WHO DRUG INFORMATION VOLUME 20• NUMBER 3 • 2006 RECOMMENDED INN LIST 56 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA WHO Drug Information Vol 20, No. 3, 2006 World Health Organization WHO Drug Information Contents Biomedicines and Vaccines Counterfeit taskforce launched 192 Fake artesunate warning sheet 193 Monoclonal antibodies: a special Resolution on counterfeiting 193 regulatory challenge? 165 Improving world health through regulation of biologicals 173 Regulatory Action and News Influenza virus vaccines for 2006–2007 Safety and Efficacy Issues northern hemisphere 196 Trastuzumab approved for primary Global progress in monitoring immuniza- breast cancer 196 tion adverse events 180 Emergency contraception over-the- Intracranial haemorrhage in patients counter 197 receiving tipranavir 180 Ocular Fusarium infections: ReNu Infliximab: hepatosplenic T cell MoistureLoc® voluntary withdrawal 197 lymphoma 181 Saquinavir: withdrawal of soft gel Lamotrigine: increased risk of non- capsule Fortovase® 197 syndromic oral clefts 181 Latest list of prequalified products and Biphosphonates: osteonecrosis of manufacturers 198 the jaw 181 Clopidogrel: new medical use 199 Enoxaparin dosage in chronic kidney Dronedarone: withdrawal of marketing disease 182 authorization 199 Terbinafine and life-threatening blood dyscrasias 183 Adverse reactions in children: why Recent Publications, report? 183 Hepatitis B reactivation and anti-TNF- Information and Events alpha agents 185 MSF issues ninth antiretroviral price list 200 Dolasetron mesylate and serious Progress in HIV/AIDS medicine access 200 cardiovascular reactions 185 Antiretroviral treatment failure and Valproic acid and pancreatitis in a child 185 patient support 200 Safety updates 186 Nanotechnology-based medicinal Concomitant ibuprofen and acetyl- products 201 salicylic acid 188 Public health, innovation and intellectual property rights 202 Topics of Current Interest Expert Committee on Drug Dependance: Recommended International recommendations 190 Nonproprietary Names: Lack of essential medicines for children 191 Access to new medicines by developing List 56 203 countries 191 163 World Health Organization WHO Drug Information Vol 20, No. 3, 2006 WHO Drug Information e-mail table of contents and subscriptions available at: http://www.who.int/druginformation 164 WHO Drug Information Vol 20, No. 3, 2006 Biomedicines and Vaccines Monoclonal antibodies: a special regulatory challenge? Use of monoclonal antibodies is an important domain of the mAb— Fab part — and for development in the search for new therapeutic some types mediate cytotoxicity with their Fc agents. Monoclonal antibody (mAb) technol- part, which binds and activates, complements ogy allows production of large amounts of and/or interacts with receptors on antigen- pure antibodies which are potentially more presenting cells. effective than conventional drugs in targeting disease. However, although mAbs have Using these molecules to neutralize or even revolutionized modern medicine, they show attack pathologic structures is not a new idea. special peculiarities. Recent events in the In 1900, Paul Ehrlich proposed that certain United Kingdom and United States have been compounds could be used to selectively target reported where subjects subsequently external pathogens or even tumours, repre- developed dramatic adverse reactions during senting “magic bullets” (1). However, the use clinical tests and also following use of a of antibodies to target structures and use them marketed product. As a consequence, the as medicines was for a long time hampered by regulatory requirements and level of safety a lack of methods to generate viable B cell evaluation for high risk mAbs may need clones. reconsideration. This became possible in 1975 through Antibodies or immunoglobulins are physiologi- identification of hybridoma technology by cal blood components produced by B cells Köhler and Milstein (2). This employs a fusion and intended to bind to and neutralize foreign of murine B cells derived from the spleen of antigens and pathogens. Johann Wolfgang immunized donors to mouse myeloma cells. von Goethe in his famous tragedy “Faust” has With this principle, the ability of the B cell to rightly identified blood as “a very special produce antibodies was combined with the juice”. In today’s view, this description would infinite growth of a tumour cell within one also cover cellular and molecular blood cellular system while allowing for the produc- components, including immunoglobulins. tion of specific antibodies. With this develop- ment, Paul Ehrlich’s dream of a magic bullet Most non-cellular blood components, such as became reality. immunoglobulins or clotting factors, are highly complex biological