How does B cell depletion therapy work, and how can it be improved?

Clark, Edward A.; Ledbetter, J A

doi:10.1136/ard.2005.042507

Cited by 27 publications

(20 citation statements)

References 42 publications

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“…Rituximab can induce apoptosis of chronic lymphocytic leukemia cells in vivo, and caspase-3 activation was shown to be correlated with posttreatment lymphocyte counts (29). It has also been shown that the factors that antagonize apoptosis, such as overexpression of antiapoptotic proteins or aberrant p53 function, are associated with Rituximab resistance (30,31).…”

Section: Discussionmentioning

confidence: 99%

Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity

Shi

Qian

et al. 2008

Cancer Research

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Despite the effectiveness of the anti-CD20 monoclonal antibody (mAb) Rituximab (C2B8) in the treatment of B-cell lymphoma, its efficacy remains variable and often modest. It seems likely that a combination of multiple mechanisms, such as complement-dependent cytotoxicity (CDC) and apoptotic signaling, underlies the therapeutic success of anti-CD20 mAbs. Unfortunately, all the current anti-CD20 mAbs effective in CDC are relatively inactive in signaling cell death and vice versa. In this study, we developed two genetically engineered tetravalent antibodies (TetraMcAb) respectively derived from the anti-CD20 mAbs C2B8 and 2F2. TetraMcAbs, with a molecular mass only 25 kDa higher than native divalent antibodies (DiMcAb), were shown not only to be as effective in mediating CDC and antibody-dependent cellular cytotoxicity against B-lymphoma cells as DiMcAbs but also to have antiproliferative and apoptosis-inducing activity markedly superior to that of DiMcAbs. Interestingly, whereas 2F2 and C2B8 were equally effective in inducing cell growth arrest and apoptosis, the functions of their tetravalent versions, 2F2(ScFvHL) 4 -Fc and C2B8(ScFvHL) 4 -Fc, were significantly different. 2F2(ScFvHL) 4 -Fc exhibited exceptionally more potent antiproliferative and apoptosis-inducing activity than that of C2B8(ScFvHL) 4 -Fc. Immunotherapeutic studies further showed that 2F2(ScFvHL) 4 -Fc was far more effective in prolonging the survival of severe combined immunodeficient mice bearing systemic Daudi or Raji tumors than C2B8, 2F2, and C2B8(ScFvHL) 4 -Fc, suggesting that it might be a promising therapeutic agent for B-cell lymphoma. [Cancer Res 2008;68(7):2400-8]

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Section: Discussionmentioning

confidence: 99%

Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity

Shi

Qian

et al. 2008

Cancer Research

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“…CDC activity may be linked to an undesirable side effect in some patients, and it has been suggested that decreasing CDC activity could potentially diminish this side effect. 27,28 For this reason, we speculate that in some instances antibodies bearing the high mannose glycoform may have a therapeutic advantage.…”

Section: © 2 0 1 2 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Production, characterization and pharmacokinetic properties of antibodies with N-linked Mannose-5 glycans

Yu¹,

Brown

Reed

et al. 2012

mAbs

183

188

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“…Several mechanisms have been invoked to explain the killing action of anti-CD20 antibodies, such as complement-induced lysis and direct apoptosis, but antibody-dependent cell-mediated cytotoxicity is likely to represent the main mechanism of action of rituximab. 18 …”

Section: Strategies For B-cell Targetingmentioning

confidence: 99%

B cells as therapeutic targets in SLE

2010

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The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.

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How does B cell depletion therapy work, and how can it be improved?

Cited by 27 publications

References 42 publications

Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity

Development of Novel Tetravalent Anti-CD20 Antibodies with Potent Antitumor Activity

Production, characterization and pharmacokinetic properties of antibodies with N-linked Mannose-5 glycans

B cells as therapeutic targets in SLE

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