In 1997, the humanization of the murine anti-VEGF mAb was reported. Like its murine counterpart, bevacizumab binds to and neutralizes all human VEGF-A isoforms and bioactive proteolytic fragments, but not mouse or rat VEGF. However, bevacizumab was observed to inhibit the growth of human tumor cell lines in nude mice.
Studies have demonstrated that bevacizumab, in combination with chemotherapy, resulted in increased survival in patients with previously untreated metastatic colorectal cancer relative to chemotherapy alone, leading to FDA approval of the first anti-angiogenic agent. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. The pharmacokinetic properties of bevacizumab in several species have been previously described and are consistent with a typical humanized monoclonal antibody. In 1997, Phase I clinical trials with bevacizumab was initiated. These Phase I studies showed that the antibody as a single agent was relatively non-toxic and that adding it to standard chemotherapy regimens did not significantly exacerbate chemotherapy associated toxicities.
In 1998, several Phase II studies were initiated with bevacizumab in different tumor types, either as a single agent or in combination with chemotherapy. bevacizumab was combined with Standard first-line chemotherapy in metastatic colorectal cancer and stage IIIb/IV non-small cell lung cancer. The potential clinical utility of VEGF inhibition in oncology is not limited to solid tumors. There is growing evidence that VEGF and VEGF receptors are expressed by a variety of leukemias and other hematologic malignancies, suggesting that inhibition of VEGF or VEGFR signaling may have a role in the treatment of such conditions. Several clinical trials are currently testing these hypotheses. Although bevacizumab was generally well tolerated, but some serious and unusual toxicities were noted. Some open-label Phase I and II clinical trials had identified a number of adverse events, including thrombosis and bleeding as potential bevacizumab-related toxicities. In addition, most common adverse reactions are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.