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Chapter: Basic & Clinical Pharmacology : Immunopharmacology

Monoclonal Antibodies (MABs)

Recent advances in the ability to manipulate the genes of immu-noglobulins have resulted in development of a wide array of humanized and chimeric monoclonal antibodies directed against therapeutic targets.


Recent advances in the ability to manipulate the genes of immu-noglobulins have resulted in development of a wide array of humanized and chimeric monoclonal antibodies directed against therapeutic targets. The only murine elements of humanized monoclonal antibodies are the complementarity-determining regions in the variable domains of immunoglobulin heavy and light chains. Complementarity-determining regions are primarily responsible for the antigen-binding capacity of antibodies. Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions. The following are brief descriptions of the engineered antibodies that have been approved by the FDA.

Antitumor MABs

Alemtuzumab is a humanized IgG1with a kappa chain that bindsto CD52 found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a small population of granulocytes. Currently, alemtuzumab is approved for the treatmentof B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and have failed fludarabine therapy. Alemtuzumab appears to deplete leukemic and normal cells by direct antibody-dependent lysis. Patients receiving this antibody become lymphopenic and may also become neutro-penic, anemic, and thrombocytopenic. As a result patients should be closely monitored for opportunistic infections and hemato-logic toxicity.

Bevacizumab is a humanized IgG1monoclonal antibody thatbinds to vascular endothelial growth factor (VEGF) and inhibits VEGF from binding to its receptor, especially on endothelial cells. It is an antiangiogenic drug that has been shown to inhibit growth of blood vessels (angiogenesis) in tumors. It is approved for first-line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy. It is also approved for treatment of non-small cell lung cancer, glioblastoma multiforme that has progressed after prior treatment, and meta-static kidney cancer when used with interferon-alpha. Since beva-cizumab is antiangiogenic, it should not be administered until patients heal from surgery. Patients taking the drug should be watched for hemorrhage, gastrointestinal perforations, and wound healing problems. Bevacizumab has also been used off label by intravitreal injection to slow progression of neovascular macular degeneration (see ranibizumab under Other MABs, below).

Cetuximab is a human-mouse chimeric monoclonal antibodythat targets epidermal growth factor receptor (EGFR). Binding of cetuximab to EGFR inhibits tumor cell growth by a variety of mechanisms, including decreases in kinase activity, matrix metal-loproteinase activity, and growth factor production, and increased apoptosis. It is indicated for use in patients with EGFR-positive metastatic colorectal cancer and, along with radiation therapy, in patients with head and neck cancer. Cetuximab may be adminis-tered in combination with irinotecan or alone in patients who cannot tolerate irinotecan. HAMAs are generated by about 4% of patients being treated with cetuximab.

Ofatumumab is a human IgG1monoclonal antibody directedagainst a different epitope on CD20 than rituximab. It is approved for patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab. Ofatumumab binds to all B cells including B-CLL. It is thought to lyse B-CLL cells in the presence of complement and to mediate antibody-dependent cellular cytotoxicity. There is a slight risk of hepatitis B virus reac-tivation in patients taking ofatumumab.

Panitumumab is a fully human IgG2kappa light chain mono-clonal antibody. It is approved for the treatment of EGFR-expressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Panitumumab binds to EGFR (similar to cetuximab), inhibiting epidermal growth factor from binding to its receptor, and prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases. It inhibits cell growth, induces apoptosis, decreases vascular growth factor production, and suppresses internalization of the EGFR. Although some dermatologic and infusion-related toxici-ties have been observed following infusion of panitumumab, the distinct advantage over cetuximab is that it is fully human, and therefore does not elicit HAMAs. This is the first FDA-approved monoclonal antibody produced from transgenic mice expressing the human immunoglobulin gene loci.

Rituximab is a chimeric murine-human monoclonal IgG1(human Fc) that binds to the CD20 molecule on normal and malignant B lymphocytes and is approved for the therapy of patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. It is also approved for the treatment of rheumatoid arthritis in combination with methotrexate in patients for whom anti-TNF-α therapy has failed. The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cyto-toxicity, and induction of apoptosis in the malignant lymphoma cells. In lymphoma this drug appears to be synergistic with che-motherapy (eg, fludarabine, CHOP). Recent reports indicate that rituximab may also be very useful in auto-immune diseases such as multiple sclerosis and systemic lupus erythematosus.

Trastuzumab is a recombinant DNA-derived, humanizedmonoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu. This anti-body blocks the natural ligand from binding and down-regulates the receptor. Trastuzumab is approved for the treatment of HER-2/neu-positive tumors in patients with breast cancer and patients with metastatic gastric or gastroesophageal junction ade-nocarcinoma. As a single agent it induces remission in about 15–20% of breast cancer patients; in combination with chemo-therapy, it increases response rates and duration as well as 1-year survival. Trastuzumab is under investigation for other tumors that express HER-2/neu .

