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Monoclonal antibodies in cancer therapy

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Various monoclonal antibodies in cancer therapy, its mechanisms and adverse reactions.

Veröffentlicht in: Gesundheit & Medizin
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Monoclonal antibodies in cancer therapy

  2. 2. Introduction Monoclonal Antibodies that are identical because they were produced by one type of immune cell (B cell), all clones of a single parent cell. It specifically bind to target cell and stimulate the patient's immune system to attack those cells. It is possible to create a MAb specific to almost any extracellular/ cell surface target.
  3. 3. When monoclonal antibodies enter the body and attach to cancer cells, they function in several different ways: They can trigger the immune system to attack and kill that cancer cell.  Second, they can block the growth signals.  Third, they can prevent the formation of new blood vessels.
  4. 4. Types of Monoclonal Antibodies
  5. 5. Mechanism of antitumor effect Antibody dependent cellular cytotoxicity (ADCC). Complement dependent cytotoxicity (CDC). Direct induction of apoptosis. MAb may be conjugated with a toxin e.g. gemtuzumab-ozogamicin. MAb can also be conjugated with radioisotope.
  6. 6. MAb act directly when binding to a cancer specific antigens and induce immunological response to cancer cells. Such as Inducing cancer cell apoptosis Inhibiting growth. Interfering with a key function. MAb was modified for delivery of a toxin, radioisotope, cytokine or other active conjugates. It is also possible to design bispecific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effector cell.
  7. 7. ADEPT (Antibody Directed Enzyme Prodrug Therapy) Involves the application of cancer associated monoclonal antibodies which are linked to a drug-activating enzyme. Subsequent systemic administration of a non-toxic agent results in its conversion to a toxic drug, and resulting in a cytotoxic effect which can be targeted at malignant cells. ADEPT is a system that aims to restrict the action of a high concentration of a cytotoxic drug to cancer sites. This is achieved by using an antibody (or antibody fragment) to deliver a non-human enzyme to cancer sites.
  8. 8. Immunoliposomes Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies. When conjugated with antibodies as targeting ligands, immunoliposomes can target tumor cells with high specificity and affinity, resulting in significantly improved antitumor activity over untargeted liposomes. Antitumor activity could be further enhanced for liposomes through ligand-mediated targeting. For liposomes, the ligands would promote the selective binding and facilitate the intracellular delivery. The most commonly used ligands include MAbs or antibody fragments.
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  10. 10. Antibody Inhibitors of EGFRs Cetuximab, Panitumumab, Necitumumab It prevents ligand-dependent signaling and receptor dimerization, thereby blocking cell growth and survival signals. Its used in metastatic colon cancer, HNSCC. ADR:- Acneiform rash, pruritis, headache, nail changes and less commonly diarrhoea. Rare ADR : infusion reaction, cardiopulmonary arrest, hypomagnesemia.
  11. 11. HER2/Neu Inhibitors Trastuzumab, Pertuzumab Trastuzumab is a humanized IgG1 monoclonal antibody that binds to the extracellular domain IV of HER2, inhibiting hetero-and homodimerization and signal transduction. Binding of trastuzumab to HER2 overexpressing cells can induce antibody-dependent, immune cell–mediated cytotoxicity. Use:- HER2-overexpressing breast and gastric cancer. ADR:- Congestive heart failure, ↑ to 20% in combination with doxorubicin due to cardiotoxicity, monitor LVEF during and after ,Acute infusion reaction, nausea, dyspnea, rashes. Trastuzumab ×
  12. 12. Inhibitors of Platelet-Derived Growth Factor Receptor (PDGFR) Olaratumab  Olaratumab is a human IgG1 monoclonal antibody that binds to PDGFRα and blocks ligand-mediated receptor activation.  Use:-Soft-tissue sarcoma in combination with doxorubicin.  ADR:-Nausea, fatigue, GI-toxicity, Neutropenia, thrombocytopenia, elevated aPTT, hypokalemia, hypophosphatemia.
  13. 13. Inhibition VEGF and the VEGFR Pathway Bevacizumab, Ranibizumab  It is a humanized monoclonal IgG1 antibody that binds to VEGF. Prevents the interaction of VEGF with its receptors on the surface of endothelial cells and inhibits receptor signaling that normally increases vascular permeability and angiogenesis. Uses: Metastatic colorectal cancer combined with chemotherapy, NSCLC combined with carboplatin and paclitaxel, Ovarian cancer combined with chemotherapy, Renal cell carcinoma combined with interferon α, Glioblastoma following prior therapy. ADR:- Hypertension, related congestive heart failure: monitor blood pressure and treat hypertension, Impaired wound healing: delay elective surgery for 1 month after the last dose, do not resume treatment for at least 1 month after surgery, Spontaneous GI perforation.
  14. 14. Ramucirumab Human IgG1 monoclonal antibody that binds to VEGFR2, blocking the binding of VEGFR ligands and thereby inhibiting ligand-induced activity in endothelial cells. Uses: Metastatic colorectal cancer, advanced gastric adenocarcinoma, and NSCLC with disease progression on or after prior therapy as a single drug or in combination with chemotherapy. ADR:- Hypertension, diarrhea, Hemorrhage, GI perforations, Impaired wound healing.
