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Antibody-Based Therapies for Emerging Infectious Diseases Arturo Casadevall, M.D., Ph.D

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Antibody-Based Therapies for Emerging Infectious Diseases Arturo Casadevall, M.D., Ph.D View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Synopses Antibody-Based Therapies for Emerging Infectious Diseases Arturo Casadevall, M.D., Ph.D. Albert Einstein College of Medicine, Bronx, New York, USA In the 19th century, it was discovered that immune sera were useful in treating infectious diseases. Serum therapy was largely abandoned in the 1940s because of the toxicity associated with the administration of heterologous sera and the introduction of effective antimicrobial chemotherapy. Recent advances in the technology of monoclonal antibody production provide the means to generate human antibody reagents and reintroduce antibody therapies, while avoiding the toxicities associated with serum therapy. Because of the versatility of antibodies, antibody-based therapies could, in theory, be developed against any existing pathogen. The advantages of antibody-based therapies include versatility, low toxicity, pathogen specificity, enhancement of immune function, and favorable pharmacokinetics; the disadvantages include high cost, limited usefulness against mixed infections, and the need for early and precise microbiologic diagnosis. The potential of antibodies as antiinfective agents has not been fully tapped. Antibody-based therapies constitute a potentially useful option against newly emergent pathogens. In the mid-1990s, successful implementation of antiinfective therapy has become increasingly diffi- SERUM TREATMENT cult because of widespread antimicrobial resistance, of Pneumonia the emergence of new pathogens, and the occurrence ntil recently the use of an unconcentrated serum for type I infec of many infections in immunocompromised patients Utions represented the only serum treatment for pneumonia which had gained general recognition. While this serum did not affect Type II, in whom antimicrobial drugs are less effective. Type III or Group IV cases, it proved to be a very effective therapeutic agent Infections caused by some new pathogens in Type I cases in which it was used intravenously in large doses. (e.g., human immunodefficiency virus [HIV] and The obvious difficulties attendant upon the use of large doses of unconcentrated anti-pneumococcus serum have been greatly reduced, Felton Cryptosporidium parvum) cannot be cured with ex- and other having succeeded in evolving not only an effective highly con- isting antimicrobial drugs. Regaining the upper centrated Type I serum but also a corresponding Type II serum. This hand in the struggle against microbes requires achievement is of very real significance, since Type I or Type II pneumo- cocci are the causative agents in over fifty per cent of all cases of lobar multidisciplinary efforts which include developing pneumonia. new antimicrobial agents (1), improving surveillance Promising results have been obtained from the intravenous use of con- for emerging microbial threats (2), teaching the cor- centrated anti-pneumococcus sera prepared in the Connaught Laboratories, and supplies of these sera are now being made available in four containers rect use of antimicrobial therapy (3), expanding the as follows: use of vaccines to prevent infection (4), developing 5 cc. & 10 cc. Concentrated Anti-Pneumococcus Serum (Type I) adjunctive immunotherapies (5), and conducting 5 cc. & 10 cc. Concentrated Anti-Pneumococcus Serum (Type II) new basic research on the mechanisms of pathogen- Should there be occasion to administer serum prior to receipt of a esis and drug resistance. In this article, the potential report of the typing of a case, a physician may mix these sera. of antibody therapy in confronting the threat of Prices and information regarding the use of Type I emergent infections will be explored. and Type II concentrated Anti-Pneumococcus Sera will be gladly supplied upon request. Antibody-Based Therapies: Then and Now CONNAUGHT LABORATORIES University of Toronto Antibody-based (serum) therapies were first used TORONTO 5 • CANADA to treat human infections in the 1890s (6,7). In the Figure 1. Advertisement for type-specific anti-pneumo- early 20th century, serum therapy was used to treat coccal sera from the March 1931 issue of the Canadian a variety of bacterial infections, including Medical Association Journal. The text in this advertise- those cased by Corynebacterium diphtheriae, Strep- ment describes advancements in the preparation of antibody solutions and emphasizes the need for using Address for correspondence: Arturo Casadevall, M.D., Ph.D., type-specific serum in the therapy of pneumococcal pneu- Department of Medicine, Albert Einstein College of Medicine, monia. Note the suggestion that type-specific