Bevacizumab Explained: Structure, Mechanism Of Action, Clinical Uses, And Side Effects

Bevacizumab Explained: Structure, Mechanism of Action, Clinical Uses, and Side Effects

Introduction

Bevacizumab, marketed primarily under the brand name Avastin®, is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). By blocking angiogenesis—the formation of new blood vessels—Bevacizumab effectively starves tumors of their blood supply, slowing their growth and metastasis.

Initially approved by the U.S. FDA in 2004 for metastatic colorectal cancer, Bevacizumab has since become a cornerstone in the treatment of several solid malignancies and ocular diseases characterized by abnormal neovascularization.

Structure of Bevacizumab

Bevacizumab is a humanized monoclonal IgG1 antibody produced using recombinant DNA technology in Chinese Hamster Ovary (CHO) cells.

Molecular Formula: C6638H10160N1720O2108S44
Molecular Weight: Approximately 149 kDa
Type: Recombinant humanized monoclonal antibody
Target: VEGF-A (Vascular Endothelial Growth Factor-A)

Structural Characteristics

Composed of two identical heavy chains and two identical light chains, typical of IgG1 antibodies.
Human framework regions (~93%) with murine (mouse) complementarity-determining regions (~7%) to maintain specific VEGF binding.
The Fab region binds to VEGF-A, while the Fc region interacts with immune effectors and provides stability and a longer half-life.
It specifically recognizes and binds VEGF-A isoforms (VEGF121, VEGF165, etc.), preventing their interaction with VEGFR-1 and VEGFR-2 receptors on endothelial cells.

Medicinal Chemistry

Bevacizumab belongs to the biologic class of drugs, not small-molecule drugs. Hence, its chemistry involves protein engineering rather than synthetic organic chemistry.

Type: Recombinant humanized monoclonal antibody against VEGF-A.
Source: Human (∼93%) and murine (∼7%) sequences.
Production: Cultured in genetically modified mammalian (CHO) cells.
Formulation: Lyophilized powder or solution for intravenous infusion; ophthalmic preparations are used off-label.

Stability and Storage

Store between 2–8°C, protected from light.
Do not freeze or shake.
Dilution and handling require aseptic conditions to prevent protein denaturation.

Pharmacological Actions

Bevacizumab acts as an anti-angiogenic and antineoplastic agent.

Primary Pharmacological Actions

Anti-angiogenic effect:
By binding VEGF-A, Bevacizumab prevents endothelial cell proliferation, migration, and survival—thereby inhibiting formation of new capillaries essential for tumor growth.
Anti-tumor effect:
Reduced blood vessel formation leads to decreased tumor perfusion, oxygenation, and nutrient supply, slowing tumor growth and metastasis.
Vascular normalization:
It transiently “normalizes” abnormal tumor vasculature, improving the delivery of chemotherapy agents and oxygenation during radiotherapy.
Reduction of vascular permeability:
It decreases vascular leakage, useful in conditions like macular edema and retinopathy.

Mechanism of Action (Detailed)

Normal VEGF Function

VEGF-A is a key mediator of angiogenesis. It binds to VEGF receptors (VEGFR-1 and VEGFR-2) on the surface of endothelial cells, triggering:

Proliferation and migration of endothelial cells
Formation of new capillaries
Increased vascular permeability

Mechanism of Bevacizumab

Bevacizumab binds and neutralizes VEGF-A, preventing its interaction with VEGFR-1 and VEGFR-2.
This results in:

Inhibition of angiogenesis (cutting off tumor blood supply)
Reduced tumor vascular permeability
Slower tumor progression
Enhanced efficacy of cytotoxic chemotherapy due to improved vascular normalization

Thus, Bevacizumab effectively starves tumors and helps stabilize ocular neovascular diseases by limiting aberrant blood vessel formation.

Pharmacokinetics

Parameter	Details
Route of Administration	Intravenous infusion
Absorption	Not applicable (given IV)
Distribution	Volume of distribution ≈ 3 L; confined to plasma and interstitial fluid
Metabolism	Catabolized by proteolytic enzymes into small peptides and amino acids
Elimination Half-life	~20 days (range: 11–50 days)
Excretion	Via reticuloendothelial system; not renally or hepatically cleared
Steady State	Reached after 100 days (approx. 4–5 doses)

Clinical Uses

Bevacizumab has a broad range of oncologic and ophthalmic indications.

1. Oncologic Indications

a. Colorectal Cancer

Use: In combination with fluorouracil-based chemotherapy for metastatic colorectal cancer.
Mechanism: Inhibits angiogenesis in tumor microenvironment.

b. Non-Small Cell Lung Cancer (NSCLC)

Use: First-line treatment with carboplatin and paclitaxel in nonsquamous NSCLC.

c. Renal Cell Carcinoma

Use: Combined with interferon alfa for metastatic RCC.

d. Glioblastoma Multiforme

Use: For recurrent disease as monotherapy.
Effect: Reduces tumor-associated edema and vascular permeability.

e. Ovarian and Cervical Cancer

Use: In combination with paclitaxel and cisplatin or topotecan for persistent, recurrent, or metastatic disease.

