CD30 monoclonal antibodies

1. Introduction

• CD30 monoclonal antibodies are targeted therapies that recognize and bind to the CD30 antigen.

• CD30 is a tumor necrosis factor receptor (TNFR) superfamily member expressed on certain malignant and activated lymphocytes.

• These antibodies are particularly important in the treatment of Hodgkin lymphoma (HL) and certain T-cell lymphomas.

• The most widely used CD30-directed therapy is brentuximab vedotin, an antibody–drug conjugate (ADC).

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2. Target: CD30 Antigen

• CD30 is a transmembrane glycoprotein with an extracellular ligand-binding domain and an intracellular signaling domain.

• Expression profile:

  • Normally present on a subset of activated B and T cells.

  • Highly expressed on Reed–Sternberg cells in classical Hodgkin lymphoma.

  • Overexpressed in systemic anaplastic large cell lymphoma (ALCL) and some cutaneous T-cell lymphomas (CTCL).

• Physiological role:

  • Participates in lymphocyte activation and regulation of apoptosis.

  • In malignancies, its overexpression contributes to tumor cell survival and proliferation.

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3. Mechanism of Action of CD30 Monoclonal Antibodies

Naked monoclonal antibodies (experimental forms)

• Bind to CD30 and trigger:

  • Antibody-dependent cellular cytotoxicity (ADCC).

  • Complement-dependent cytotoxicity (CDC).

  • Direct induction of apoptosis.

Antibody–drug conjugates (ADC)

• Example: brentuximab vedotin.

• Consists of an anti-CD30 monoclonal antibody linked to a cytotoxic agent (monomethyl auristatin E, MMAE).

• Mechanism:

  • Antibody binds CD30 on tumor cells.

  • Complex internalized and trafficked to lysosomes.

  • MMAE released inside cell, disrupting microtubules and inducing cell cycle arrest and apoptosis.

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4. Approved Agent: Brentuximab Vedotin

• Structure: Chimeric IgG1 anti-CD30 monoclonal antibody + MMAE via protease-cleavable linker.

• Indications:

  • Classical Hodgkin lymphoma (CHL):

    • After failure of autologous stem cell transplant (ASCT) or ≥2 prior chemotherapy regimens.

    • As consolidation post-ASCT in high-risk patients.

    • In combination with chemotherapy for untreated stage III/IV CHL.

  • Systemic anaplastic large cell lymphoma (sALCL) after prior therapy failure.

  • Primary cutaneous ALCL and CD30-expressing mycosis fungoides after prior systemic therapy.

  • Certain relapsed or refractory CD30-expressing lymphomas.

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5. Pharmacokinetics (Brentuximab Vedotin)

• Administration: Intravenous infusion, not bolus.

• Distribution: Primarily intravascular; binds CD30-positive cells.

• Metabolism:

  • Antibody degraded to peptides/amino acids.

  • MMAE metabolized via CYP3A4/5.

• Elimination half-life: ~4–6 days for antibody component; MMAE ~3–4 days.

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6. Dosing and Administration

• Typical dose: 1.8 mg/kg IV every 3 weeks (maximum 180 mg) for most indications.

• Lower dose (1.2 mg/kg) in combination regimens.

• Dose adjustments required for toxicity or certain comorbidities.

• Pre-medication generally not required unless prior infusion reactions occurred.

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7. Adverse Effects

Common

• Peripheral neuropathy (sensory > motor).

• Fatigue, nausea, vomiting, diarrhea.

• Pyrexia, rash, pruritus.

• Neutropenia, anemia, thrombocytopenia.

Serious

• Progressive multifocal leukoencephalopathy (PML).

• Severe infusion reactions.

• Tumor lysis syndrome in patients with high tumor burden.

• Pulmonary toxicity (rare but reported).

• Severe skin reactions (e.g., Stevens–Johnson syndrome, toxic epidermal necrolysis).

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8. Contraindications and Precautions

• Known hypersensitivity to brentuximab vedotin or its components.

• Concurrent use with bleomycin: increases pulmonary toxicity risk.

• Pregnancy: potential for fetal harm; contraception required during and after treatment.

• Lactation: breastfeeding not recommended during therapy.

• Use caution in patients with preexisting neuropathy or hepatic/renal impairment.

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9. Drug Interactions

• CYP3A4/5 inhibitors: may increase MMAE exposure (e.g., ketoconazole).

• CYP3A4 inducers: may decrease MMAE exposure (e.g., rifampin).

• Co-administration with other neurotoxic drugs may increase neuropathy risk.

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10. Monitoring Requirements

• Baseline and periodic complete blood counts.

• Monitor for peripheral neuropathy signs/symptoms.

• Monitor for infusion-related reactions during administration.

• Assess for infections and opportunistic pathogens.

• Neurologic monitoring for signs of PML.

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11. Advantages and Limitations

Advantages

• Highly targeted therapy for CD30-expressing malignancies.

• Multiple mechanisms of tumor cell killing via ADC design.

• Can be combined with chemotherapy or used as monotherapy.

Limitations

• Risk of significant neuropathy, especially with prolonged use.

• Myelosuppression and infection risk.

• High cost and requirement for IV administration in specialized settings.