent cytotoxic agents to corresponding antigen-overexpressed tumor cells is a clinically validated therapeutic strategy. Ofatumumab (OFA, trade name Arzerra) is a fully human CD20-specific antibody that is active against CD20-positive B-cell lymphoma/chronic lymphocytic leukemia cells. In order to further enhance the anticancer effect of OFA, anti-CD20 OFA has been conjugated with highly cytotoxic monomethyl auristatin E (MMAE) through a cathepsin-B-cleavable valine-citrulline (vc) dipeptide linkage to form OFA-vcMMAE and the anti-tumor activity of OFA-vcMMAE against CD20-positive B lymphoma cells are then evaluated in vitro and in vivo. As a result, conjugation of OFA with MMAE has kept the initial effector functional activities of OFA such as binding affinity, complement-dependent cytotoxicity (CDC) as well as antibody-dependent cell-mediated cytotoxicity (ADCC). In addition, the conjugation of MMAE significantly improved the cytotoxic activity of OFA against CD20-positive cells (i.e., Raji, Daudi and WIL2-S cells) but not against CD20-negative K562 cells. On the other hand, OFA-vcMMAE was modulated from the CD20-positive cell surface and then entered the lysosomes by receptor-mediated endocytosis, underwent proteolytic degradation and released active drug MMAE to induce apoptotic cell death through a caspase-3-like protease-dependent pathway. Surprisingly, OFA-vcMMAE completely inhibited the growth of CD20-positive Daudi and Ramos lymphoma xenografts in vivo, and exhibited greater anti-tumor activity than unconjugated OFA, suggesting that the anti-tumor activity of anti-CD20 antibody can be enhanced by conjugation with MMAE. In the near future, this new approach might be used as a clinical treatment of CD20-positive B lymphoid malignancies.

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Role of ofatumumab in treatment of chronic lymphocytic leukemia

Cited by 7 publications

References 21 publications

A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

Multiple Sclerosis

Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin

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