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Sunday, August 10, 2025

CD33 monoclonal antibodies


1. Introduction

  • CD33 monoclonal antibodies are targeted biologic agents that bind to the CD33 antigen on myeloid cells.

  • Primarily used in the treatment of acute myeloid leukemia (AML) and other CD33-positive hematologic malignancies.

  • Can be “naked” antibodies or conjugated with cytotoxic payloads (antibody–drug conjugates).

  • The most notable approved CD33-targeted therapy is gemtuzumab ozogamicin.

2. Target: CD33 Antigen

  • CD33 (Siglec-3) is a transmembrane glycoprotein and member of the sialic acid–binding immunoglobulin-like lectin family.

  • Expressed on:

    • Myeloid progenitor cells.

    • Mature myeloid cells (monocytes, granulocytes).

    • Myeloid leukemia blasts in ~85–90% of AML patients.

  • Not expressed on normal hematopoietic stem cells or non-hematopoietic tissues, allowing targeted therapy without permanent stem cell depletion.

  • Acts as an inhibitory receptor modulating myeloid cell function via immunoreceptor tyrosine-based inhibitory motifs (ITIMs).

3. Mechanism of Action

Unconjugated antibodies (experimental forms)

  • Bind to CD33, block signaling pathways, and induce immune-mediated killing through:

    • Antibody-dependent cellular cytotoxicity (ADCC).

    • Complement-dependent cytotoxicity (CDC).

    • Antibody-dependent cellular phagocytosis (ADCP).

Antibody–drug conjugates (e.g., gemtuzumab ozogamicin)

  • Antibody binds CD33 on leukemia cells and is internalized.

  • Cytotoxic payload (calicheamicin derivative) is released inside the cell.

  • Calicheamicin binds DNA, causing double-strand breaks and apoptosis.

4. Approved Agent: Gemtuzumab Ozogamicin

  • Structure: humanized IgG4 anti-CD33 monoclonal antibody linked to N-acetyl-gamma-calicheamicin dimethyl hydrazide.

  • Indications:

    • Newly diagnosed CD33-positive AML in adults and pediatric patients ≥1 month (in combination with chemotherapy).

    • Relapsed/refractory CD33-positive AML as monotherapy.

  • Formulation: intravenous infusion after dilution.

5. Pharmacokinetics (Gemtuzumab Ozogamicin)

  • Administration: IV infusion over 2 hours; not given as a rapid bolus.

  • Distribution: primarily intravascular; target-mediated distribution to CD33-positive cells.

  • Metabolism: proteolytic degradation of antibody component; payload metabolized to inactive products.

  • Elimination half-life: prolonged with repeated doses as circulating blasts decrease.

6. Dosing Regimens (Examples)

  • Newly diagnosed AML (adults): fractionated dosing on days 1, 4, and 7 in combination with daunorubicin and cytarabine (“7+3” regimen).

  • Monotherapy: single agent dosing schedules vary for relapsed AML.

  • Pediatrics: similar fractionated dosing adjusted for body surface area.

7. Adverse Effects

Infusion-related reactions

  • Fever, chills, hypotension, tachycardia, dyspnea, rash.

Hematologic toxicity

  • Severe myelosuppression (neutropenia, thrombocytopenia, anemia).

  • Prolonged cytopenias may occur.

Hepatic toxicity

  • Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome, especially after hematopoietic stem cell transplantation or high cumulative doses.

Other common effects

  • Nausea, vomiting, mucositis, headache, infection risk, fatigue.

8. Contraindications and Precautions

  • Hypersensitivity to the drug or formulation components.

  • Active uncontrolled infection.

  • Preexisting significant hepatic impairment (use with caution).

  • Pregnancy: risk of fetal harm; contraception required during and after treatment.

  • Avoid use with other hepatotoxic agents if possible to reduce VOD risk.

9. Drug Interactions

  • No major CYP450 interactions (monoclonal antibodies are not metabolized by hepatic enzymes).

  • Increased risk of hepatotoxicity with other hepatotoxic drugs.

  • Increased infection risk with concomitant immunosuppressants.

10. Monitoring Requirements

  • Before and during therapy:

    • Complete blood count with differential.

    • Liver function tests, bilirubin, coagulation profile.

  • During infusion: monitor for infusion-related reactions; have emergency medications available.

  • Post-therapy: monitor for signs of VOD, particularly after transplant.

11. Advantages and Limitations

Advantages

  • Targets a widely expressed antigen in AML blasts.

  • Sparing of hematopoietic stem cells allows marrow recovery after treatment.

  • Can be used in combination or as monotherapy.

Limitations

  • Risk of severe hepatotoxicity and myelosuppression.

  • Not effective in CD33-negative AML.

  • Resistance may occur through downregulation of CD33 or drug efflux mechanisms.




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