AbstractImmunobiologicals are the biologically active agents with immunological actions that are useful for the managementÂ  of immunologically mediated diseases of infectious or non-infectious origin.Keywords :Immunobiologicals,Epitope,Interferon,Monoclonal antibodies

N, MOHAN

R, Karthik

English

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Vol 6, Issue 1, 2018 ISSN -  2321-4406 IMMUNOBIOLOGICALSKARTHIK R*, MOHAN NDepartment of Oral Medicine and Radiology, Vinayaka Missions Sankarachariyar Dental College, Salem, Tamil Nadu, India.  Email: drkarthik17@gmail.comImmunobiologicals are the biologically active agents with immunological actions that are useful for the management of immunologically mediated diseases of infectious or non-infectious origin.Keywords: Immunobiologicals, Epitope, Interferon, Monoclonal antibodies.INTRODUCTIONBiologicals are molecules that modify the cascade of immunological processes leading to inflammation. Principal immunobiologicals are monoclonal antibodies (Mabs), fusion inhibitors, and interferons (IFNs). Paul Ehrlich first described Mab as “magic bullets” in search of toxins.An antibody is a protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. Each antibody recognizes a specific antigen unique to its target.Mabs are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell. Polyclonal antibodies are antibodies that are derived from different cell lines. They differ in amino acid sequence.The antigen associated with tumor cells are called as the “TUMOR MARKER.” Antibodies produced as a result of specific tumor markers monoclonally can be conjugated with drug molecule which, in turn, can be targeted to the specific cells or tumor tissues. Targeting antibodies with drugs involve the following steps: (1) Identification of the new antigen produced by the tumor cells, (2) production of antibody monoclonally against the identified new antigen, and (3) formation of drug antibody conjugate or complexes.These complexes concentrate at the tumor site and deliver the drug. There are several advantages when drugs are delivered as antibody conjugates. The conjugates can specifically reach the target cells without causing any damage to the normal tissue. The drug antibody conjugate could be expected to be the ideal agents for drug targeting in chemotherapy.Production of MabAn antigen is injected into a mouse, and after a few weeks, its spleen is removed and plasma cells are extracted. The mouse’s spleen cells are fused with myeloma cells to create hybrid cells called hybridoma cells. Each hybridoma cell indefinitely produces identical antibody, and the hybridoma cells are then screened using an antigen/antibody assay that will reveal which cells produce the desired antibody. The collection of selected hybridoma cells that produce the preferred antibody is rescreened multiple times until a pure line is isolated. These cells are grown in a culture and/or injected into mice to induce tumors. The cells can also be frozen and saved for later use. The hybridoma method for producing Mab is useful because large amounts of specifically tailored identical antibodies can be produced easily [1].PRODUCTION OF MABMabs are classified according to the decreased order of antigenicity of their components intomurine, chimeric, primatized, and humanized.TYPES OF MAB1. Murine Mab: Whole antibody is of murine origin produced by hybridoma technology. Major problems with murine Mabs include reduced stimulation of cytotoxicity, formation of complexes after repeated administration, allergic reactions, and anaphylactic shock, for example, Afelimomab.2. Chimeric Mab: Chimeric antibodies composed of murine variable regions fused onto human constant regions developed by recombinant DNA technology. Antibodies are approximately 65% human origin. This reduces immunogenicity, thus increases serum half-life, for example, Basiliximab and Cetuximab.3. Humanized Mab: Humanized antibodies are produced by grafting murine hypervariable domains into human antibodies are Research ArticleReceived: 