Monoclonal Antibody-Mediated Chemotherapy

Aka: Monoclonal Antibody-Mediated Chemotherapy, Monoclonal Antibody Immunoconjugate Therapy, Pertuzamab, Perjeta, Ibritumomab tiuxetan, Zevalin, Rituximab, Rituxan, Tositumomab, Bexxar, Alemtuzumab, Campath, Gemtuzumab ozogamacin, Mylotarg, Cetuximab, Erbitux, Panitumumab, Vectibix, Bevacizumab, Avastin, Trastuzumab, Herceptin, Pertuzamab, Perjeta

1. See Also
   1. Immune Checkpoint Inhibitor
   2. Targeted Cancer Therapy
   3. Immune Checkpoint Inhibitor
   4. CAR T-Cell Therapy
   5. Small Molecule Inhibitor-Mediated Chemotherapy
   6. Chemotherapy
   7. Monoclonal Antibody
2. 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
3. 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
4. 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. Long half-lives of days to weeks
5. Adverse Effects: EGFR Inhibitors
   1. Adverse effects related to EGFR targeted on cancer cells, but also present in skin and GI tract
   2. Dermatitis often is an indicator that the EGFR inhibitor is working
   3. Diarrhea occurs in 50% of patients on EGFR inhibitors
6. Adverse Effects: VEGF inhibitors which inhibit Angiogenesis (e.g. Avastin)
   1. Adverse effects are vascular related
   2. Bleeding
   3. Thrombosis
   4. Hypertension
7. Disadvantages
   1. Very expensive (typically upwards of $10,000 per course)
8. Preparations: Antigen Targets
   1. Target: Cell Surface Markers (CD20)
      1. Ibritumomab tiuxetan (Zevalin): Used Non-Hodgkin's Lymphoma
      2. Rituximab (Rituxan): Used in Non-Hodgkin's Lymphoma and Rheumatoid Arthritis
      3. Tositumomab (Bexxar): Used in Non-Hodgkin's Lymphoma
   2. Target: Cell Surface Markers (CD52)
      1. Alemtuzumab (Campath): Used in CLL
   3. Target: Cell Surface Markers (CD33)
      1. Gemtuzumab ozogamacin (Mylotarg): Used in AML
   4. Target: Epidermal Growth Factor Receptor (EGFR, HER1)
      1. Cetuximab (Erbitux): Used in Colon Cancer and head and neck tumors
      2. Panitumumab (Vectibix): Used in Colon Cancer
      3. EGFR agents have been effective in metastatic Colorectal Cancer (without RAS mutation)
      4. Adverse effects include acne, Hypomagnesemia
   5. Target: Vascular Endothelial Growth Factor (VEGF)
      1. Bevacizumab (Avastin): Used in Colon Cancer and Non-Small Cell Lung Cancer
   6. Target: HER2-neu
      1. Trastuzumab (Herceptin): Used in Breast Cancer (where HER2-neu is overexpressed)
         1. Trastuzumab has been very effective in HER2 positive Breast Cancer
      2. Pertuzamab (Perjeta)
      3. Adverse effects include cardiotoxicity, Diarrhea
9. Preparations: Immune Checkpoint Inhibitor
   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)
10. References
    1. Adams (2005) Nat Biotechnol 23:1147-57 [PubMed]
    2. Smith (2021) Am Fam Physician 103(3): 155-63 [PubMed]