Educational Forum

Monoclonal : Pharmacological relevance

Jasleen Kaur, D.K. Badyal, P.P. Khosla

ABSTRACT

Monoclonal antibodies (MAbs), a new class of biological agents, are used these days in therapeutics and diagnosis. MAbs also labeled as ‘magic bullets’, are highly specific Department of Pharmacology, antibodies produced by a clone of single hybrid cells formed in the laboratory by fusion Christian Medical College and of B cell with the tumor cell. The hybridoma formed yields higher amount of MAbs. Hospital, Ludhiana, India MAbs can be produced in vitro and in vivo. Animals are utilized to produce MAbs, but these antibodies are associated with immunogenic and ethical problems. Of late, Received: 12.7.2006 Revised: 29.8.2006 recombinant DNA technology, genetic engineering,phage display and transgenic animals Accepted: 26.9.2006 are used to produce humanized MAbs or pure human MAbs, which have fewer adverse effects. MAbs alone or conjugated with drugs, toxins, or radioactive atoms are used for Correspondence to: treatment of cancer, autoimmune disorders, graft rejections, infectious diseases, asthma, Jasleen Kaur and various cardiovascular disorders. New MAbs are being developed which are more E-mail: [email protected] specific and less toxic.

KEY WORDS: Antibodies, biological response modifiers, cancer , immunosuppressant, immunotherapeutics..com).

Introduction killer cells, and so on, when injected into patients, home in on Ags that grow on the surface of killer cells. Therefore, MAbs Humans and animals have the ability to make antibodies.medknow are also labeled as biological response modifiers. Since they (Abs) to recognize any antigenic determinant (epitope) and to affect the , they are also called even discriminate between similar epitopes. These antibodies immunotherapeutics as opposed to chemotherapeutics, provide the basis for protection against various diseases. The which are drugs used to interfere cell growth (cancer). MAb use of vaccine for immunization is an excellent e(wwwxample of therapy is a form of passive immune therapy because the preventive use of Abs. Abs usage has now extended to antibodies are made in large quantities outside the body (in treatment; hence, these are promoted as potential candidates the laboratory) rather than by a person’s immune system. for the managementThis of various PDFa diseases. site is hosted Theavailable Abs synthesized by forMedknow freeTherefore, download thesePublications MAbs dofrom not require the person’s immune against a particular (Ag) are known as monoclonal system to take an ‘active’ role in fighting the cancer. antibodies (MAbs). By definition, MAbs are a class of highly The development of the immortal hybridoma requires the specific Abs produced by the clones of a single hybrid cell use of animals. No method of generating a hybridoma that formed in the laboratory by the fusion of B-lymphocytes with avoids the use of animals has been found. Recent in vitro a tumor cell. techniques allow the intracellular production of antigen-binding [1] MAbs are also known as ‘magic bullet’. The idea of ‘magic fragments, but such techniques are still experimental bullet’ was first proposed by Paul Ehrlich who at the beginning and have an uncertain yield, efficacy and antibody function.[3] th of the 20 century figured ‘if a compound could be made to There are two methods for growing these cells: injecting them selectively target a disease causing organism, then a toxin for into the peritoneal cavity of a mouse or using in vitro cell- that organism could be delivered along with the agent of culture techniques.[4] selectivity’. The market for therapeutic MAbs is a most potential sector within the pharmaceutical industry. These Production of MAbs antibodies are forecast to drive the market towards the $30 The process of producing MAbs was invented by Kohler billion mark by the year 2011 due to a high level of innovation. and Milstein in 1975.[5] They shared the Nobel Prize in Several MAbs are set to be launched in the next 5 years.[2] Physiology/Medicine in 1984 for the discovery of MAb. The Experimental cancer studies have used various substances key idea was to use a line of myeloma cells that had lost the attached to MAbs such as radioactive material, drugs, immune ability to secrete antibodies. They came up with a technique

