Rituximab for chronic lymphocytic leukemia

Robak, Tadeusz

doi:10.1517/14712598.2012.665444

Cited by 21 publications

(9 citation statements)

References 79 publications

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“…5,6 Improved versions of rituximab have been developed with the scope of enhancing response rates and reducing relapse or resistance. 7,8 One modification applied for CD20 and other therapeutic antibodies is termed "glycoengineering" and results in the decreased fucosylation of the carbohydrate attached to the Asn-297 glycosylation site of the Fc portion of the antibody. [9][10][11][12][13][14][15] Obinutuzumab (GA101) is a glycoengineered CD20 antibody derived from the murine Bly-1 antibody and is currently in pivotal clinical trials for the treatment of B-NHL and CLL in direct comparison with rituximab.…”

Section: Introductionmentioning

confidence: 99%

Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab

Golay

Roit

Bologna

et al. 2013

Blood

205

143

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Key Points• Phagocytosis of CLL targets by neutrophils is a novel mechanism of action of the glycoengineered anti-CD20 antibody obinutuzumab.• This mechanism takes place in physiological conditions and requires CD16B and CD32A.Obinutuzumab (GA101) is a glycoengineered type 2 CD20 antibody with enhanced CD16A-binding and natural killer-mediated cytotoxicity. CD16B is highly homologous to CD16A and a major FcgR on human polymorphonuclear neutrophils (PMNs). We show here that glycoengineered obinutuzumab or rituximab bound CD16B with approximately sevenfold higher affinity, compared with nonglycoengineered wild-type parental antibodies. Furthermore, glycoengineered obinutuzumab activated PMNs, either purified or in chronic lymphoblastic leukemia whole blood, more efficiently than wild-type rituximab. Activation resulted in a 50% increase in CD11b expression and 70% down-modulation of CD62L on neutrophils and in release of tumor necrosis factor alpha, IL-6, and IL-8. Activation was not accompanied by generation of reactive oxygen species or antibody-dependent cellular cytotoxicity activity, but led to up to 47% phagocytosis of glycoengineered anti-CD20 opsonized chronic lymphoblastic leukemia targets by purified PMNs. Significant phagocytosis was observed in whole blood, but only in the presence of glycoengineered antibodies, and was followed by up to 50% PMN death. Finally we show, using anti-CD16B and anti-CD32A Fab and F(ab') 2 fragments, that both of these receptors are involved in PMN activation, phagocytosis, and cell death induced by glycoengineered antibodies. We conclude that phagocytosis by PMNs is an additional mechanism of action of obinutuzumab mediated through its higher binding affinity for CD16B. (Blood. 2013;122(20):3482-3491) IntroductionThe chimeric unmodified, wild-type CD20 IgG1 monoclonal antibody rituximab (MabThera and Rituxan) has shown significant therapeutic activity in B-non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL).1,2 Rituximab is thought to act largely through immune-mediated mechanisms: complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and/or antibody-dependent phagocytosis (ADCP) by macrophages/monocytes.3,4 CD20 IgG1 antibodies can differ in their functional properties according to their binding mode to CD20. They are classified as type 1 when they show high CDC such as rituximab or as type 2 when they show high homotypic adhesion and direct cell death, respectively. 5,6 Improved versions of rituximab have been developed with the scope of enhancing response rates and reducing relapse or resistance. 7,8 One modification applied for CD20 and other therapeutic antibodies is termed "glycoengineering" and results in the decreased fucosylation of the carbohydrate attached to the Asn-297 glycosylation site of the Fc portion of the antibody. [9][10][11][12][13][14][15] Obinutuzumab (GA101) is a glycoengineered CD20 antibody derived from the murine Bly-1 antibody and is currently in pivotal clinical trials for the treatment of...

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Section: Introductionmentioning

confidence: 99%

Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab

Golay

Roit

Bologna

et al. 2013

Blood

205

143

View full text Add to dashboard Cite

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“…34,35). Therefore, in consideration of the wide experience in using rituximab in the therapeutic approaches for the treatment of B-cell malignancies and in particular for B-CLL (12,13), and taking into account the well-known properties of PLGA for drug delivery systems (10), we have planned to engineer PLGA NP with rituximab (NP-Rt). Subsequently, NPs loaded with Nutlin-3 were engineered with rituximab (NP-Rt-Nut).…”

