Monoclonal Antibody-Mediated Chemotherapy

Aka: Monoclonal Antibody-Mediated Chemotherapy, Monoclonal Antibody Immunoconjugate Therapy

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II. History

  1. Initially targeted to CD20 on immune cells to treat Lymphoma and Leukemia
  2. Lead to immunosuppressive use in Autoimmune Conditions such as Rheumatoid Arthritis

III. Mechanism

  1. Targeted to solid tumors (e.g. Breast Cancer, Lung Cancer and Colon Cancer)
  2. Bind extracellular Ligands and receptor binding sites
  3. Monoclonal antibodies act at targeted cells via oncogene downregulation or tumor cell flagging for destruction

IV. Pharmacokinetics

  1. Large molecules (150,000 Da)
  2. Water-soluble
  3. Proteins are denatured by intestinal acids (therefore must be used intravenously)
  4. No hepatic metabolism (therefore no significant Drug Interactions)
  5. Antibodies have long half-lives of days to weeks

V. Disadvantages

  1. Very expensive (typically upwards of $10,000 per course)

VI. Medications: Surface Antigen Targets

  1. General
    1. Monoclonal Antibody targets are specific cell surface receptors
  2. Target: CD20
    1. See CD20 Monoclonal Antibody
    2. Rituximab (Rituxan): Used in Non-Hodgkin's Lymphoma and Rheumatoid Arthritis
    3. Ibritumomab tiuxetan (Zevalin): Used Non-Hodgkin's Lymphoma
    4. Tositumomab (Bexxar): Used in Non-Hodgkin's Lymphoma
  3. Target: CD22
    1. See CD22 Monoclonal Antibody
    2. CD22 is a B Cell lectin and adhesion molecule
      1. CD22 is involved in cell signaling and adhesion to Monocytes and T-Cells
    3. Moxetumomab pasudotox-tdfk (Lumoxiti)
      1. Conjugated Monoclonal Antibody that delivers the cytotoxic drug Pseudomonas exotoxin A to cancer cells
      2. Used in Hairy Cell Leukemia
      3. Risks of Hemolytic Uremic Syndrome, capillary leak syndrome, renal toxicity, Electrolyte abnormalities
    4. Inotuzumab Ozogamicin (Besponsa)
      1. Conjugated Monoclonal Antibody that delivers the cytotoxic drug calicheamicin to cancer cells
      2. Used against B Cell precursors in Acute Lymphoblastic Leukemia
      3. Risks of hepatotoxicity and veno-occlusive disease
  4. Target: CD30
    1. See CD30 Monoclonal Antibody
    2. CD30 is a Tumor Necrosis Factor (TNF) receptor found on the surface of White Blood Cells
      1. CD30 is overexpressed in hematopoietic malignancies
    3. Brentuximab vedotin (Adcetris)
      1. Conjugated Monoclonal Antibody that delivers the cytotoxic drug monomethyl auristatin E (MMAE) to cancer cells
      2. Used in Hodgkins Lymphoma
  5. Target: CD33
    1. See CD33 Monoclonal Antibody
    2. CD33 is a small Protein on the surface of myeloid cells and Monocyte-Macrophage precursors
      1. CD33 interacts with SHP-1 and SHP-2 Protein kinases for intracellular signaling
    3. Gemtuzumab ozogamacin (Mylotarg)
      1. Conjugated Monoclonal Antibody that delivers the cytotoxic drug calicheamicin to cancer cells
      2. Used in Acute Myelogenous Leukemia (AML)
  6. Target: CD38
    1. See CD38 Monoclonal Antibody
    2. Daratumumab (Darzalex)
  7. Target: CD52
    1. See CD52 Monoclonal Antibody
    2. Alemtuzumab: Restricted use for CLL (Campath) and Multiple Sclerosis (Lemtrada)
  8. Target: CCR4
    1. See CCR4 Monoclonal Antibody
    2. CCR4 is a cell surface receptor that binds Cytokines (CCL2, CCL4, CCL5, CCL17 and CCL22)
      1. CCR4 binding by Cytokine triggers chemotaxis of inflammatory cells (e.g. Natural Killer Cells)
    3. Mogamulizumab-kpkc (Poteligeo): Used in Cutaneous T Cell Lymphoma
  9. Target: GD2
    1. See GD2 Monoclonal Antibody
    2. GD2 is the cell surface receptor Glycolipid disialoganglioside
    3. Dinutuximab (Unituxin): Used in Neuroblastoma

VII. Medications: Tyrosine Kinase Targets

  1. See Tyrosine Kinase
  2. See Small Molecule Inhibitor-Mediated Chemotherapy
  3. Target: Epidermal Growth Factor Receptor (EGFR, HER1)
    1. See EGFR Monoclonal Antibody
    2. See EGFR Inhibitor
    3. Cetuximab (Erbitux): Used in Colon Cancer and head and neck tumors
    4. Panitumumab (Vectibix): Used in Colon Cancer
    5. EGFR agents have been effective in metastatic Colorectal Cancer (without RAS mutation)
    6. Adverse effects related to EGFR targeted on cancer cells, but also present in skin and GI Tract
      1. Adverse effects include acne, Hypomagnesemia
      2. Dermatitis often is an indicator that the EGFR Inhibitor is working
      3. Diarrhea occurs in 50% of patients on EGFR Inhibitors
  4. Target: Vascular Endothelial Growth Factor (VEGF)
    1. See VEGFR Monoclonal Antibody
    2. See VEGFR Inhibitor
    3. VEGF Inhibitors suppress Angiogenesis (e.g. Avastin)
    4. Adverse effects include Bleeding, Thrombosis and Hypertension
    5. Bevacizumab (Avastin): Used in Colon Cancer and Non-Small Cell Lung Cancer
    6. Ramucirumab (Cyramza): Used in Colon Cancer, Hepatocellular Carcinoma and Gastric Cancer
  5. Target: HER2-neu
    1. See Anti-HER2 Monoclonal Antibody
    2. Adverse effects include cardiotoxicity, Diarrhea
    3. Pertuzamab (Perjeta)
    4. Trastuzumab (Herceptin): Used in Breast Cancer (where HER2-neu is overexpressed)
      1. Trastuzumab has been very effective in HER2 positive Breast Cancer
    5. Ado-Trastuzumab Emtansine (Kadcyla)
      1. Trastuzumab is conjugated to the cytotoxic agent emtansine (DM1), a microtubule inhibitor
      2. Delivers cytotoxic DM1 to HER2 positive cells (e.g. Breast Cancer)
      3. Risk of Trastuzumab adverse effects, as well as hepatotoxicity, bleeding

VIII. Medications: Immune Checkpoint Inhibitors

  1. See Immune Checkpoint Inhibitor
  2. Target: Cytotoxic T Lymphocyte associated-4 (CTLA-4)
    1. Ipilimumab (Yervoy)
  3. Target: Programmed Cell Death Protein 1 (PD-1)
    1. Pembrolizumab (Keytruda)
    2. Nivolumab (Opdivo)
  4. Target: Programmed death Ligand-1 (PDL-1)
    1. Atezolizumab (Tecentriq)
    2. Avelumab (Bavencio)
    3. Durvalumab (Imfinzi)

IX. References

  1. Olson (2020) Clinical Pharmacology, Medmaster, Miami, Fl, p. 131-5
  2. Adams (2005) Nat Biotechnol 23:1147-57 [PubMed]
  3. Smith (2021) Am Fam Physician 103(3): 155-63 [PubMed]

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