Indian J Pharmacol | February 2007 | Vol 39 | Issue 1 | 5-14 5 Kaur et al.: Monoclonal antibodies to fuse these cells with healthy antibody producing B cells. a hollow fiber or a membrane, with a low-molecular-weight This fusion resulted in a clone of cells that retained the myeloma cutoff (10,000-30,000 kD), called semipermeable-membrane­ cell lines and ability to live indefinitely in tissue culture. The based system permits cells to grow at high densities in culture. procedure yielded a cell line capable of producing one type of The objective of this system is to isolate the cells and MAbs antibody protein for a long period. The fused cell was called a produced in a small chamber separated by a barrier from a hybridoma and produced large quantities of MAbs. larger compartment that contains the culture media. Culture Production in animals [Figure 1] can be supplemented with numerous factors that help optimize When injected into a mouse, the hybridoma cells multiply growth of the hybridoma. These methods produce MAbs in and produce fluid (ascites) in its abdomen. This fluid contains concentrations often as high as those found in ascitic fluid a high concentration of antibody. The mouse ascites method is and are free of mouse ascitic fluid contaminants. These inexpensive and easy to use. However, if too much fluid methods reduce the use of animals and are the methods of accumulates or if the hybridoma is an aggressive cancer, the choice for large-scale production by the pharmaceutical mouse will likely experience pain or distress. If a procedure industry because of the ease of culture.[7,8] produces pain or distress in animals, regulations call for a Although in vitro techniques can be used for more than search for alternatives. The mouse ascites method usually 90% of MAb production, it must be recognized that there are produces very high MAbs concentration that often does not situations in which in vitro methods will be ineffective, as some require further concentration procedures that can denature hybridomas do not grow well in culture or are lost in culture. antibody and decrease effectiveness. It avoids the effects of Because hybridoma characteristics vary and MAb production contaminants as in in vitro batch-culture fluid method and no needs are diverse, in vitro techniques are not suitable in all expert guidance is required to teach the method. However, it situations. These techniques might impede research, involves the continued use of mice requiring daily observation especially if large numbers of MAbs are to be screened for and the MAbs produced contains various mouse proteins and efficacy or specificity in the treatment of diseases. In vitro other contaminants that might require purification.[6] methods generally require the use of fetal calf serum, which limits some antibody uses and which is a concern from the Production in cell-culture animal-welfare perspective. The loss of proper glycosylation One alternative is to grow hybridoma cells in a tissue of the antibody (in contrast with in vivo production) might culture medium, but this technique requires some expertise, make the antibody product unsuitable for in vivo experiments special media and can be expensive and time-consuming. There because of increased immunogenicity, reduced binding has been considerable research on in vitro methods for growing affinity, changes.com). in biologic functions or accelerated clearance hybridomas and these newer methods are less expensive, in vivo. MAbs produced by membrane-based in vitro methods faster, and produce antibodies in higher concentration than are contaminated with dead hybridoma cells and their has been the case in the past. Following are the in vitro products, thus require early and expensive purification. In production methods that are available. vitro culture methods are generally more expensive than the Batch tissue-culture methods. The simplest approach for ascites method for small or medium-scale production of producing MAb in vitro is to grow the hybridoma cultures in MAbs. batches and purify the MAbs from the culture medium. Fetal.medknow bovine serum is used in most tissue culture media. The MAb Evolution of MAbs concentration achieved is low (around a few micrograms per The significance of MAbs lies in their specificity and milliliter) and some MAbs are denatured during concentration (www immortality. Whereas hybridoma development of murine or purification process. MAbs was the requisite for the development of MAbs as drugs, Semipermeable-membrane-based system. A barrier, either the inherent immunogenicity of rodent sequences in humans This PDFa site is hosted available by forMedknow freehas presented download Publications obstacles fromto the clinical application of MAbs. Figure 1. Basic steps in production of monoclonal antibodies in Sensitization to MAb therapeutics poses significant risk to animals the patient and may blunt the efficacy of these therapies. The advent of chimeric antibodies lessened but did not eliminate the rodent content of MAbs. Thus, immunogenicity remained a concern. Further, elimination of rodent sequences enabled the production of humanized MAbs. This was followed by current technology using phage display and finally, transgenic mice technology, which allows for the generation of fully human therapeutic MAbs. The reduced immunogenicity of this new generation of MAbs is expected to enhance efficacy, safety, and ease of use.[9] The MAbs are also classified into generations as per their evolution and immunogenicity as follows: 1. First generation MAbs. Majority of the earlier MAbs available were murine, rabbit, or rat proteins purified following immunization of the animal with an antigen