  15. 15. Immune Checkpoint Inhibitors Mechanisms of T-Cell Activation o Antigen-mediated activation of T cells is initiated by engagement of the TCR with antigen presented on MHC protein on the surface of an APC, “signal 1.” o Engagement of CD28 costimulatory molecules on T cells is required for effective T-cell activation that includes cell proliferation, migration, and production of cytokines, “signal 2”. o T-cell activation is tightly controlled by immune- suppressive cells and cytokines as well as by coinhibitory molecules present on T cells, such as CTLA-4 or PD-1. o CTLA-4 competes with costimulatory CD28 for binding to the B7 protein ligands. o Binding of CTLA-4 to B7 proteins interrupts the initial CD28 costimulatory signals and serves as an early negative regulator of the T-cell activation responses, that is, an immune checkpoint.
  16. 16. Inhibitors of Cytotoxic T Lymphocyte–Associated Protein 4 (CTLA4) The CTLA-4 is upregulated during the antigen priming of T cells and binds B7 on APCs to attenuate the T-cell response and thus reduce the risk for chronic autoimmune-dependent inflammation. Ipilimumab / Tremelimumab (formerly ticilimumab) It is a fully human IgG1 monoclonal antibody that binds to CTLA-4 and is approved for the treatment of late-stage melanoma. Blocks the interaction of CTLA-4 with B7 ligands on APCs and thereby augments T-cell activation. Inhibition of CTLA-4 signaling can also inhibit regulatory T-cell function that dampens cytotoxic T- cell activity and thus increases the antitumor immune response further. Metastatic melanoma as single agent or in combination with nivolumab (anti-PD1). Autoimmune inflammatory toxicities in majority of patients (>70%),Most frequent: skin (pruritus, rash, vitiligo), GI tract (diarrhoea, colitis), Less frequent: hepatitis, pneumonitis, hypophysitis, hypo- or hyperthyroidism, myocarditis.
  17. 17. Inhibitors of Programmed Cell Death 1 (PD-1) Activation of the PD-1 checkpoint pathway in T cells by PD-L1 or PD-L2 evokes a negative regulatory immune response and inactivates T cells. Nivolumab Fully human monoclonal IgG4 antibody that blocks the interaction between PD-1 and its ligands. Advanced melanoma that progressed after ipilimumab (anti–CTLA-4), Previously treated NSCLC ,Advanced renal cell carcinoma,Relapsed/refractory Hodgkin lymphoma. Adverse effects: rash, fatigue, dyspnoea, musculoskeletal pain, decreased appetite, cough, nausea, constipation. Immune-related serious adverse effects include pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, hypophysitis, hypo- and hyperthyroidism.
  18. 18. Pembrolizumab It is (formerly called lambrolizumab) is a humanized monoclonal IgG4-κ isotype antibody that blocks interaction between PD-1 and its ligands. Advanced melanoma that progressed after ipilimumab (anti–CTLA-4), NSCLC that express PD-L1 and progressed under chemotherapy, NSCLC with wild-type EGFR and ALK and disease progression after chemotherapy, HNSCC with disease progression after chemotherapy.  ADR same as Nivolumab.
  19. 19. Antagonists of PD-1 Ligand 1 Atezolimumab (anti-PD-L1 fully human IgG1) Atezolizumab blocks the interaction of PD-L1 with PD-1 and B7-H1. PD-L1 is expressed in many cancers and thus can suppress the activation of cytotoxic T cells that enter the tumor. Atezolizumab can remove this inhibitory effect and promote an effective antitumor response. NSCLC that is treatment resistant, Urothelial cancer that is locally advanced or metastatic. Adverse effects: fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, constipation, In patients with urothelial cancer: urinary tract infections, Immune-related pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, hypo- and hyperthyroidism, hypophysitis, adrenal insufficiency, pancreatitis, Guillain-Barré syndrome, severe infections. Durvalumab (approved in 2017 for metastatic urothelial cancer) and Avelumab (approved in 2017 for metastatic urothelial and Merkel cell cancer) are also being evaluated for efficacy toward cancers of the head and neck, stomach, lung, and ovary, as well as hepatocellular cancer.
  20. 20. CD20 Inhibitors Rituximab, Ofatumumab and Obinutuzumab Rituximab is a chimeric murine/human monoclonal IgG1 antibody that targets the CD20 B-cell surface antigen. On binding to CD20, rituximab mediates B-cell lysis through CDC and ADCC. Non-Hodgkin lymphoma, Chronic lymphocytic leukemia, Rheumatological and other autoimmune disease, including multiple sclerosis, CLL after treatment failure. ADR:- Infusion-related toxicity with fever, rash, and dyspnea, B-cell depletion, late-onset neutropenia risk of hypersensitivity reaction: use slow increase in infusion rate and antihistamines. Rare: severe mucocutaneous skin reaction, including Stevens-Johnson syndrome. Risk of tumour lysis syndrome in patients with high tumour burden in the circulation: use lower dose initially. Reactivation of hepatitis B virus or JC polyoma virus. Frequent adverse effects: cytopenia, fever, cough, musculoskeletal disorders.