2. Ophthalmologic Indications (Off-label)

Although not FDA-approved for ocular use, Bevacizumab is widely used off-label for:

Age-related macular degeneration (AMD)
Diabetic macular edema (DME)
Retinal vein occlusion
Neovascular glaucoma

In these conditions, VEGF overexpression leads to abnormal retinal neovascularization and leakage, causing vision loss.
Bevacizumab helps regress these vessels and reduce macular edema.

Dosage and Administration

General Principles

Administer only as intravenous infusion (not IV bolus).
Dilute in 0.9% sodium chloride.
First infusion over 90 minutes, subsequent ones may be shortened if tolerated.
Continue until disease progression or unacceptable toxicity.

Typical Doses

Indication	Dosage (Adult)	Frequency
Metastatic colorectal cancer	5–10 mg/kg IV	Every 2 weeks
NSCLC (nonsquamous)	15 mg/kg IV	Every 3 weeks
Renal cell carcinoma	10 mg/kg IV	Every 2 weeks
Glioblastoma	10 mg/kg IV	Every 2 weeks
Ovarian/Cervical cancer	15 mg/kg IV	Every 3 weeks
Ophthalmic (off-label)	1.25 mg/0.05 mL (intravitreal)	Every 4–6 weeks

Adverse Effects

Common Side Effects

Hypertension
Headache
Fatigue
Proteinuria
Epistaxis and minor bleeding
Gastrointestinal upset

Serious Adverse Effects

Gastrointestinal perforation
Hemorrhage (including pulmonary or GI bleeding)
Arterial thromboembolism (stroke, myocardial infarction)
Delayed wound healing
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
Nephrotic syndrome (due to glomerular microangiopathy)

Ophthalmic Use Complications

Endophthalmitis
Retinal detachment
Intraocular inflammation

Contraindications

Hypersensitivity to Bevacizumab or any component of the formulation.
Pregnancy (Category C – potential teratogenicity due to VEGF inhibition).
Recent surgery or open wounds (impaired wound healing).
Active bleeding or severe hemorrhage risk.
Uncontrolled hypertension.

Precautions and Warnings

Pregnancy & Lactation: Avoid; may cause fetal harm.
Surgery: Withhold at least 28 days before and after surgery.
Hypertension: Monitor blood pressure regularly.
Proteinuria: Regular urine protein checks required.
Cardiac toxicity: Caution with prior anthracycline therapy.

Drug Interactions

No major CYP450-mediated interactions.
Additive toxicity possible with:
- Cytotoxic chemotherapy (increased risk of bleeding and perforation)
- Antiplatelets/anticoagulants (risk of hemorrhage)
- Radiotherapy (delayed wound healing)

Clinical Trials and Efficacy

Bevacizumab’s efficacy has been demonstrated in several landmark trials:

Trial	Cancer Type	Key Findings
AVF2107g	Colorectal cancer	Improved median survival by ~4.7 months with Bevacizumab + FOLFOX
E4599	NSCLC	Significant improvement in overall survival
AVAglio	Glioblastoma	Prolonged progression-free survival

Pharmacovigilance and Monitoring

Parameters to monitor:

Blood pressure (before each dose)
Urine protein (dipstick or 24-hour protein)
Signs of bleeding or perforation
Neurological symptoms (for RPLS)
Wound healing status

Biosimilars

Several Bevacizumab biosimilars are now available globally, enhancing accessibility:

Mvasi® (Amgen)
Zirabev® (Pfizer)
Abevmy® (Biocon/Viatris)
Bevacirel®, Bevatas® (India)

These are approved based on equivalence in efficacy, safety, and immunogenicity compared to the reference product.

Conclusion

Bevacizumab remains a landmark in targeted cancer therapy, offering survival benefits across multiple malignancies through VEGF inhibition. Its evolving role in ophthalmology further emphasizes the therapeutic potential of anti-angiogenic strategies.
However, the drug demands careful patient selection and vigilant monitoring due to risks of hypertension, bleeding, and wound healing complications.
As biosimilars emerge, the accessibility of this life-saving biologic continues to expand globally.

Frequently Asked Questions (FAQs)

1. What is the primary mechanism of action of Bevacizumab?

Bevacizumab binds to VEGF-A, preventing it from activating VEGF receptors on endothelial cells. This inhibits angiogenesis, cutting off the tumor’s blood supply.

2. Can Bevacizumab be used for eye disorders?

Yes. Although not officially approved for ophthalmic use, it is widely used off-label for age-related macular degeneration and diabetic macular edema.

3. What are the main side effects of Bevacizumab?

Common side effects include hypertension, proteinuria, fatigue, and bleeding. Serious risks include GI perforation, thromboembolic events, and impaired wound healing.

4. Why should Bevacizumab be avoided before surgery?

Because it inhibits new blood vessel formation, it can impair wound healing. Hence, it should be withheld at least 4 weeks before and after surgery.

5. Are Bevacizumab biosimilars as effective as the original Avastin?

Yes. Approved biosimilars such as Mvasi® and Zirabev® have demonstrated comparable efficacy, safety, and pharmacokinetic profiles.

Bevacizumab Explained: Structure, Mechanism of Action, Clinical Uses, and Side Effects