16 February 2018, Revised and Accepted: 05 April 2018ABSTRACTapproximately 90–95% human origin this bind weakly to the antigens, for example, Apolizumab and Atlizumab.4. Human Mab: Human Mabs are produced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of Mab, for example, Belimumab and Cixutumumab.Mechanism of action of MabAntibody-dependent cell-mediated cytotoxicity (ADCC)ADCC immunoglobulin’s clustered on the surface of the targeted cells and exposes its tail (Fc) region to be recognized by the Fc receptors present on the surface of the macrophages and neutrophils. This causes lysis of tumor cell.RadioimmunotherapyIt involves the use of radioactively conjugated murine antibodies against cellular antigens. Emitted radiation causes tumor cell lysis. More applicable to lymphomas as they are highly radiosensitive malignancies.Antibody-mediated enzyme prodrug therapyAn antibody developed against a tumor antigen is linked to a drug-activating enzyme and injected to the blood subsequent systemic administration of non-toxic agent or prodrug results in its conversion to a toxic drug and results in cytotoxic effect.ImmunoliposomesThese are antibody conjugated liposome’s can carry drugs or therapeutic nucleotides and when conjugated with Mab, deliver the entrapped drug or toxin, especially to the target cells.ImmunotoxinsImmunotoxins are proteins that contain a toxin along with an antibody that binds specifically to target cells. All protein toxins are work by enzymatically inhibiting protein synthesis. Various plant and biological toxins have been genetically fused/chemically conjugated with the antibodies that bind to cancer cells.Antibody drug conjugatesAntibody-drug conjugates are Mab attached to biologically active drugs by chemical linkers with liable bonds reduce side effects and show wide therapeutic window doxorubicin, duanomycin, chlorambucil, etc., can be conjugated with Mab.Fragments of MabsCytokine blocking agents Target Type IndicationAfelimomab Anti-TNF-α Protein SepsisInfliximab (Remicade) Anti-TNF-α Chimeric Behcet’s disease Toxic epidermal necrolysisEtanercept (Enbrel) Anti-TNF-α and TNF-ß Fusion protein PemphigusAgents targeting cell surface epitopesAlefacept (Amevive) CD-2-LFA-3 Fusion protein PsoriasisAlemtuzumab (Campath) CD-52 Humanized Chronic lymphocytic leukemiaApolizumab HLA-DR beta Humanized Non-Hodgkin’s lymphomaBelimumab (Benlysta) B-cell-activating factor (BAFF) Humanized Sjogren’s syndrome Systemic lupus erythematosus (SLE)Bevacizumab (Avastin) Vascular endothelial growth factor (VEGF) Humanized Colorectal cancerBasiliximab (Simulect) CD-25 Humanized Mab Transplant rejectionCetuximab (Erbitux) Epidermal growth factor receptor (EGFR) Chimeric Head and neck cancerCertolizumab (Cimzia) Inhibition of TNF-α signaling Humanized Crohn’s diseaseCixutumumab IGF-1 receptor Human Metastatic Rhabdomyosarcoma Hepatocellular carcinomaDaclizumab (Zenapax) CD-25 Humanized Mab Transplant rejectionDenileukin Diftitox (Ontak) CD25/Ib 2 Fusion toxin Cutaneous T-cell lymphomaEfalizumab (Raptiva) CD-11 a/CD18 Humanized Mab PsoriasisEculizumab (Soliris) Complement system protein C5 Humanized Paroxysmal nocturnal hemoglobinuriaGemtuzumab (Mylotarg) CD-33 Humanized Acute myelogenous leukemiaIbritumomab (Zevalin) CD-20 Murine Non-Hodgkin’s lymphoma (with Yttrium-90 or Indium-111)Mepolizumab (Nucala) IL-5 α of Eosinophil Humanized AsthmaSiplizumab CD-2 Humanized Mab Graft versus host disease psoriasisTocilizumab (Actemra) IL-6 Humanized Rheumatoid arthritisVisilizumab (Nuvion) CD-3 Humanized Cohn’s disease ulcerative colitisMabs: Monoclonal antibodies, IL: Interleukin, TNF: Tumor necrosis factorMab DosagesInfliximab (REMICADE) 5 mg/kg/dose i.v alone or in combination with other agents 100 mg injectionEtanercept (ENBREL) 25 mg subcutaneously. Twice weekly for minimum 12 weeksAlefacept (AMEVIVE) 10–15 mg intramuscular injection once weekly for 12 weeksEfalizumab (RAPTIVA) 0.7 mg/kg subcutaneous injection (conditioning dose) followed by weekly subcutaneous doses of 1 mg/kg (maximum