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preparation. These were labeled as first generation genomes are then converted into plasmids that antibodies. can subsequently produce specific Fabs in Patient often generated Abs to these foreign . bacteria.[9] These host antibodies are referred to as human anti- (b) Transgenic mice. Transgenic technology has been mouse antibody (HAMA) or human anti-rat antibodies or exploited to make a transgenic mice that have human anti-rabbit antibodies (HARA). The host antibody human Ab gene loci inserted into their bodies blocked the effectiveness of therapy by prematurely (using embryo stem cell method) and their own clearing the treatment antibodies and limiting possibilities genes for making antibodies ‘knocked out’. for future .[10] HAMA or HARA responses Therefore, mouse can be immunized with the could be associated with immune-complex related desired antigen and produces human Abs.[9] adverse events, such as serum sickness or anaphylaxis. (c) Phage display. This is another technique for making In addition, these first generation MAbs are not able to human MAbs. It is used when MAbs do not directly recruit human effector functions such as antibody- recognize antigen or when antigen is undetectable dependent cellular cytotoxicity (ADCC) and complement- normally and expressed only in disease. Phage dependent cytotoxicity (CDC), which cause destruction display libraries are available.[9] of a malignant cell. Plant genetic engineering has also led to the production of 2. Second generation MAbs. To overcome the obstacles of plant-derived MAbs (MAbsP), which provides a safe and first generation antibodies, Winter et al. pioneered the economically feasible alternative to the current methods of techniques to humanize MAbs, by removing the reactions antibody production in animal systems. Transgenic plants have that many earlier MAbs caused in some patients.[11] proven to be an efficient production system for the expression Nowadays, DNA technology or genetic engineering is used of functional therapeutic proteins. Plant-derived MAbP have to construct hybrids composed of human antibody the same advantages, namely, lack of animal pathogenic regions linked with a murine or primate backbone. These contaminants, low production cost and ease of agricultural are labeled as second generation MAbs and are referred scale-up compared with the conventional fermentation to as chimeric, humanized, primatized, or pure human methods. Since the initial report of functional MAbs expressed MAbs.[12,13] in transgenic plants, therapeutic and diagnostic MAbsP have (i) Chimeric Abs. These are composite of antibodies from been successfully produced in transgenic tobacco, soybean, two different species. The Ab combines the Ag alfalfa, and other plants. Two MAbsP have recently been used binding parts (variable region) of the mouse Ab with for topical passive.com). immunization against Streptococcus mutans the effector parts (constant region) of a human Ab, and herpes simplex virus in animals. Till date, no study has e.g., , , abciximab.[12,13] reported the use of systemic administration of MAbP to provide (ii) Humanized Abs. Human antibody containing the immunoprotection.[14,15] complementarity-determining region from a non- Large scale production of MAbs human source. The Ab combines only the amino acids responsible for making the Ag binding site (the.medknow The development of a commercial hypervariable region) of a mouse Ab with the rest of production process involves much more than just scaling-up human Ab molecule thus replacing its own the laboratory process and making it cost-effective. It involves hypervariable regions, e.g., , herceptin, establishing the hybridoma cell bank with cells that are free of vitaxin.[12,13] (www adventitious agents such as viruses and mycoplasma, that have (iii) Primatized Abs. It is a composite of primate variable stability in continuous culture for antibody-production rate regions and human constant regions.[12,13] and cell viability and that do not have unusual or expensive (iv) Genetically Thisengineered PDFa Abs site. Fisab hosted portionavailable from by rodent forMedknow freemedia downloadrequirements. Publications The from style and mode of operation of the Abs is attatched to Fc portion of human Abs. Human bioreactor used to produce the antibody must be explored. MAbs have been produced by immortalizing human B The antibody-based product must be processed to high levels lymphocytes with the Epstein-Barr virus and using of purity and specific contaminants such as DNA and endotoxin special immunodeficient mice immunologically must be reduced to extremely low levels. Appropriate labeling reconstituted with immunocompetent cells of tissue. or drug conjugation methods must also be developed. The Using genetic engineering it is possible to make mouse- product must be formulated, so that it has performance human hybrid antibodies. characteristics that are stable over a reasonable period of time. (v) Human MAbs can be produced by the following Adequate test procedures must be developed to assure product techniques: purity, activity, stability, and safety on a lot-to-lot-basis. (a) Recombinant DNA technology. By inserting Compliance with drug regulations, guidelines, and procedures random human genes coding for variable Fab must be guaranteed. In the coming decade, it is likely that the portion of human Abs into the genome of two arms of biotechnology, hybridoma technology and filamentous bacteriophages. As the bacteriophage recombinant DNA technology, will be used together to generate replicate they display Fab portion Ab on their unique protein molecules.[16] surface. The bacteriophages are subsequently Nomenclature mixed with an antigen to select those producing complementary Fabs. Those bacteriophage The United States adopted name (USAN) Council has

