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Completed
Research on SP-D/anti-Fc receptor bifunctional proteins as a novel approach to the treatment of infectious diseases
FunderNetherlands Organisation for Scientific Research (NWO)
Duration01 Apr 2006 - 14 Jan 2011
Project code06488
Open Access mandatePublications: NoResearch data: No
Identifiers
Project timeline100%
Description
Because pathogens become increasingly resistant to therapeutic drugs, and because of the emergence of new pathogens, novel approaches to the treatment of infectious diseases are required. Recently, both the Fc" Receptor I (CD89) and the Fc( Receptor I (CD64) have been described as effective trigger molecules for bispecific antibody therapy. Bispecific antibodies, consisting of an antibody directed against a specific pathogen coupled to an antibody directed against either CD89 or CD64, promote effective phagocytosis and killing of the pathogen by phagocytes. In addition, targeting to CD64 leads to immunological memory ("vaccination effect"). A major disadvantage of the use of bispecific antibodies is the fact that each pathogen requires the generation of a new bispecific antibody. To circumvent this problem, we want to use collectins, such as surfactant protein D (SP-D), to target a broad spectrum of pathogens to Fc receptors. SP-D binds a great variety of pathogens via its carbohydrate recognition domain. We have already generated a bifunctional protein consisting of a recombinant fragment of SP-D (rfSP-D) chemically cross-linked to a F(ab) fragment of an antibody directed against human CD89. This bifunctional protein, designated rfSP-D/anti-CD89, markedly enhances uptake of influenza A virus, Candida albicans and Escherichia coli by human neutrophils in vitro, promotes neutrophil-mediated killing of C. albicans and E. coli, and enhances neutrophil activation by influenza A virus. In the project proposed here we will determine the effectiveness of rfSP-D/anti-CD89 in in vivo models of infection. We will compare it with a similar bifunctional protein rfSP-D/anti-CD64, which contains a F(ab) fragment against human CD64, and which may have the additional advantage of generating immunological memory. In addition, we will test whether the bispecific molecules can be produced as fusion proteins in an expression system. That would allow production on an industrial scale.
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Because pathogens become increasingly resistant to therapeutic drugs, and because of the emergence of new pathogens, novel approaches to the treatment of infectious diseases are required. Recently, both the Fc" Receptor I (CD89) and the Fc( Receptor I (CD64) have been described as effective trigger molecules for bispecific antibody therapy. Bispecific antibodies, consisting of an antibody directed against a specific pathogen coupled to an antibody directed against either CD89 or CD64, promote effective phagocytosis and killing of the pathogen by phagocytes. In addition, targeting to CD64 leads to immunological memory ("vaccination effect"). A major disadvantage of the use of bispecific antibodies is the fact that each pathogen requires the generation of a new bispecific antibody. To circumvent this problem, we want to use collectins, such as surfactant protein D (SP-D), to target a broad spectrum of pathogens to Fc receptors. SP-D binds a great variety of pathogens via its carbohydrate recognition domain. We have already generated a bifunctional protein consisting of a recombinant fragment of SP-D (rfSP-D) chemically cross-linked to a F(ab) fragment of an antibody directed against human CD89. This bifunctional protein, designated rfSP-D/anti-CD89, markedly enhances uptake of influenza A virus, Candida albicans and Escherichia coli by human neutrophils in vitro, promotes neutrophil-mediated killing of C. albicans and E. coli, and enhances neutrophil activation by influenza A virus. In the project proposed here we will determine the effectiveness of rfSP-D/anti-CD89 in in vivo models of infection. We will compare it with a similar bifunctional protein rfSP-D/anti-CD64, which contains a F(ab) fragment against human CD64, and which may have the additional advantage of generating immunological memory. In addition, we will test whether the bispecific molecules can be produced as fusion proteins in an expression system. That would allow production on an industrial scale.
