Targeted Monoclonal Antibodies: Anti-HER2 (Trastuzumab and Pertuzumab)

Mechanism

Pharmacological Class and Group

Humanized IgG1 monoclonal antibodies selectively directed against the human epidermal growth factor receptor 2 (HER2/neu / ErbB2).

Mechanism of Action

The HER2 receptor is a transmembrane receptor tyrosine kinase of the ErbB family that lacks a known direct exogenous ligand; It is activated by the formation of homodimers or heterodimers with other ErbB receptors (ErbB1, ErbB3, ErbB4), activating the MAPK and PI3K-Akt-mTOR pathways of mitogenic proliferation and intracellular cell invasion.

Dual Action Mechanism: Blocking Heterodimerization and NK Cell Recruitment

1. Trastuzumab (Domain IV Blocking): It binds selectively and with high affinity to the juxtamembrane extracellular domain IV of the HER2 receptor, blocking the enzymatic cleavage of the extracellular domain (preventing the generation of the active oncogenic fragment p95HER2) and inducing the internalization and lysosomal degradation of the receptor.

2. Pertuzumab (Domain II Blocking): Binds specifically to the extracellular dimerization domain II of HER2. This physically prevents the coupling and formation of HER2 heterodimers with other ErbB receptors, selectively blocking the critical HER2-HER3 coupling:

Pertuzumab HER2-HER3 Dimerization Suppression of MAPK / PI3K-Akt Pathway Signaling

3. Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): The Fc portion of IgG1 antibodies bound to the tumor receptor is specifically recognized by the FcγRIIIa receptor of peripheral natural killer (NK) cells, activating the local release of perforin granules and granzymes that induce tumor cell lysis.

Pharmacokinetics

High Resolution Pharmacokinetics

• Distribution: Reduced peripheral volume of distribution equivalent to the vascular plasma volume, achieving stable concentrations after the loading phase.
• Metabolism: They are not metabolized by cytochrome enzymes of the liver. They undergo non-specific proteolytic catabolic clearance through the reticulocyte mononuclear phagocytic system after their membrane cell internalization.
• Elimination: They are eliminated progressively. It does not require dose adjustment in mild-moderate renal or hepatic failure.
• Half-life (t_1/2): The elimination half-life is long, approximately 18 to 28 days for trastuzumab, facilitating maintenance regimens every 3 weeks. Pertuzumab has a half-life of approximately 18 days.

Indicators and dose

Clinical Indications and Frequent Regimens

• Early and Advanced HER2+ Breast Cancer (Combination Therapy): Trastuzumab + Pertuzumab combined with chemotherapy (Docetaxel) as first line therapy in metastatic disease.
• Metastatic HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma: Trastuzumab combined with platinum-based chemotherapy and fluoropyrimidine.

Dosage and Clinical Adjustment

Trastuzumab IV (Schedule every 3 weeks):

• Initial loading dose of 8 mg/kg IV as a 90-minute infusion; followed by maintenance dose of 6 mg/kg IV as a short 30-minute infusion every 21 days.

Pertuzumab IV:

• Initial loading dose of 840 mg IV as a 60-minute infusion; followed by maintenance dose of 420 mg IV every 21 days.
• LVEF monitoring: If during treatment the LVEF declines by an absolute value of > 10% compared to the baseline value and is below 50%, treatment should be temporarily suspended for 3 weeks, and the control echocardiography should be repeated.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active ingredient or proteins of CHO (Chinese Hamster Ovary) origin.
• Severe underlying cardiac dysfunction (LVEF < 40%).
• Dyspnea at rest of any active clinical origin.

Relative Contraindications

• Basal LVEF borderline between 40-50%.
• Recent or simultaneous previous treatment with anthracyclines (multiplies the risk of cardiotoxicity due to synergism of myocardial damage).

Adverse Effects (ADR) and Specific Toxicity

• Systemic: Mild to moderate infusion reactions (fever, chills, nausea) during the first infusion, preventable or controllable with paracetamol and antihistamines.
• Cardiotoxicity (Type II): Myocardial dysfunction with drop in LVEF with a reversible and non-cumulative course (unlike type I damage from anthracyclines). It is associated with the inhibition of the ErbB2 receptor expressed in cardiomyocytes, which regulates cell survival and repair of the cardiac wall against pressure overload. Requires monitoring with echocardiogram every 3 months.
• Dermatological: Diarrhea and mild-moderate skin rash (common when combining pertuzumab with trastuzumab).

Differentiation of Cardiac Toxicity: Type I (Anthracyclines) vs. Type II (Trastuzumab)

It is a critical concept in medical oncology that differentiates profiles of drug-induced structural myocardial damage:

• Type I Damage (Anthracyclines): Cellular cell death due to apoptosis and myocardial necrosis. It is an irreversible cumulative dose-dependent process. It shows obvious ultrastructural changes in the endomyocardial biopsy.
• Type II Damage (Trastuzumab): Dysfunction of myocardial cellular contractility without structural cell death. It is reversible by temporarily or permanently suspending the molecule and reinstating ACEIs and beta-blockers. It is not cumulative and re-exposure after LVEF recovery is clinically feasible.