Rituximab production

Figure 5.9 Principal oligosaccharide structures found on recombinant rituximab. Reprinted from J. Chromatogr., A, 913, Wan, H. Z., Kaneshiro, S., Frenz, J. and Cacia, J., Rapid method for monitoring galactosylation levels dnring recombinant antibody production by electrospray mass spectrometry with selective-ion monitoring , 437-446, Copyright (2001), with permission from Elsevier Science.

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).

Committee for Proprietary Medicinal Products (CPMP) of the EMEA recommends approval of rituximab for patients with Intermediate Grade NHL. 

Rituximab named the number one selling, brand name, cancer therapeutic product in the world (approximately US 1.3 billion). 

Rituximab represents the most important scientific achievement of the past decade. It was the first therapeutic antibody approved for the treatment of cancer and specifically for N H L. The current IWRC for N H L had their origin with the rituximab response criteria. Clinical development was completed in record time. Dossiers were filed simultaneously in the United States and in Europe. The US fihng utilized an electronic format (computer-aided product license application, CAPLA). These and many other achievements during clinical development served to provide tremendous impetus to the monoclonal antibody research area. The renewed enthusiasm in this area has yielded many new Mabs with activity in both hematologic malignancies and in autoimmune diseases. Several of these have been approved (e.g. herceptin, alemtuzumab, mylotarg, others) and many others are under active investigation. 

Reactions following initial infusions of antibody are common, but these can usually be handled by a cautious rate of infusion, appropriate hydration and diuresis, and, if necessary, praned-ication. Twenty six percent of initial reactions are reported to be mild, 48 % moderate, and 26 % severe. The initial infusion reaction to some mAbs, for example, rituximab (see below), may provoke tumor lysis syndrome, cytokine release syndrome, and systemic inflammatory response syndrome. Tumor lysis syndrome, noted particularly with rituximab, can occur following cancer treatment and sometimes without treatment. It is believed to be the result of breakdown products of cancer cells leading to increased levels of some metabolites and reflected in conditions such as hypercalcemia, hyperkalemia, hyperphosphatemia, acute uric acid nephropathy, and acute renal failure. The syndrome can occur in the early stages of mAb therapy and is potentially life-threatening. Cytokine release syndrome, also called cytokine storm, is commonly seen after... 

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