Indian J Pharmacol | February 2007 | Vol 39 | Issue 1 | 5-14 7 Kaur et al.: Monoclonal antibodies outlined specific guidelines for the nomenclature of MAbs.[17] It delivers the toxic substance to where it is needed most, These guidelines provide a foundation of knowledge about a minimizing damage to normal cell. Examples are: specific MAb just by looking at the generic name. 1. - Radiolabeled MAb to treat B cell • All MAbs end in the suffix - mab. It is used to identify a non-Hodgkin’s . class of medicines. 2. - Radiolabeled MAb for non-Hodgkin’s • The infix preceding - mab denotes the source of the lymphoma product. 3. (Mylotarg) - Immunotoxin MAb e.g., u = human i = primate for AML. It is the only immunotoxin to receive FDA o = mouse e = hamster approval. It contains a toxin called calicheamicin. It is a = rat xi = chimera attached to an antibody directed against CD33 antigen zu = humanized present on cells, • The infix preceeding the source of the Ab refers to Mechanism of action of Mabs medicine target. The mechanism by which MAbs achieve therapeutic effect e.g., vi(r) – viral ci(r) - cardiovascular is not very clear. Potential mechanisms include:[19] ba(c) – bacterial co(l) – colonic tumor 1. Blocking or steric hindrance of the function of target li(m) – immune le(s) – infectious lesions antigen i.e., T-lymphocytes, B lymphocytes, tumour me(l) – ma(r) – mammary -α (TNFα) and (IL) which are go(t) – testicular tumor go(v) – ovarian tumor capable of transducing intracellular signals. pr(o) – prostate tumor tu(m) – miscellaneous tumor 2. Cytotoxicity to the cell expressing target AG by ADCC or When combining a target or disease infix stem with the source CDC. stem for chimeric or humanized MAb the last consonant of 3. Inhibition of growth factors: Epidermal growth factor this target syllable is often dropped to make the name more receptor (EGFR) is a cell surface receptor involved in pronounceable (e.g., -tum- changed to -tu-). regulation of cell proliferation and survival. Also new Target source MAb stem vessels grow to feed the cancer cells through this factor. e.g., ci(r) -xi -mab Abciximab Theses factors can be inhibited to arrest growth of cancer tu(m) -zu -mab cells e.g., act as EGFR inhibitor. • The starting prefix is a distinct syllable carrying no special Pharmacokinetics meaning and unique for each drug. If the product is MAbs are used by intravascular route and remain essentially radiolabeled or conjugated to another chemical such as a .com). intravascular. Intravenous injection may not always be toxin, a separate word is used to identify the conjugate. appropriate for long-term treatment for a variety of reasons. Types of MAbs that are used in treatment Hour-long infusions require a hospital environment and are often associated with mild to very severe side effects.[19] Naked MAbs Continuous and sustained delivery of antibodies can lead to These are those without any drug or radioactive material induction of neutralizing anti-idiotypic immune responses, attached to them. They attach themselves to specific Ag on.medknow which sometimes develop when massive doses of purified cells, e.g. cancer cells. They mark the cancer cells for the immunoglobulins are repeatedly injected into patients. immune system to destroy it. Others attach to certain Ag Additionally, the bioavailability of therapeutic antibodies is often sites called receptors where other molecules that(www stimulate detrimental to the treatment efficacy. They have small volume the cancer cell growth might otherwise attach. By blocking of distribution and limited tissue penetration. They remain in other molecules from attaching there, MAbs prevent cancer circulation for 2 days to 2 weeks. Another limitation is the high cells from growing rapidly. Some examples of naked MAbs cost of recombinant proteins certified for human use.[19] available for use are:This PDFa site is hosted available by forMedknow freeAntibodies download Publications can have from exquisite specificity of target 1. Trastuzumab - For advanced breast cancer recognition and thus generate highly selective outcomes 2. Rituximab - For B cell non-Hodgkin’s lymphoma following their systemic administration. While antibodies can 3. Cetuximab - For advanced have high specificity, the doses required to treat patients, 4. - For metastatic colorectal cancer particularly for a chronic condition, are typically large. 5. - For B cell chronic lymphocytic leukemia Fortunately, advances in production and purification Conjugated MAbs capacities have allowed for the exceptionally large amounts MAbs, because of their inherent specificity, are ideal of highly purified MAbs to be produced. Additionally, genetic targeting agents. They can be used to deliver radionuclides, engineering of antibodies has provided a stable of antibody- toxins, or cytotoxic drugs to a specific tissue or malignant cell like proteins that can be easier to prepare. population. These are attached to drugs toxins or radioactive Genetic manipulations of the immunoglobulin molecules atoms.[18] They are also referred to ‘tagged’ ‘labeled’ or ‘loaded’ are effective means of altering stability, functional affinity, antibodies. MAbs with radioactive particles attached are pharmacokinetics, and biodistribution of the antibodies referred to as radiolabeled and this type of therapy is known as required for the generation of the ‘magic bullet.’ radioimmunotherapy. MAbs attached to toxins are known as Adverse effects immunotoxins. The MAb acts as a homing device, circulating Adverse effects with MAbs are related to one of three in the body until it finds a cancer cell with a matching antigen. mechanisms:[20]

