Bevacizumab Anticancer [1822

Country of Origin:

US

Originator:

Genentech

First Introduction:

US

Introduced by:

Genentech/Roche

Trade Name:

Avastin

CAS Registry No:

216974-75-3

Class:

Recombinant humanized antibody

Type:

IgGl monoclonal anti-VEGF

Molecular Weight:

149 kDa

Expression system:

CHO cell line

Manufacturer:

Genentech

Bevacizumab, a humanized IgGl monoclonal antibody against vascular endothelial growth factor (VEGF), inhibits tumor angiogenesis and delays disease progression. It was launched in the US last year as an intravenous infusion for the treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy. Bevacizumab was developed by engineering the VEGF binding residues of the murine neutralizing antibody A.4.6.1 into the framework of the consensus human IgGl. Its amino acid sequence is approximately 93% human IgG and 7% murine antibody and is produced in a CHO cell expression system. Bevacizumab binds VEGF with high affinity (Kd = 0.5 nM) and prevents its interaction with tyrosine kinase receptors VEGFR1 and VEGFR2 on the surface of endothelial cells, thereby inhibiting cell proliferation and microvascular growth. In mouse models, administration of bevacizumab blocked the growth of human tumor xenografts and reduced the size and number of metastases. The recommended dosage of be-vacizumab is 5 mg/kg administered once every 2 weeks as an intravenous infusion until disease progression is detected. Based on a population pharmacokinetic analysis of patients who received 1-20mg/kg of bevacizumab once every 1-3 weeks, the estimated half-life was approximately 20 days, and the predicted time to reach steady state was 100 days. The maximum and minimum steady-state serum concentrations at 2.5mg/kg/week dose were 226 and 88 mg/mL, respectively. Clearance of bevacizumab is low, and varies with body weight, gender and tumor burden. In patients with colorectal cancer receiving bevacizumab 5-10mg/kg in combination with fluorouracil and leucovorin, mean total clearance was 2.79ml/kg/day. In clinical studies involving the administration of bevacizumab (5 mg/kg every 2 weeks) or placebo in addition to bolus-IFL (irinotecan 125mg/m2 i.v., 5-fluorouracil 500mg/ m2i.v. , and leucovorin 20mg/m i.v. administered once weekly for four weeks every six weeks), the median overall survival was significantly increased from 15.6 months in the bolus IFL + placebo arm to 20.3 months in the bolus IFL + bevacizumab arm. Similar increases were also seen in progression-free survival (6.4 versus 10.6 months), overall response rate (35% versus 45%), and duration of response (7.1 months versus 10.4 months). The most common adverse events in these trials were hypertension, diarrhea and leucopenia. Other clinically significant adverse events reported occasionally were gastrointestinal perforations, thromboembolic events, bleeding and proteinuria. Because wound healing may be impaired by inhibition of VEGF, bevacizumab therapy is not recommended until 28 days after primary surgery.

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