serum can 1300 Morris Park Ave., Bronx, New York 10461, USA; fax: be mixed for empiric therapy of pneumonia. (Reprinted 718-340-8968; e-mail: [email protected]. with permission.) Reprinted from Emerging Infectious Diseases Vol. 2, No. 3, 200-208, July-September 1996 Emerging Infectious Diseases 200 Vol. 2, No. 3—July-September 1996 Synopses Table 1. Serum therapy, human MAbs, and antimicrobial chemotherpy Vol. 2, No. 3—July-September 1996 201 Emerging Infectious Diseases Synopses tococcus pneumoniae, Neisseria meningitides, donment of antibodies as antimicrobial agents was Haemophilus influenzae, group A streptococcus, and followed by major advances in the technology of an- Clostridium tetani (6,7). By the 1930s, serum tibody production. In 1975, hybridoma technology therapy was standard treatment for lobar pneumo- provided the means to generate unlimited amounts nia (Figure 1). Several large controlled trials showed of monoclonal antibodies (MAbs) (19). In recent that administering type-specific serum reduced the years, major advances have been made in the tech- death rate in patients with pneumococcal pneumo- niques used to generate human antibodies and nia by approximately 50% (6). However, when humanize murine MAbs (20). antimicrobial chemotherapy was discovered in the The juxtaposition of three recent developments mid-1930s, serum therapy for bacterial infections makes the reintroduction of antibody-based thera- was rapidly abandoned. Antimicrobial chemotherapy pies an option for serious consideration. First, had important advantages over serum therapy: it because of advances in technology, human antibody was more effective and less toxic. The immediate reagents can be synthesized; thus the toxicities tra- side effects of serum therapy included fevers, chills, ditionally associated with serum therapy can be and allergic reactions (8,9). A delayed toxic reaction avoided. Second, the emergence of new pathogens, of serum therapy was “serum sickness,” a syndrome the reemergence of old pathogens, and the increased characterized by rash, proteinuria, and arthralgia; prevalence of drug-resistant microorganisms have this occurred in 10% to 50% of patients who received caused the effectiveness of existing therapeutic op- heterologous serum and was probably caused by tions to decline. Third, the difficulties involved in immune complexes. Other disadvantages of serum treating infections in immunocompromised patients therapy included the need to establish a precise di- suggest the need for adjunctive immunotherapy. agnosis before selecting serum, lot-to-lot variation of serum, and the need for considerable physician expertise (Table 1). Serum therapy could fail because Polyclonal Sera Versus Monoclonal Antibodies of inadequate dosage, delayed treatment, mis-label- for Therapy ing of serum, and because the infection was mixed Immune sera contain antibodies of multiple speci- or complicated (i.e., empyema) (10). Producing thera- ficities and isotypes. Problems with immune sera peutic sera was very expensive because of the costs include lot-to-lot variation (21), low content of spe- of animal husbandry, antibody purification, refrig- cific antibodies (22), and some hazards in the eration, and standardization by the mouse protection transmission of infectious diseases (23). Commer- tests. When antimicrobial chemotherapy was first cially available intravenous immunoglobulin introduced, enthusiasm was expressed for combin- preparations obtained from human donors differ in ing serum therapy and antimicrobial chemotherapy. their opsonic activity for common pathogens such Support for combined therapy came from animal as Staphylococcus epidermidis, H. influenzae type studies, which suggested that combination therapy b, S. pneumoniae, group B streptococcus, and was more effective than either therapy alone against Escherichia coli, reflecting the characteristics of the several pathogens, including group A streptococcus donor pool (22). In contrast MAbs are generated in (11), pneumococcus (12), and meningococcus (13), vitro by either hybridoma technology or recombinant and some authorities recommended combined DNA techniques. MAbs are homogenous immuno- therapy for serious infections (14,15). However, sev- globulins that, by definition, recognize one epitope eral studies showed that combined therapy was not and have markedly higher specific activity than more effective than antimicrobial chemotherapy polyclonal preparations. For example, 0.7 mg of two alone and that it caused significantly more side ef- human MAbs to tetanus toxin have the same activ- fects (16-18). Therefore, serum therapy was ity as 100 to 170 mg of immune globulin (24). The abandoned because it offered no measurable advan- higher specific activity of MAbs may also translate tage in efficacy over chemotherapy and had into greater therapeutic efficacy.
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