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1. Xenogenetic nature of MAb used Although T cells reappear in the circulation during the course 2. Suppression of physiological function of treatment, these cells are CD3-negative and are not capable 3. Activation of inflammatory cells or mediators after binding of T-cell activation. However, the use of OKT-3 was hampered of MAb to its target due to production of Ags and rapid clearance from circulation. Adverse effects with naked MAbs are usually mild and often This led to development of humanized OKT-3 which is under related to an ‘allergic’ reaction and occur while the drug is investigation.[27] being first infused. This reaction is attributed to massive Acute graft rejection is a T-cell mediated immune response cytokine release resulting from transient activation of T and depends on presence of IL-2. IL-2 binds to IL-2 receptor. lymphocytes.[19] Reactions may include fever, chills, weakness, In the search for more specific immunosupression with MAb headache, nausea, vomiting, diarrhea, low blood pressure, and L- 2 Receptor (IL-2R), that is expressed on T-cells, which rashes. Some MAbs cause leucopenia, , and were chosen as target. Chimeric and humanized MAbs, anemia. Conjugated MAbs cause more side effects and the , and daclizumab were developed to bind to IL- actual effects depend to which substance it is attached. 2R. They competitively antagonized IL-2 or caused Sometimes it also causes suppression of physiological function elimination of activated T-cells. They have been efficacious in depending on specificity of tissue targets. Thus anti- preventing acute rejection episode after renal transplant.[28– lymphocytes MAb cause immunosupression. There is also an 30] Table 1 lists the MAbs used in immunosupression. increased risk of infection and cancer development. AntiTNF- Autoimmune diseases - inhibition of autoimmune reactivity α MAb treatment has been reported to increase the reactivation For the treatment of autoimmune disease, MAbs need to of tuberculosis because it interferes with the cellular response target immune response cells, i.e., B or T-cells. MAb may against mycobacteria and this adverse effect is more in areas function as an immunosuppressant by removing activated with high incidence of tuberculosis.[21] AntiTNF-α MAb cells, blocking their function or normalizing elevated levels of treatment also leads to development of .[22] proinflammatory cytokine. Therapeutic targets in this Rituximab may lead to depletion of plasma cells and cause condition include T-cell surface Ags, T-cells activation Ags, hypogammaglobulinemia due to its action on B-cells.[23] molecules involved in T/B cell interaction, adhesion Therapeutic Potentials of MAbs molecules, and cytokines. The most promising result emerged from TNF-α blocking MAbs were being used in laboratory research and in medical therapy in rheumatoid arthritis (RA) and Crohn’s disease. tests since the mid 1970s, but their effectiveness in disease TNF is a cytokine produced by activated monocytes and treatment was limited. MAbs created much excitement in the macrophages..com). The cytokine is actively produced at the medical world and in the financial world in 1980s especially as synovial and mucosal sites of inflammation in RA and Crohn’s a potential cure for cancer. Although this resulted in great disease. It is involved in vasodilation, increased vascular optimism that a therapeutic ‘magic bullet’ could be engineered, permeability, and activation of platelets and regulation of success with MAbs was many years away. By early 21st century, production of acute phase proteins involved in inflammation. several drugs based on MAbs were introduced for a wide variety TNF is also actively produced in various infectious diseases of therapeutic uses. Herceptin, a humanized MAb for breast.medknow such as sepsis, malaria, adult respiratory disease syndrome, cancer treatment, became the first drug designed by and AIDS. biomolecular engineering approach to be approved by the TNF is considered to have an important role in FDA.[24] A recent survey suggested that ¼ of all biotech drugs autoimmune inflammatory disease.[31,32] This led to the in development are MAb based.[19] At least an (wwwadditional discovery of infliximab which is a chimeric MAb and found to 400 MAbs are under clinical trials to treat cancer, transplant be effective in various animal models and clinical trail for RA rejection or to combat autoimmune or infectious diseases.[25] and Crohn’s disease. It is clinically beneficial in Crohn’s It is now possible toThis obtain PDFengineereda site is hostedantibodies, available chimeric, by forMedknow freedisease, download reduces Publications the response from duration and also reduces or humanized or fully human MAbs via the use of phage display fistula formation.[33,34] The first trail of usefulness of infliximab technology or of transgenic mice. Important therapeutic [Table 1] in RA was shown in 1994.[35] Infliximab halts implications of MAbs are given in the preceding chapter. radiographic progression of RA and also clinically cures the Immunosupression - inhibition of alloimmune reactivity disease.[36,37] , a humanized IgG1 MAb is also In 1985, Muromonab CD-3 (OKT3) a murine MAb, was approved for the treatment of RA. It binds to soluble and cell the first to be approved by the US FDA for clinical use in membrane-bound TNF-α. It is proved to be efficacious and humans, for prevention of graft rejection in renal transplant halts radiological progression of the disease.[38,39] Anti TNF-α patient.[26] As first line or in steroid resistance rejection MAb treatment has shown promise in patients with therapy, OTK3 has proved efficacious and improved graft seronegative spondyloarthropathies and psoriatic arthritis.[40– survival. It specifically reacts with the T-cell receptor-CD3 42] Anti-IL-6 and anti-IL-6 receptor MAbs have also been found complex on the surface of circulating human T cells.[27] OKT3 to be useful in RA as IL-6 is elevated in patients with RA and binds to a glycoprotein (the 20-kd epsilon chain) on the CD3 levels of RA correlates with disease activity and extent of complex to activate circulating T cells, resulting in transient joint erosion.[43,44] activation of T cells, release of cytokines and blocking of T- Cancer cell proliferation and differentiation. Nearly all functional T Classical therapeutic modalities such as surgery, radiation, cells are transiently eliminated from the peripheral circulation. and chemotherapy not only fail to cure the great majority of

Indian J Pharmacol | February 2007 | Vol 39 | Issue 1 | 5-14 9 Kaur et al.: Monoclonal antibodies

