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Sunday, August 10, 2025

CD38 monoclonal antibodies


1. Introduction

  • CD38 monoclonal antibodies are targeted biologic therapies designed to bind the CD38 glycoprotein on cell surfaces.

  • Primarily used in the management of multiple myeloma and certain other hematologic malignancies.

  • Represent an important advance in immunotherapy by exploiting direct cytotoxicity and immune-mediated mechanisms to eliminate malignant cells.

2. Target: CD38 Antigen

  • CD38 is a type II transmembrane glycoprotein with enzymatic and receptor functions.

  • Widely expressed on plasma cells, activated B cells, activated T cells, NK cells, monocytes, and some non-hematopoietic tissues.

  • Highly expressed on malignant plasma cells in multiple myeloma, making it an ideal therapeutic target.

  • Functions:

    • Enzymatic activity in cyclic ADP-ribose metabolism (calcium signaling).

    • Cell adhesion and receptor-mediated signaling.

3. Mechanism of Action of CD38 Monoclonal Antibodies

  • Bind specifically to CD38 on the surface of malignant cells.

  • Trigger cell death through multiple mechanisms:

    • Antibody-dependent cellular cytotoxicity (ADCC): recruits NK cells and macrophages to destroy targeted cells.

    • Complement-dependent cytotoxicity (CDC): activates complement cascade leading to cell lysis.

    • Antibody-dependent cellular phagocytosis (ADCP): macrophage-mediated ingestion of opsonized tumor cells.

    • Direct apoptosis: receptor cross-linking can induce programmed cell death.

    • Modulation of enzymatic activity: may affect the tumor microenvironment and immune function.

4. Approved Agents

Daratumumab

  • First anti-CD38 monoclonal antibody approved for multiple myeloma.

  • Available as intravenous infusion and subcutaneous injection.

  • Used alone or in combination with other myeloma regimens.

Isatuximab

  • Targets a different epitope of CD38 than daratumumab.

  • Administered intravenously, typically with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma.

MOR202 (Felzartamab) – investigational/limited access

  • Being studied for multiple myeloma and autoimmune diseases.

5. Pharmacokinetics

  • Administration: IV infusion or subcutaneous injection (daratumumab).

  • Distribution: primarily in vascular and interstitial spaces.

  • Metabolism: degraded into peptides and amino acids via normal protein catabolism.

  • Half-life: increases with repeated dosing due to target-mediated clearance reduction.

6. Clinical Indications

Multiple Myeloma

  • Relapsed/refractory disease as monotherapy or in combination with proteasome inhibitors, immunomodulatory drugs, and corticosteroids.

  • Newly diagnosed transplant-ineligible patients in combination with standard regimens.

Other Investigational Uses

  • AL amyloidosis (daratumumab).

  • Some autoimmune diseases (systemic lupus erythematosus, membranous nephropathy) under study.

7. Dosing and Administration (Examples)

Daratumumab (IV)

  • Initial weekly dosing for several weeks, then reduced frequency (every 2 weeks, then every 4 weeks).

  • Pre-medication with corticosteroids, antihistamines, and antipyretics to reduce infusion reactions.

Daratumumab (Subcutaneous)

  • Fixed dose with shorter administration time.

  • Lower risk of infusion-related reactions compared to IV route.

Isatuximab

  • Usually given weekly in cycle 1, then every 2 weeks.

  • Similar pre-medication requirements to daratumumab.

8. Adverse Effects

Infusion-related Reactions (most common early)

  • Cough, nasal congestion, throat irritation, chills, nausea, rash, dyspnea.

  • More frequent with first infusion; reduced with subsequent doses and subcutaneous administration.

Hematologic

  • Neutropenia, anemia, thrombocytopenia.

Infections

  • Upper respiratory tract infections, pneumonia, herpes zoster reactivation.

Other

  • Fatigue, diarrhea, constipation, back pain, edema.

  • Rare: severe hypersensitivity reactions, bronchospasm, hypotension.

9. Contraindications and Precautions

  • Known severe hypersensitivity to the active drug or excipients.

  • Pregnancy: potential for fetal harm; effective contraception recommended during and after therapy.

  • Lactation: avoid breastfeeding during and for a period after treatment.

  • Blood transfusion interference: daratumumab can interfere with indirect antiglobulin test (Coombs test); blood banks must be informed before transfusion.

10. Drug Interactions

  • No significant CYP450 interactions (monoclonal antibodies are not metabolized via hepatic enzymes).

  • Concomitant immunosuppressants may increase infection risk.

  • Vaccinations: live vaccines should be avoided during and for several months after treatment.

11. Monitoring

  • Baseline and periodic complete blood counts.

  • Monitor for infusion-related reactions during and after administration.

  • Screen for infections and provide prophylaxis where appropriate (e.g., antivirals for herpes zoster).

  • Coordination with blood bank services for transfusion compatibility testing.

12. Advantages and Limitations

Advantages

  • High specificity for malignant plasma cells with limited off-target effects.

  • Multiple mechanisms of action against tumor cells.

  • Can be combined with many standard myeloma regimens for enhanced efficacy.

Limitations

  • Infusion reactions, especially early in treatment.

  • Risk of myelosuppression and infection.

  • Need for prolonged administration and monitoring.

  • Resistance can develop over time through antigen modulation or microenvironment changes.




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