MABs Used to Deliver Isotopes to Tumors

Arcitumomab is a murine Fab fragment from an anti-carcinoembryonic antigen (CEA) antibody labeled with techne-tium 99m (99mTc) that is used for imaging patients with metastatic colorectal carcinoma (immunoscintigraphy) to determine extent of disease. CEA is often upregulated on tumor in patients with gastrointestinal carcinomas. The use of the Fab fragment decreases the immunogenicity of the agent so that it can be given more than once; intact murine monoclonal antibodies would elicit stronger HAMA.

Capromab pendetide is a murine monoclonal antibody spe-cific for prostate specific membrane antigen. It is coupled to isoto-pic indium (111In) and is used in immunoscintigraphy for patients with biopsy-confirmed prostate cancer and post-prostatectomy in patients with rising prostate specific antibody level to determine extent of disease.

Ibritumomab tiuxetan is an anti-CD20 murine monoclonalantibody labeled with isotopic yttrium (90Y) or 111In. The radia-tion of the isotope coupled to the antibody provides the major antitumor activity. Ibritumomab is approved for use in patients with relapsed or refractory low-grade, follicular, or B-cell non-Hodgkin’s lymphoma, including patients with rituximab-refrac-tory follicular disease. It is used in conjunction with rituximab in a two-step therapeutic regimen.

Tositumomab is another anti-CD20 monoclonal antibodyand is complexed with iodine 131 (131I). Tositumomab is used in two-step therapy in patients with CD20-positive, follicular non-Hodgkin’s lymphoma whose disease is refractory to rituximab and standard chemotherapy. Toxicities are similar to those for ibritu-momab and include severe cytopenias such as thrombocytopenia and neutropenia. Tositumomab should not be administered to patients with greater than 25% bone marrow involvement.

MABs Used as Immunosuppressants and Anti-Inflammatory Agents

A. Anti-TNF-Alpha MABs

Adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab are antibodies that bind TNF-α, a proinflammatory cytokine that is important in rheumatoid arthritis and similar inflammatory diseases . Blocking TNF-α from binding to TNF receptors on inflammatory cells results in suppres-sion of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration. An increased risk of infection or reactivation of M tuber-culosis, hepatitis B virus, and invasive systemic fungi is common toeach of these anti-TNF monoclonal antibodies. Patients may also be at increased risk for malignancies including lymphoma.

Adalimumab is a completely human IgG1approved for use inpatients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis. Like the other anti-TNF-α biologicals, adali-mumab blocks the interaction of TNF-α with TNF receptors on cell surfaces; it does not bind TNF-β. Adalimumab lyses cells expressingTNF-αinthepresenceofcomplement.Pharmacodynamic studies showed that administration of adalimumab reduced levels of C-reactive protein, erythrocyte sedimentation rate, serum IL-6, and matrix metalloproteinases MMP-1 and MMP-3.

Certolizumab pegol is a recombinant humanized Fab frag-ment that binds to TNF-α. It is coupled to a 40-kDa polyethylene glycol. It neutralizes the activity of membrane-associated and sol-uble TNF-α without lysing cells. Certolizumab is indicated for patients with Crohn’s disease and rheumatoid arthritis.

Etanercept is a dimeric fusion protein composed of human IgG1constant regions fused to the TNF receptor. Etanercept binds to both TNF-α and TNF-β and appears to have effects similar to those of adalimumab and infliximab, ie, inhibition of TNF-α-mediated inflammation, but its half-life is shorter due to its physical form (fusion protein) and the route of injection (subcutaneously, twice weekly). Etanercept is approved for adult rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis and psoriatic arthritis. It may be used in combination with meth-otrexate in some patients with arthritis.

Golimumab is a human IgG monoclonal antibody that alsobinds to soluble and membrane-associated TNF-α. It is an intact human IgG1 and, like certolizumab pegol, it does not lyse cells expressing membrane-associated TNF-α. It is indicated for patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It has the advantage of increased half-life such that subcu-taneous injections may be self-administered only once per month.

Infliximab is a human-mouse chimeric IgG1monoclonal anti-body possessing human constant (Fc) regions and murine variable regions. It is administered intravenously but has the same anti-TNF-α activity as adalimumab and etanercept. Infliximab is cur-rently approved for use in Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis.

B. Abatacept

Abatacept is a recombinant fusion protein composed of the extra-cellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to hinge, CH2, and CH3 domains of human IgG1. CTLA-4 delivers an inhibitory signal to T cells. It binds more tightly to CD80/86 than CD28 (Figure 55–7). This fusion protein blocks activation of T cells by binding to CD80 or CD86 so that CD28 on T cells cannot bind and stimulate the T cell and lead to cytokine release. Abatacept is approved for patients with rheumatoid arthritis and juvenile idiopathic arthritis. Patients should not take other anti-TNF drugs or anakinra while taking abatacept. As with anti-TNF monoclonal agents, patients should be screened and treated for latent tuberculosis infection before starting abatacept.