Table 1

Monoclonal antibodies approved for use in therapeutics

Generic name Trade name Type of MAb Indication Mechanism of action

To suppress immune system Muromonab CD-3 Orthoclone OKT3 Murine monoclonal Renal graft rejection The first MAb approved for use in humans. It is an IgG2a antibody. Binds to a molecule of to form receptor-CD3 complex and prevents acute rejection of organ. Basiliximab Simulect Human–mouse chimaera Renal graft rejection Binds to the IL-2Rα receptor of T cells IgG1K Daclizumab Zenapax Humanized Renal graft rejection Binds to f IL-2 receptor on activated T cell surface Ranibizumab Lucentis IgG1 recombinant humanized Neovascular (wet) age-related Inhibits vascular endothelial IgG1 kappa isotype macular degeneration growth factor activity monoclonal antibodies Infliximab Remicade Human–mouse chimaera Rheumatoid arthritis Binds to and blocks TNF-α. IgG1 monoclonal antibodies Crohn’s disease Other uses Abciximab Reopro Human–mouse chimaera Antiplatelet Inhibits platelet clumping by binding to surface receptors that are normally linked by fibrinogen Xolair Recombinant DNA-derived Allergic asthma Binds to and prevent IgE binding to humanized IgG1 mast cells Tysabri Humanized monoclonal Multiple Sclerosis Attaches to alpha-4- and antibodies renders it unable to stick to VLA-4. .com). This interferes with the process by which lymphocytes are able to enter the CNS and thus reduce the damage that they cause in MS Raptiva Recombinant humanized Plaque psoriasis Interrupts the CD11A and lymphocyte IgG1 kappa monoclonal antibody function-associated antigen-1 interaction Adalimumab Humira Humanized monoclonal .medknowRheumatoid arthritis, It binds specifically to TNF-α and antibodies psoriasis blocks its interaction with the p55 and p75 cell surface TNF receptors Palivizumab Synagsis Humanized IgG1(www Antiviral For prophylaxis in premature infants monoclonal antibodies (Respiratory Syncytial virus) against Respiratory Syncytial virus infection and This PDFa site is hosted available by forMedknow free download Publications frombronchopulmonary dysplasia malignant tumors, but also their employment often leads to Unconjugated antibodies show significant efficacy in the severe and debilitating side effects. Immunotherapy as a treatment of breast cancer, non-Hodgkin’s lymphoma, and fourth modality of cancer therapy has already been developed chronic lymphocytic leukemia. Promising new targets for and proven to be quite effective. Strategies for the unconjugated antibody therapy include cellular growth factor employment of antibodies for anti- receptors, receptors, or mediators of tumor-driven include: (1) Immune reaction directed destruction of cancer angiogenesis and B cell surface antigens other than CD20. One cell, (2) interference with the growth and differentiation of immunoconjugate containing an antibody and a chemotherapy malignant cells, (3) antigen epitope directed transport of anti­ agent exhibits clinically meaningful anti-tumor activity in acute cancer agents to malignant cells, (4) anti-idiotype vaccines, myeloid leukemia.[46] Clinical trials of MAb therapy are in and (5) development of engineered (humanized) mouse progress for almost every type of cancer. Rituximab was the monoclonals for anti-cancer therapy. In addition, a variety of first MAb used for treatment of cancer [Table 2]. It is chimeric different agents (e.g., toxins, radionuclides, IgG-1 MAb directed against CD20, which is a transmembrane chemotherapeutic drugs, etc.) have been conjugated to protein on mature B-lymphocytes. Its efficacy has been mouse and human MAbs for selective delivery to cancer demonstrated against low grade and follicular non-Hodgkin’s cells.[45] lymphoma relapse.[47] Rituximab has also been useful in

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Waldenstrom’s macroglobulinemia, posttransplantation generated endothelial cells.[52] In Phase II clinical trial it has lymphoma, and multiple myeloma.[48-49] CD52 MAb (Campath­ shown promise in shrinking solid tumors. Bevacizumab which 1H) has also been studied to lyse malignant hemopoetic blocks the vascular endothelial growth factor (VEGF) receptor cells.[50] CD52 MAb provides an effective therapy for chronic has been approved by US FDA for the treatment of colorectal leukemia of T-cell or B-cell origin that is resistant to cancer.[53] Bevacizumab has shown promising results in clear- conventional chemotherapy. Anti-tumor therapy with MAbs cell renal cancer in various clinical trials.[54] The promising targets growth factor receptor too. result of naked and conjugated type MAb in cancer may make Angiogenesis also plays a central role in the growth and MAb therapy significant in the management of these patients. of cancers. Antibodies directed against EGFR It is expected that MAb-based immunotherapy may be directly inhibit the growth of tumors bearing such receptors. accepted as a conventional form of therapy and employed Trastuzumab, a humanized Ab targets HER2 receptor found not only in terminal cancer patients but also, in other in breast cancer. It is the first MAb approved by US FDA for instances like, during and following surgical resection. the treatment of solid tumors.[51] Trastuzumab blocks HER2 Antiplatelet therapy receptor action and this receptor is expressed on the surface Table 2 shows various MAbs used in therapeutics. Acute membrane of tumor cells in 30% patients with breast cancer coronary syndromes and percutneous coronary intervention and signifies poor prognosis. Strategies aimed at interfering share a common physiological mechanism of intimal with tumor blood supply offer promise for new cancer disruption and platelet aggregation. Glycoprotein IIb/IIIa therapies. Vitaxin (an anti-alpha-v/beta-3 antibody) interferes receptor antagonist which interrupt the final common with blood vessel formation by inducing in newly pathway of platelet activation and aggregation are used for

Table 2

Monoclonal antibodies approved for use in malignancy

Generic name Trade name Monoclonal antibodies type Indication Mechanism of action

Rituximab Rituxan Human–mouse chimaera IgG1 Lymphoma Binds to CD20 molecule found on most B-cells. Transtuzumab Herceptin Humanized monoclonal Metastatic breast Binds to HER2, a receptor for epidermal growth antibodies cancer factor (EGF) found on tumour cells i.e. breast .com).cancer , lymphoma. Stops cell division and growth. Gemtuzumab Mylotarg Recombinant humanized IgG4, AML Conjugate of MAb with calicheamicin. ozogamicin kappa antibody Calicheamicin is an oligosaccharide which causes double strand break in DNA. First immunotoxin to fight against cancer. MAb binds .medknow to CD33 expressed by cancerous cells in AML. Alemtuzumab Campath Recombinant DNA-derived CLL Binds to CD52 molecule on WBC humanized MAb Ibritumomab Zevalin Conjugated MAb Non-Hodgkin’s Conjugate of MAb to either Radioisotope tiuxetan (www Lymphoma • Indium-111 • Yttrium-90 Binds to CD20 molecule on B cells and This PDF is available for free downloadlymphoma from Tositumomab Bexxar a Conjugatedsite hosted MAb by MedknowNon-Hodgkin PublicationsConjugate of MAb with I131. Binds to CD-20 lymphoma expressed on normal B-cells Cetuximab Erbitux Recombinant, human/mouse Colorectal Head and Blocks HER1, epidermal growth factor receptor chimeric MAb Neck cancer Becavizumab Avastin Humanized MAb Colorectal cancer Blocks vascular endothelial growth factor receptor. Lymphocide Humanized MAb. Completed Indolent and aggressive Binds to CD22 on B cell. Phase II study NHLs, autoimmune diseases like SLE and Sjogren’s syndrome 131ILym-1 Oncolym Mouse MAb B-cell non-Hodgkin’s Binds to HLA-DR encoded histocompatibility Ag lymphoma. Currently in expressed at high levels on lymphoma cells Phase III trial. Vitaxin Humanized monoclonal antibody Solid tumours Blocks the vascular integrin (alpha-v/ beta-3) found on blood vessels of tumour Edrecolomab Panorex Murine MAb Colorectal cancer Binds to glycoprotein 17-1 A.

