Review
Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy

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Abstract

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in vivo. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high affinity VEGF receptors. VEGF plays an essential role in developmental angiogenesis and is important also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. 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. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

Section snippets

Identification of VEGF

In 1983, Senger et al. [9] reported the partial purification from the conditioned medium of a guinea-pig tumor cell line of “vascular permeability factor” (VPF), a protein that induced vascular leakage in the skin. Because VPF was not isolated and sequenced, this factor remained molecularly unknown at that time.

In 1989, our laboratory reported the isolation and NH2-terminal sequencing of VEGF, an endothelial cell-specific mitogen, from medium conditioned by bovine pituitary cells [10]. The

The VEGF isoforms

The human VEGF-A gene is organized in eight exons [14], [15]. Alternative exon splicing results in the generation of four main VEGF isoforms, having, respectively, 121, 165, 189, and 206 amino acids following signal sequence cleavage (VEGF121, VEGF165, VEGF189, and VEGF206) [12]. VEGF165 is the predominant isoform. Numerous less frequent splice variants have been also reported, including VEGF145, VEGF183 VEGF162, and VEGF165b (reviewed in [16]).

Alternative splicing regulates the bioavailability

VEGF receptors

There are two VEGF receptor tyrosine kinases (RTKs), Flt-1, known also as VEGFR-1 [27], [28] and KDR, Flk-1, or VEGFR-2 [29], [30], [31].

There is now agreement that VEGFR-2 is the major mediator of the mitogenic, angiogenic, and permeability-enhancing effects of VEGF. For a detailed review of the biological and signaling properties of the VEGF receptors, see [16].

Under some circumstances, VEGFR-1 may function as a “decoy” receptor that sequesters VEGF and prevents its interaction with VEGFR-2

Regulation of VEGF gene expression

Oxygen tension plays a major role in regulating the expression of a variety of genes, including VEGF, and HIF-1 is a key transcriptional regulator of hypoxic responses [40]. A link between the product of the von Hippel–Lindau (VHL) tumor suppressor gene and HIF-1-dependent responses has been established (for review sees [41]). The VHL gene is inactivated in patients with von Hippel–Lindau disease, an autosomal dominant neoplasia syndrome characterized by capillary hemangioblastomas in retina

Role of VEGF in tumor angiogenesis

In situ hybridization studies demonstrate VEGF mRNA expression in many human tumors. These include lung [50], breast [51], gastrointestinal tract [52], renal [53], and ovarian carcinomas [54]. However, the expression of VEGF appears to be variable, not only among different tumor types, but also within the same tumor (for reviews see [8], [16]). Renal cell carcinomas have a particularly high VEGF expression is renal cell carcinoma, in agreement with the notion that inactivating VHL mutations

Preclinical studies

In 1997, we reported the humanization of the murine anti-VEGF Mab A.4.6.1. [78]. Like its murine counterpart, bevacizumab binds to and neutralizes all human VEGF-A isoforms and bioactive proteolytic fragments, but not mouse or rat VEGF. The binding epitope of bevacizumab has been defined by crystal structure analysis of a complex Fab ligand [79]. The pharmacokinetic properties of bevacizumab in several species have been previously described and are consistent with a typical humanized monoclonal

Ongoing studies and perspectives

For the first-line treatment of metastatic colorectal cancer, the addition of bevacizumab to bolus IFL chemotherapy conferred a clinically meaningful and statistically significant benefit for all study endpoints, including overall survival, progression free survival, and response rate, and was associated with an acceptable side effect profile.

The improvement in survival attributable to bevacizumab is similar or greater than that observed in any Phase III trial for the treatment of colorectal

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