C. Alefacept

Alefacept is an engineered protein consisting of the CD2-binding portion of leukocyte-function-associated antigen-3 (LFA-3) fused to a human IgG1 Fc region (hinge, CH2, and CH3). It is approved for the treatment of plaque psoriasis. It inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal CD2/LFA-3 interaction (Figure 55–7). 

Treatment of patients with alefacept also results in a dose-dependent reduction of the total number of circu-lating T cells, especially CD4 and CD8 memory effector subsets that predominate in psoriatic plaques. Peripheral T-cell counts of patients receiving alefacept must be monitored and the drug dis-continued if CD4 lymphocyte levels fall below 250 cells/μL.

D. Basiliximab and Daclizumab

Basiliximab is a chimeric mouse-human IgG1 that binds to CD25, the IL-2 receptor alpha chain on activated lymphocytes. Daclizumab is a humanized IgG1 that also binds to the alpha subunit of the IL-2 receptor. Both agents function as IL-2 antago-nists, blocking IL-2 from binding to activated lymphocytes, and are therefore immunosuppressive. They are indicated for prophy-laxis of acute organ rejection in renal transplant patients and either may be used as part of an immunosuppressive regimen that also includes glucocorticoids and cyclosporine A.

E. Natalizumab

Natalizumab is a humanized IgG4 monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surfaces of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their cognate receptor. It isindicated for patients with multiple sclerosis and Crohn’s disease who have not tolerated or had inadequate responses to conven-tional treatments.

F. Omalizumab

Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled corticosteroids . The antibody blocks the binding of IgE to the high-affinity Fc ε receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such as histamine and leukotrienes. Total serum IgE levels may remain elevated in patients for up to 1 year after admin-istration of this antibody.

G. Tocilizumab

Tocilizumab is recombinant humanized IgG1 that binds to soluble and membrane-associated IL-6 receptors. It inhibits IL-6-mediated signaling on lymphocytes, suppressing inflammatory processes. It is indicated for treatment of patients with rheumatoid arthritis who are refractory to other anti-TNF-α biologicals. It may be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs. Patients taking tocilizumab have the same increased risk of infection as those taking anti-TNF-α monoclonal antibodies.

H. Ustekinumab

Ustekinumab is a human IgG1 monoclonal antibody that binds to the p40 subunit of IL-12 and IL-23 cytokines. It blocks IL-12 and IL-23 from binding to their receptors, therefore inhibiting recep-tor-mediated signaling in lymphocytes. Ustekinumab is indicated for patients with moderate to severe plaque psoriasis. The advantageof ustekinumab over anti-TNF-α drugs for psoriasis is faster and longer term improvement in symptoms along with very infre-quent dosing.

Other MABs

Abciximab is a Fab fragment of a murine-human monoclonalantibody that binds to the integrin GPIIb/IIIa receptor on acti-vated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation. It is indicated as an adjunct to per-cutaneous coronary intervention for the prevention of cardiac ischemic complications. 

Denosumab is a human IgG2monoclonal antibody specific forhuman RANKL (receptor activator of nuclear factor kappa-B ligand). By binding RANKL it inhibits the maturation of osteoclasts, the cells responsible for bone resorption. Denosumab is indicated for treatment of postmenopausal women with osteoporosis at high risk for fracture. Before starting denosumab, patients must be evaluated to be sure they are not hypocalcemic. During treatment, patients should receive supplements of calcium and vitamin D.

Eculizumab is a humanized IgG monoclonal antibody thatbinds the C5 complement component, inhibiting its cleavage into C5a and C5b thereby inhibiting the terminal pore-forming lytic activity of complement. Eculizumab is approved for patients with paroxysmal nocturnal hemoglobinuria (PNH) and dramatically reduces the need for red blood cell transfusions. It prevents PNH symptoms of anemia, fatigue, thrombosis, and hemoglobinemia by inhibiting intravascular hemolysis due to red cell lysis. Clinicians must be aware of increased risk of meningococcal infec-tion in patients receiving this anti-C5 monoclonal antibody.

Palivizumab is a monoclonal antibody that binds to the fusionprotein of respiratory syncytial virus, preventing infection in sus-ceptible cells in the airways. It is used in neonates at risk for this viral infection and reduces the frequency of infection and hospi-talization by about 50% .

Ranibizumab is a recombinant human IgG1Fab that binds toVEGF-A. It also prevents new blood vessel formation by blocking VEGF from binding to its receptor. Ranibizumab is labeled for intravitreal injection in patients with neovascular age-related macu-lar degeneration and sudden blurring or vision loss secondary to macular edema following retinal vein occlusion. Pegaptanib is a pegylated oligonucleotide that binds extracellular VEGF and is also given by intravitreous injection to slow macular degeneration.

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