MAb - Mmonoclonal antibodies

Indian J Pharmacol | February 2007 | Vol 39 | Issue 1 | 5-14 11 Kaur et al.: Monoclonal antibodies acute therapy. Abciximab was the first antagonist to be and thus could slow the disease progression.[67] evaluated [Table 1]. It inhibits the clumping of platelets by Refractory Wegener’s granulomatosis binding to surface receptors that normally are linked by Humanized antilymphocyte MAbs may provide an effective fibrinogen. It is helpful in preventing the reclogging of the treatment in patients with systemic vasculitis which is coronary arteries.[55-57] refractory or intolerant to steroids or cytotoxic agents.[68] Infectious disease Systemic erythematosus (SLE) Palivizumab, a humanized MAb directed against IL-6 levels are elevated in human and murine SLE. Blocking Respiratory Syncytial virus is used for the treatment of the action of IL-6 ameliorates disease activity in murine model premature infants and infants with bronchopulmonary of SLE. A humanized MAb is in Phase I of clinical trial. T cells, dysplasia [Table 1].[58] A MAb was also found to be useful to B cells and monocytes from patients with SLE expressess CD40 cure West Nile fever in mice.[59] L on their surface which have been found to produce Opthalmological disorders autoantibodies in vitro.[69] Therefore, humanized anti-CD40L Daclizumab has shown to be efficacious for noninfectious IDEC-131 was tried for SLE but not found to be successful.[70] uveitis.[60] Ranibizumab (Lucentis) is a recombinant humanized Another humanized anti-CD40L Mab, ruplizumab was effective IgG1 kappa isotype monoclonal antibody fragment designed in SLE, but increased the incidence of myocardial infarction. for intraocular use, which competitively binds and inhibits Therefore the trials were discontinued.[71] VEGF. Therefore, indicated for the treatment of neovascular Rituximab has also been shown to be effective in patients (wet) age related macular degeneration.[61] of SLE with glomerulonephritis,[72] by causing B-cell depletion. B-cells in SLE display abnormal signaling, express aberrant Multiple sclerosis cell surface markers and finally produce autoantibody and Natalizumab, a humanized MAb was approved by FDA in present auto antigen to T cells at increased rates.[73] November, 2004 for relapsing form of multiple sclerosis, but was withdrawn in February 2005 after three patients in the Active immunotherapy drug’s developed progressive multifocal leukoencephalopathy Direct evidence of the importance of gangliosides as (PML) during clinical trial.[62,63] On 24th March, 2006 the FDA potential targets for active immunotherapy has been suggested lifted the hold on clinical trials of natalizumab after confirming by the observation that human MAbs against these glycolipids that there were no additional PML cases. In March, 2006, FDA induce shrinkage of human cutaneous melanoma metastasis. consulted its advisory committee on drugs for peripheral and Thus, the cellular over-expression and shedding of gangliosides central nervous systems about the possibility of making into the interstitial.com). space may play a central role in cell growth natalizumab available to appropriate MS patients. The regulation, immune tolerance and tumor-angiogenesis, thereby committee recommended a risk-minimization program with representing a new target for anticancer therapy.[74] Anti- mandatory patient registration and periodic follow-up.[63] iodiotype vaccine has been developed from proteins derived from the outer membrane proteins of Neisseria meningitidis Asthma B. 1E10 vaccine, is an anti-idiotype vaccine designed to mimic Omalizumab MAb has shown promise in allergic asthma the N-Glycolyl-GM3 gangliosides. This monoclonal antibody is [Table 1]. It acts by binding to IgE thus preventing IgE from .medknowan Ab2-type-antibody which recognizes the Ab1 antibody called binding to mast cells. Omalizumab has shown to reduce serum P3, the latter is a MAb that specifically recognize gangliosides IgE levels, reduce inhaled steroid consumption and was also as antigens. Results of the phase I clinical trials proved that well tolerated by children and adults.[64] (www the three vaccines were safe and able to elicit specific antibody Psoriasis responses. Phase II trials are being undertaken in several Data suggest that MAbs directed against T-cell mediated neoplastic diseases, with these vaccines.[74] Vaccination of inflammation are clinicallyThis effective PDFa site in the is treatmenthosted available of psoriasis. by forMedknow freeimmunologically download Publications responding from metastatic colorectal MAbs directed against key components of inflammatory process patients with SCV 106 leads to slowing of disease progression, have been studied for safer, selective, and effective tumor dissemination and significantly prolongs survival time.[75] immunosuppressant agent as psoriasis is a T-cell mediated Increased CMI responses to HIV-1 envelope glycoprotein autoimmune disease in which proinflammatory Th-1 cytokine measured by lymphocyte proliferation were associated with play an essential role. Efalizumab is the agent that is near the HIV-1 recombinant envelope glycoprotein vaccines.[76] HIV-1­ market launch [Table 1]. It is a humanized MAb that interrupts specific T helper cell responses can be successfully increased the interaction between the T-cell surface molecule lymphocyte by therapeutic immunization in individuals with chronic function associated antigen LFA1 (composed of 2 subunits infection on suppressive antiretroviral therapy.[77] Further CD11a and CD18) and intercellular adhesion molecule1, which studies will be needed to determine whether the augmentation is found on the surface of antigen-presenting cells. It is used as of these responses correlate with long-term clinical benefits. [65,66] a once weekly self-administered subcutaneous injection. It In diagnostics is administered every other week and carries a risk of tuberculosis Generally, MAbs are being used as invaluable reagents in reactivation, serious infections, and demyelinating disease. diagnostics. In fact, they have played a major role in deciphering Juvenile diabetes the functions of various bio-molecules in cryptic biosynthetic Anti-CD3 MAb is in phase II trial for type I juvenile DM. pathways. These have also become the reagents of choice for This MAb targets an antigen expressed on T lymphocytes identification and characterization of tumor specific antigens that is responsible for destruction of islet cells of pancreas and have become a valuable tool in the classification of

