Rituximab action mechanism

Several mechanisms have been proposed for the action mechanism of rituximab including ADCC, CDC, complement dependent cellular cytotoxicity (CDCC), and a direct pro-apoptotic effect (3,4,10). However, the mechanism of action of rituximab has yet to be fully elucidated. 

Rituximab is a chimeric antibody that contains the human IgGx constant region and murine variable region, and binds the membrane-associated human CD20 antigen. Evidence for multiple mechanisms of rituximab action has been reported [96, 97]. Rituximab can deplete CD20-positive B cells via ADCC, CDC, or apoptosis however, it is not clear which is the most important mechanism in humans. Resistance to rituximab s in-vivo effects has been reported, but the underlying resistance mechanisms are not well understood. 

Rituximab and its Mechanism of Action Other Monoclonal Antibodies in the Treatment OF Hematologic Malignancies The Fc7 Receptor Gene Polymorphism and in Vitro Data... 

This chapter reviews our current understanding of the mechanism of action of monoclonal antibody (especially rituximab), as well as the role of Fey receptor and Fey receptor gene polymorphisms, and their impact on treatment outcomes in hematologic malignancies including follicular lymphoma (FL), diffuse large B-cell lymphoma (DL-BCL), Waldenstrom s macroglobulinemia (WM), and chronic lymphocytic leukemia (CLL). 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

The response rate of the patients with VV, VF, and FF genotypes at FCGR3A-158 was 50%, 33%, and 42% (p = 0.78), while that of patients with HH, HR. and RR genotypes at FCGR2A-131 was 67%, 29%, and 57% (p = 0.70), respectively. The investigators concluded that unlike FL, a mechanism of tumor clearance other than ADCC may be more important in the action of rituximab toward CLL cells (69). Fmther studies with larger number of CLL patients are warranted to reach a clear understanding of the precise mechanism of rituximab activity on CLL cells. 

Smith MR. Rituximab (monoclonal anti-CD20 antibody) mechanisms of action and resistance. Oncogene 2003 22 7359-7368. 

Maloney, D.G., Smith, B., Rose, A. Rituximab mechanism of action and resistance. Semin. Oncol. 2002, 29, 2-9. 

Fig. 1 Mechanism of action of rituximab. The chimeric (mouse/human) antibody, rituximab, binds to the CD20 antigen on B-cells and (a) activates complement to effect CDC, (b) attracts effector cells via Fc receptors to effect ADCC, and (c) transmits a signal into the cell to induce apoptosis. (See Color Plate p. xxii).

Provides an insight into the key laboratory and in vivo studies that helped elucidate the mechanisms of action of rituximab. D. R. Anderson, A. GriUo-Lopez, C. Yams et al., Biochem. Soc. Trans. 1997, 2, 705 -708. 

Rhizopus oryzae lactate dehydrogenase 24 rhizosecretion 48 ribosome 13 rice 27 rifamycin 14 rituxan 213 rituximab 213 application 226 approval 225 B-cell recovery 222 clinical development 215 combination 223 development 221 EMEA 225 first phase I study 219 future applications 226, 228 IDEC 219 indications 226 interferon 224 mechanism of action 215 optimizing the dose and schedule 222 pharmacokinetic 222 phase I and I/II clinical trials 219 phase I/II 216... 

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