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History and Practice: Antibodies in Infectious Diseases

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  • Author: Adam Hey1
  • Editors: James E. Crowe Jr.2, Diana Boraschi3, Rino Rappuoli4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Preclinical Safety, Biologics, Novartis AG, Basel, Switzerland; 2: Vanderbilt University School of Medicine, Nashville, TN; 3: National Research Council, Pisa, Italy; 4: Novartis Vaccines, Siena, Italy
  • Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.AID-0026-2014
  • Received 14 November 2014 Accepted 15 November 2014 Published 13 March 2015
  • Adam Hey, adamhey8@gmail.com
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  • Abstract:

    Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with and . However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments.

  • Citation: Hey A. 2015. History and Practice: Antibodies in Infectious Diseases. Microbiol Spectrum 3(2):AID-0026-2014. doi:10.1128/microbiolspec.AID-0026-2014.

Key Concept Ranking

Immune Systems
0.62519383
Complement System
0.5966828
Viral Proteins
0.51189905
Infectious Diseases
0.4655191
0.62519383

References

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30. Weintraub JA, Hilton JF, White JM, Hoover CI, Wycoff KL, Yu L, Larrick JW, Featherstone JD. 2005. Clinical trial of a plant-derived antibody on recolonization of mutans streptococci. Caries Res 19:241–250. [PubMed][CrossRef]
31. Baer M, Sawa T, Flynn P. 2009. An engineered human antibody Fab fragment specific for Pseudomonas aeruginosa PcrV antigen has potent anti-bacterial activity. Infect Immun 77:1083–1090. [PubMed][CrossRef]
32. Secher T, Fauconnier L, Szade A. 2011. Anti-pseudomonas aeruginosa serotype 011 LPS immunoglobulin M monoclonal antibody panobacumab (KBPA101) confers protection in a murine model of acute lung infection. J Antimicrob Chemother 66:1100–1109. [PubMed][CrossRef]
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34. Lowy I, Molrine DC, Leav BA. 2010. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362:197–205. [PubMed][CrossRef]
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36. Broering TJ, Garrity KA, Boatright NK. 2009. Identification and characterization of broadly neutralizing human monoclonal antibodies directed against the E2 envelope glycoprotein of hepatitis C virus. J Virol 83:12473–12482. [PubMed][CrossRef]
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39. Li L, Sun T, Yang K. 2010. Monoclonal CCR5 antibody for treatment of people with HIV infection (review). Cochrane Database Syst Rev 8:CD008439. [PubMed][CrossRef]
40. Quiambao B, Bakker A, Bermal NN. 2009. Evaluation of the safety and neutralizing activity of CL184, a monoclonal antibody cocktail against rabies, in a phase II study in healthy adolescents and children. Quebec, Canada: Presentation at RITA XX, Rabies in the Americas.
41. Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA. 2005. Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18b7 in subjects with treated cryptococcal meningitis. Antimicrob Agents Chemother 49:952–958. [PubMed][CrossRef]
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2015-03-13
2017-11-23

Abstract:

Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with and . However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments.

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Figures

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FIGURE 1

(Left panel) Model of antibody structure exemplified by IgG. On top the antigen-binding sites in orange each contain one variable light and variable heavy domain with the three complementarity determining regions (CDRs) that are responsible for the specific binding of the antibody to its target. For each arm of the antibody, an additional set of variable heavy and light domains, together with the CDR-containing domains, represent the two fragment antigen binding (Fab) regions. The two Fabs are held together via two disulfide bridges. Below the Fabs is the Fc region, which contains four constant heavy domains. On the upper pair of these domains are binding sites for oligosaccharides, which have major importance for the ability of the antibody Fc part to trigger effector functions when the Fc portion is bound to Fc gamma receptors on natural killer cells, neutrophil granulocytes, monocytes/macrophages, dendritic cells, and B cells. (Right panel) Examples of some of the antibody-derived alternative formats used to exploit the specific features of the CDRs, the Fabs, and the Fc parts of the antibodies. ScFv: The single chain fragment variable consists of the variable domains of the heavy and light chains held together by a flexible linker. This can also be used as a carrier of a cytotoxic drug in a so-called antibody drug complex (ADC) where the specificity of the ScFv is used to target the cytotoxic drug to, e.g., a tumor. Bite (bi-specific T cell engager): Fusion proteins consisting of two ScFvs, one directed against the target on a tumor cell and the other against the T cell receptor (CD3). Diabody: ScFv dimers where short linker peptides (five amino acids) ensure dimerization, and not folding, of the ScFvs. Fab and F(ab) fragments: Single Fab fragments or fragments containing two Fabs linked via disulfide bridges. This is used where effector functions related to the Fc part of the antibody are unwanted and where a smaller size is desired to obtain better tissue penetration in, e.g., tumors. Due to the lack of the FcRn binding via the Fc part, Fab and F(ab) fragments have much shorter half-lives (hours or days) than full-size antibodies (weeks). These can also be used as carriers of cytotoxic payloads or cytotoxic radioactive isotopes and for the F(ab) fragments can be constructed as bi-specifics which can cross-link immune cells and target cells. Fc fusion protein: Fusion protein containing the Fc domain of an immunoglobulin bound to a peptide. The peptide can be a ligand for a specific receptor on a target cell or a blocking peptide for a soluble ligand. The Fc part provides a longer half-life to the construct and the potential to bind to and engage effector functions in the killing of, e.g., tumor cells or infected cells. ADCs/RIAs and bi-specifics: Full-size IgG antibodies carrying either a cytotoxic chemical or radioactive payload, which may also carry different CDRs, enabling cross-linking of effector and target cells for increased killing. doi:10.1128/microbiolspec.AID-0026-2014.f1

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.AID-0026-2014
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FIGURE 2

Effector functions of antibodies. (a) Antibodies bind to pathogen-derived or endogenous antigens expressed on the surface of an infected cell, which triggers binding to Fc receptors on natural killer cells and lysis of the infected cell by antibody-dependent cellular cytotoxicity. (b) Antibodies bind to pathogen-derived or endogenous antigens expressed on the surface of infected cells, which triggers activation of complement through binding of complement factor C1q. (c) Neutralization. Top: Bacterial toxin neutralized by bound antigen. Bottom: Antibody bound to either receptor for the virus or to the virus itself, which blocks virus binding and entry into the cell. (d) Antibody bound to viral surface proteins binds to Fc receptors on phagocytic cells, e.g., macrophages, and triggers endocytosis and destruction of virus in endolysosome. doi:10.1128/microbiolspec.AID-0026-2014.f2

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.AID-0026-2014
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Tables

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TABLE 1

Approved and pending antibody-based therapies

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.AID-0026-2014
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TABLE 2

Pros and cons of antibody based therapies related to serum therapy and antibiotics

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.AID-0026-2014

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