Section: Discussionmentioning

confidence: 99%

“…Standard treatments for B-cell malignancies, such as Bchronic lymphocytic leukemia (B-CLL), the most common lymphoid malignancy in Western countries, include monoor polychemotherapies, usually combined with monoclonal antibodies (Ab), such as anti-CD20 rituximab (12). In this respect, a recent meta-analysis showed that patients affected by B-CLL receiving chemotherapy plus rituximab benefit in terms of overall survival (OS) as well as progression-free survival (PFS) compared with those with chemotherapy alone, especially fludarabine or fludarabine and cyclophosphamide (R-FC regimen; ref.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticles Engineered with Rituximab and Loaded with Nutlin-3 Show Promising Therapeutic Activity in B-Leukemic Xenografts

Voltan

Secchiero

Ruozi

et al. 2013

Clinical Cancer Research

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Purpose: Because the nongenotoxic inhibitor of the p53/MDM2 interactions Nutlin-3 has shown promising in vitro therapeutic activity against a variety of p53 wild-type cancer cells, in this study we evaluated an innovative strategy able to specifically target Nutlin-3 toward CD20 þ malignant cells.Experimental Design: The cytotoxic effects of Nutlin-3 encapsulated into poly(lactide-co-glycolide) nanoparticles (NP-Nut) and into rituximab (anti-CD20 antibody)-engineered NP (NP-Rt-Nut) as well as of NPs engineered with rituximab alone (NP-Rt) were initially analyzed in vitro in JVM-2 B-leukemic cells, by assessing both the functional activation of the p53 pathway (by Nutlin-3) and/or the activation of the complement cascade (by rituximab). Moreover, the potential therapeutic efficacy of NP-Nut, NP-Rt, and NPRt-Nut were comparatively assessed in vivo in CD20 þ JVM-2 leukemic xenograft SCID mice.Results: Functional in vitro assays showed that NP-Nut and NP-Rt-Nut exhibited a comparable ability to activate the p53 pathway in the p53 wild-type JVM-2 leukemic cells. On the other hand, NP-Rt and NPRt-Nut, but not NP nor NP-Nut, were able to promote activation of the complement cascade. Of note, the in vivo intratumoral injection in JVM-2 B-leukemic/xenograft mice showed that NP-Rt-Nut displayed the maximal therapeutic activity promoting a survival rate significantly higher not only with respect to control animals, treated either with vehicle or with empty NP, but also with respect to animals treated with NP-Nut or NP-Rt. Conclusions: Our data show for the first time the potential antileukemic activity of rituximabengineered Nutlin-3-loaded NPs in xenograft SCID mice.

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“…Rituximab (Rituxan) is a chimeric type I anti-CD20 mAb. This antibody is used as single agent or combination therapy in relapsed or refractory indolent-non Hodgkins lymphoma (NHL) [63] and CLL patients [64]. Rituximab exerts its cytotoxicity through CDC, ADCC and week direct apoptosis [65].…”

Section: Anti-cd20 Mabmentioning

confidence: 99%

Novel and emerging targeted-based cancer therapy agents and methods

Hojjat‐Farsangi

2015

Tumor Biol.

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After several decades of uncovering the cancer features and following the improvement of therapeutic agents, however cancer remains as one of the major reasons of mortality. Chemotherapy is one of the main treatment options and has significantly improved the overall survival of cancer patients, but chemotherapeutic agents are highly toxic for normal cells. Therefore, there is a great unmet medical need to develop new therapeutic principles and agents. Targeted-based cancer therapy (TBCT) agents and methods have revolutionized the cancer treatment efficacy. Monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) are among the most effective agents of TBCT. These drugs have improved the prognosis and survival of cancer patients; however, the therapeutic resistance has subdued the effects. Several mechanisms lead to drug resistance such as mutations in the drug targets, activation of compensatory pathways, and intrinsic or acquired resistance of cancer stem cells. Therefore, new modalities, improving current generation of inhibitors and mAbs, and optimizing the combinational therapy regimens are necessary to decrease the current obstacles in front of TBCT. Moreover, the success of new TBCT agents such as mAbs, SMIs, and immunomodulatory agents has sparked further therapeutic modalities with novel targets to inhibit. Due to the lack of cumulative information describing different agents and methods of TBCT, this review focuses on the most important agents and methods of TBCT that are currently under investigation.

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Rituximab for chronic lymphocytic leukemia

Cited by 21 publications

References 79 publications

Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab

Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab

Nanoparticles Engineered with Rituximab and Loaded with Nutlin-3 Show Promising Therapeutic Activity in B-Leukemic Xenografts

Novel and emerging targeted-based cancer therapy agents and methods

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