single dose not to exceed a total of 200 mg). A single vial delivers 125 mgDenileukin Diftitox (ONTAK) 9–18 mcg/kg/d intravenous infusion daily for 5 days every 3 weeks, six courses are required to show partial or complete response. A single vial delivers 150 mcg/ml per vialMabs: Monoclonal antibodiesFragments of Mabs Fab and F(ab) 2 are less immunogenic but have greater tumor penetration power than normal antibody and are helpful in detecting smaller lesions (<2 cm) not seen on computed tomography. ScFv is mainly used as delivery vehicles for cancer therapy.Table 1: Immunobiologicals [2]Table 2: Dosages of some Mab17 Karthik and Mohan Innovare Journal of Medical Science, Vol 6, Issue 1, 16-19may lead to the damage of normal cells.5. Tumor uptake may be increased through administering high doses.Disadvantages of Mab 1. Mab production, a time-consuming process because entire process requires 3–4 months for one fusion experiment.2.	 Average	affinity	of	Mab	is	generally	lower.3. Any physical/chemical treatment will affect all Mabs in that production.IFNIFNs are a family of glycoproteins which are synthesized by leukocytes (IFN-α),	 fibroblasts	 (IFN-β),	 and	 immune	 cells	 (IFN-ɤ)	 against	 viral	infections and other non-viral challenges that in addition to having antiviral	properties,	also	modulate	various	cellular	functions.	IFN-α	is	mainly used for therapeutic purposes.IFN synthesized by recombinant techniques have therapeutic value in the treatment of viral infections of the skin and cutaneous malignancies. They are the products of bacterial fermentation of particular strain of Escherichia coli consisting genetically engineered plasmid containing a specific IFN gene from human leukocytes.Mechanism of action of IFNAntiviralIt induces enzyme 2՜-5′	a synthetase, polymerizes ATP, activates cellular endonuclease, and degrade both viral and cellular RNA.Antiproliferative effectIt inhibits mitosis of the cells and downregulates their growth factors.Immunoregulatory effectIt induces expression of Classes I and II MHC complexes antigens on immune cells, enhances number of natural killer cells.Principle indications of IFNIFN-α2ARecurrent aphthous stomatitisIFN-α2A	 administered	 orally	 once	 daily	 in	 a	 low	 concentration	(1200 IU/day) for 1 week [3].HemangiomaIFN-α2A	 3	 million	 units/m2 per day should be used only in life-threatening hemangiomas act by inhibiting angiogenesis in whom high-dose corticosteroid therapy failed [4].Chronic hepatitis B infectionAbout 10 MU/L pegylated IFN-alpha is used in the treatment of chronic hepatitis B infection [5].Malignant melanomaAbout 20 MU/m2 i.v over 20 min for 5 consecutive days/week for 4 weeks (induction phase) followed by 10 MU/m2 s.c injection 3	 times/week	 for	 48	 weeks	 (maintenance	 phase).	 IFN-α2b	 has	a dual effect of TAP1 (antigen-presenting cells of MHC complex) upregulation in antigen-presenting cells and in silent metastatic melanoma cells [6].Condyloma acuminataIFN ɤUsed for the treatment of recalcitrant moderate-to-severe atopic dermatitis acts by inhibiting IgE synthesis by promoting proliferation of Th1 cells administered by weekly subcutaneous injections [8].Intravenous immunoglobulinsIntravenous immunoglobulins are heterogeneous human gamma globulins consisting IgG with trace of IgA and IgM prepared by cold ethanol fractionalization of pooled human sera harvested from thousands of donors. Intravenous immunoglobulins are an important safe, effective therapeutic option as an immunomodulatory agent in the management of skin disorders where corticosteroids and immunosuppressive agents cannot be used.Mechanism of action of intravenous immunoglobulins1. Neutralization of microbe or toxin.2. Inhibition of cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis	factor-α.3. Superantigen neutralization.4. Modulation of complement activation.5. Acceleration of IgG catabolism.6. Saturation of Fc receptors on macrophages (Fc receptors play a role in cytotoxic cell-mediated immunity and opsonization).7. Suppression of antibody