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  22. 22. Monoclonal Antibody–Cytotoxin Conjugates
  23. 23. Gemtuzumab Ozogamicin  It is a humanized monoclonal antibody against CD33 covalently linked to a semisynthetic derivative of calicheamicin, a potent antitumor antibiotic. It undergoes endocytosis; cleavage of calicheamicin from the antibody takes place within the lysosome. The potent toxin then enters the nucleus, binds in the minor groove of DNA, and causes double-strand DNA breaks and cell death. Use: Patients more than 60 years of age with AML in first relapse. ADR:- myelosuppression, Hepatocellular damage such as Hyperbilirubinemia and enzyme elevation.
  24. 24. Brentuximab Vedotin It is an anti-CD30 IgG1 monoclonal antibody linked with the microtubule-disrupting agent MMAE (monomethyl auristatin E). Binding of the antibody to CD30-expressing cells is followed by internalization and the intracellular release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network, inducing cell cycle arrest and apoptotic cell death. ADR:- neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. Ado-trastuzumab Emtansine It combines the HER2-targeted properties of trastuzumab with the anti-microtubule agent DM1, allowing intracellular drug delivery to HER2+ cells in the treatment of HER+ breast cancer. The complex binds to the EGFR2 (HER2) and enters the cell by receptor-mediated endocytosis. The DM1 (emtansine) is released into the cytosol as the complex is cleaved by proteases in lysosomes. The DM1 disrupts microtubule-dependent events, causing mitotic arrest, disruption of intracellular trafficking, and apoptosis. ADR:- Cardiac dysfunction, hepatic toxicity.
  25. 25. Denileukin Diftitox It is an immunotoxin made from the genetic recombination of IL-2 and the catalytically active fragment of diphtheria toxin. Introduction of the diphtheria toxin fragment into cells leads to ADP-ribosylation and inactivation of eukaryotic elongation factor EF-2, inhibition of protein synthesis, and thence cell death. Use:- Recurrent/refractory cutaneous T-cell lymphomas. Significant toxicities include acute hypersensitivity reactions, a vascular leak syndrome, and constitutional toxicities; glucocorticoid premedication significantly decreases toxicity.
  26. 26. Radioimmunoconjugates  It provide targeted delivery of radionuclides to tumor cells. The  particles emitted by 131I can be used for both imaging and therapy, but protein-iodine conjugates have the drawback of releasing free 131I and 131I-tyrosine into the blood and thus present a health hazard to people in contact with the patient. The β-emitter 90Y (yttrium) has emerged as an alternative to 131I, based on its higher energy and longer path length. Currently available radioimmunoconjugates consist of murine monoclonal antibodies against CD20 conjugated with 131I (tositumomab) or 90Y (ibritumomab). Used in relapsed lymphoma of 65%–80%. Adverse effects include antibody-related hypersensitivity, bone marrow suppression, and secondary leukemias.
  27. 27. Recent approvals 2018 Drugs Indication Keytruda (Pembrolizumab)  Recurrent or metastatic cervical cancer.  Primary mediastinal B-cell lymphoma.  Hepatocellular carcinoma.  Merkel cell carcinoma. Libtayo (Cemiplimab-rwlc)  Cutaneous squamous cell carcinoma. Lumoxiti (moxetumomab pasudotox-tdf)  Relapsed or refractory hairy cell leukemia. Opdivo (Nivolumab)  Advanced small cell lung cancer.  MSI-H or dMMR metastatic colorectal cancer Poteligeo (Mogamulizumab-kpkc)  Mycosis fungoides or Sézary syndrome
  28. 28. 2019 Drugs Indications Bavencio (Avelumab) plus Inlyta (axitinib)  First line treatment of advanced renal cell carcinoma. Cyramza (Ramucirumab)  Hepatocellular carcinoma with elevated alpha- fetoprotein (AFP). Herceptin Hylecta (trastuzumab and hyaluronidase-oysk)  HER2-overexpressing breast cancer. Keytruda (pembrolizumab)  Recurrent esophageal cancer with PD-L1 expressing tumors .  Previously treated metastatic small cell lung cancer.  Advanced renal cell carcinoma.  Stage III non-small cell lung cancer.  Treatment of advanced endometrial carcinoma. Polivy (polatuzumab vedotin-piiq)  Diffuse large B-cell lymphoma. Tecentriq (atezolizumab)  Extensive-stage small cell lung cancer .  Triple negative breast cancer. Venclexta (venetoclax) plus Gazyva (Obinutuzumab)  Chronic lymphocytic leukemia or small lymphocytic lymphoma.
  29. 29. Conclusion MAb are Antigen specific, can be produced against any type of antigen, hence vast diagnostic applications Target specificity, a novel therapeutic approach particularly in cancer. MAbs have not only been used as diagnostics, therapeutics, research reagents, drug target for for various infectious diseases but also cancerous, metabolic and hormonal disorders. MAb technology in conjunction with recombinant DNA technology has successfully led to the reconstruction of chimeric, humanized and fully human antibodies and has enormous potentials for therapeutic uses.
  30. 30. Thank you