molecules both as regards Evolution of monoclonal antibodies structure and mechanism of action. Their The first monoclonal antibody products to be clinical investigation requires special consid- licensed were fully murine. An immune re- eration and this article reviews use of mAbs in sponse against the murine mAb is mounted therapeutics, describes the peculiarities of this upon exposure in humans, and often led to a product class, and how — from a regulator’s reduction of efficacy by neutralizing antibodies perspective — clinical trials should be consid- or to safety problems such as infusion reac- ered with regard to approval and product tions. In order to reduce immunogenicity (3), dossier requirements . scientists initiated an evolutionary process, commencing with chimeric antibodies. The Paul Ehrlich’s magic bullet International Nonproprietary Name (INN) of Antibodies bind to a corresponding antigen in these molecules commonly ends with the a highly specific manner, like a key in a lock. suffix “-ximab”, representing the chimeric They recognize their antigen with the variable principle (fe.g., infliximab, Remicade®). Article prepared by Dr. Christian K Schneider, Paul-Ehrlich-Institut, Federal Agency for Sera and Vaccines, Germany. Correspondence to: [email protected] 165 Biomedicines and Vaccines WHO Drug Information Vol 20, No. 3, 2006 As a next step, mAbs were humanized by tumour cells. Recently, a new principle has insertion of human sequences (suffix: -zumab, been added to the armamentarium — target- e.g., trastuzumab, Herceptin®). Using the ing of tumour vascularization by neutralization latest techniques, production of fully human of human vascular endothelial growth factor mAbs has become possible and has reduced (VEGF) by bevacizumab (Avastin®). immunogenicity even further (suffix: -umab). The only fully human mAb licensed so far in The second mechanism is the classical anti- Europe is adalimumab (Humira®), an antibody infective principle. An example is palivizumab against human tumour necrosis factor alpha (Synagis®), which is directed against the (TNF-alpha). antigenic site A on the fusion or F protein of respiratory syncytial virus (RSV). MAbs have also undergone an evolution from a functional point of view. While the classical The third, and quite popular, mechanism of approach of neutralizing infectious agents or action is modulation of the immune system by attacking tumour cells with mAbs is still being neutralizing cytokines or antagonistic targeting used and represents a powerful tool, the trend of membrane-bound activation molecules. is to develop more specific targets, such as Examples are: immunomodulators binding to substructures of physiological molecules. A recent example is • adalimumab (Humira®) and infliximab the anti-CD28 mAb TGN1412, directed (Remicade®) which target soluble and against a distinct substructure of the human membrane-bound TNF-alpha; CD28 molecule, the C’’D loop (4), exhibiting a distinct pharmacodynamic effect. This “supra- • efalizumab (Raptiva®) which binds to the agonist” has gained sad attention due to CD11-a subunit of lymphocyte function- serious adverse events during a first-in-man associated antigen 1 (LFA1) on leukocytes. trial in the United Kingdom (5). • basiliximab (Simulect®) and daclizumab Additionally, compounds with different mecha- (Zenapax®) which block T cell activation by nisms of action have been developed, such as interaction with a part of the interleukin-2 mAbs coupled to cytotoxic agents, radio- receptor (IL-2R), the CD25 antigen on T nuclides, or bispecific antibodies (combina- cells. In this way, both antibodies inhibit tions of different antigen specificities within binding of the T cell activating cytokine one molecule). Since it has been shown that interleukin-2 (IL-2). the strength of interaction with the Fc receptor on monocytic cells is also of high importance Another licensed mAb, which cannot be to efficacy, (6, 7), engineering to enhance (8) subsumed to these three basic mechanisms, or lower Fc receptor interaction has also is abciximab (ReoPro®), a chimeric Fab gained some interest in the pursuit of more fragment directed against the glycoprotein- efficacious and/or safe mAbs. (GP) IIb/IIIa-(αIIbβ3) receptor on human thrombocytes. This is indicated in cardiological Currently licensed mAbs indications like unstable angina pectoris or Information on 15 currently licensed mAbs is percutaneous coronary intervention. available in scientific journals or from the European Public Assessment Reports on the Need for a holistic approach European Medicines Agency (EMEA) website Monoclonal antibodies are high molecular (9). Besides diagnostic antibodies like sule- weight proteins with complex secondary and somab (Leukoscan®),