production and idiotypic (the variable part of an antibody including the unique antigen-binding site is known as idiotype) antibodies.8. Helps to clear immune complexes from the body in patients affected with systemic lupus erythematosus.Indication Doses and durationPemphigus vulgaris 2 g/kg i.v. single dose monthly or 1 g/kg/day×3 days every month or 0.5 g/kg/day×5 days every monthToxic epidermal necrolysis 0.8–5.8 g/kg for 1–5 daysDermatomyositis 2 g/kg i.v single dose monthly for 2–4 monthsGraft versus host disease (GVHD) 250–500 mg/kg weekly from day 8 to day 111 after bone marrow transplantationAutoimmune urticaria 0.4/kg/day for 5 daysKawasaki disease 2 g/kg i.v as single doseCongenital/acquired agammaglobulinemia or hypogammaglobulinemia 0.25 g/kg every 3 weeks in childhoodScleromyxedema 2 g/kg i.v. monthly for 3 monthsPyoderma gangrenosum 1–2 g/kg i.v. monthly for 2–4 monthsTable 3: Indications and doses of intravenous immunoglobulinsProblems of drug delivery by Mab [12]1. Slow elimination of Mab from the blood.2. Poor vascular permeability.3. Cross-reactivity with normal tissues, metabolism of Mab conjugates.4. May bind with the targeted epitopes present on other tissues, which 1 MU per lesion (maximum of 5 lesions in a single course). Intralesional injections should be 3 times weekly on alternate days for 3 weeks directed toward the center of the base of the lesion, which produce a small wheal if done correctly. An additional course may be administered at 12–16 weeks [7].AIDS-related Kaposi’s sarcoma30 MU/m2/dose subcutaneously or intramuscularly 3 times a week for 16 weeks of treatment till maximum response.5% lyophilized powder dissolved in 5% dextrose. Available as immuglob 2.5 g/100 ml or 5 g/200 ml Vial. Since it is not compatible with normal saline, it has to be diluted with 5% dextrose in water. 18 Karthik and Mohan Innovare Journal of Medical Science, Vol 6, Issue 1, 16-19Disadvantages of intravenous immunoglobulins1. All intravenous immunoglobulins must be screened to minimize the risk of transmission of HIV, hepatitis B virus, and hepatitis C virus infection.2. Can interact with live virus vaccines. Such vaccines should not be given 14 days before or 3 months after intravenous immunoglobulin administration.3. Have risk of autoimmunity owing to infusion of antibodies.4.	 Rebound	 flare-up	can	occur	after	discontinuation	of	 intravenous	immunoglobulins.5. Anaphylactic reactions can occur.REFERENCES1. Zwick MB, Wang M, Poignard P, Stiegler G, Katinger H, Burton DR, et al. Neutralization synergy of human immunodeficiency virus type 1 primary isolates by cocktails of broadly neutralizing antibodies. J Virol 2001;75:12198-208.2. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118-29.3. Hutchinson VA, Angenend JL, Mok WL, Cummins JM, Richards AB. Chronic recurrent aphthous stomatitis: Oral treatment with low-dose interferon alpha. Mol Biother 1990;2:160-4.4. Zhang L, Zheng JW, Yuan WE. Treatment of alarming head and neck infantile hemangiomas with interferon-α2a: A clinical study in eleven consecutive patients. Drug Des Devel Ther 2015;9:723-7.5. van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Darwish Murad S, de Man RA, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39:804-10.6. Heise R, Amann PM, Ensslen S, Marquardt Y, Czaja K, Joussen S, et al. Interferon alpha signalling and its relevance for the upregulatory effect of transporter proteins associated with antigen processing (TAP) in patients with malignant melanoma. PLoS One 2016;11:e0146325.7. Boot JM, Blog FB, Stolz E. Intralesional interferon alfa-2b treatment of condylomataacuminata previously resistant to podophyllum resin application. Genitourin Med 1989;65:50-3.8. Guttman-Yassky E, Dhingra N, Leung DY. New era of biologic therapeutics in atopic dermatitis. Expert Opin Biol Ther 2013;13:549-61.19 Karthik and Mohan Innovare Journal of Medical Science, Vol 6, Issue 1, 16-19

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IMMUNOBIOLOGICALS

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