12 Indian J Pharmacol | February 2007 | Vol 39 | Issue 1 | 5-14 Kaur et al.: Monoclonal antibodies cancer.[78] The ability of MAb to accumulate at tumor sites, led monoclonal antibodies for immunoscintigraphy and immunotherapy. Semin to its approval for localization of cancer, for example, Nucl Med 1989; 19:202-20. igorvomab for ovarian cancer, teenamab K-1 for melanoma, 17. Van Laan S. Nomenclature for biological products: Monoclonal antibodies. American medical association. [cited 2006 Feb]. Available from: votumab, and acrolunumab for colorectal cancer and sulemab www.ama-assn.org. for detection of infection.[19] MAbs will be useful agents for 18. Weiner LM. An overview of MAb therapy of cancer. Semin Oncol 1999;26: diagnostic imaging of prostate cancer.[79] MAbs are used 41-50. commercially in pregnancy tests where they are directed 19. Breedveld FC. Therapeutic monoclonal antibodies. Lancet 2000;355:735­ against proteins in urine, determine glucose level in diabetes, 40. 20. Pelegrin M, Gros L, Dreja H, Piechaczyk M. Monoclonal antibody-based genetic detect antibiotic residues in milk, and to detect salmonella immunotherapy. Curr Gene Ther 2004;4:347-56. too. 21. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor Conclusion alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. MAbs are new biological agents that have good clinical 22. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: The effect of effects and an extended choice in the treatment spectrum to and anti tumor necrosis factor therapy in 18572 patients. Arthritis Rheum 2004;50:1740-51. the patients who were not responding to the existent 23. Tsokos GC. B cells-be gone. B-cell depletion in the treatment of rheumatoid treatments. The use of MAbs for the treatment of autoimmune arthritis. N Engl J Med 2004;350:2546-8. diseases, infections, and malignancies is an evolving field. New 24. Ryu DD, Nam DH. Recent progress in biomolecular engineering. Biotechnol therapeutic approaches are rapidly emerging and further Prog 2000;16:2-16. studies may help in designing more specific MAbs that would 25. Desgranges C. Monoclonal antibodies and theapeutics. Pathol Biol 2004;52:351-64. spare the normal tissue, have less adverse effects and improve 26. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of the patient’s quality of life. Soon, new therapeutic drugs and cadaveric renal transplants. Ortho multicenter transplant study group. N Engl high-value biomolecules will be designed and produced by J Med 1985;313:337-42. biomolecular engineering for the treatment and prevention of 27. Norman DJ, Vincenti F, de Mattos AM, Barry JM, Levitt DJ, Wedel NI, et al. not-so-easily cured diseases such as cancers, genetic diseases, Phase I trial of HuM 291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. Transplantation 2000;70:1707-12. age-related diseases, and other metabolic diseases. 28. Nashan B, Moore R, Amlot P, Scmidt AG, Abeywickrama K, Soulillu JP. References Randomized trial of basiliximab versus placebo for control of acute ceelular rejectionin renal allograft recepints. Lancet 1997;350:1193-8. 1. Baker DD. Monoclonal antibodies. Indian J Med Sci 2001;55:651-4. 29. Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, et al. 2. The future of monoclonal antibody therapeutics: Innovation in antibody Interleukin-2.com). receptor blockade with daclizumab to prevent acute rejection in engineering, key growth strategies and forecasts to 2011; 2006: Available from renal transplantation. N Engl J Med 1998;338:161-5. http://www.research and markets.com/report. 30. Nashan B, Light S, Hardie IR, Lin A, Johnson JR. Reduction of acute renal 3. Frenken LG, Hessing JG, Van den Hondel CA, Verrips CT. Recent advances allograft rejection with daclizumab. 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