Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1998-08-31
2003-03-04
Minnifield, Nita (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S093480, C424S141100, C424S184100, C424S190100, C424S234100, C435S070210, C435S071100, C530S388200, C530S388400, C530S389500, C530S300000
Reexamination Certificate
active
06528061
ABSTRACT:
BACKGROUND OF THE INVENTION
(i) Field of the Invention
The present invention pertains to immunogenic polypeptides, which comprise at least an epitope recognized by a protective monoclonal antibody having a high affinity and a high specificity for a surface polysaccharide of a pathogenic microorganism. The polypeptides induce an immune response in vivo against the pathogenic microorganism. The invention also relates to methods for selecting such immunogenic polypeptides, and also immunogenic or vaccinal compositions containing the polypeptides.
(ii) Description of the Related Art
Throughout this application various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Polysaccharide molecules have been shown to be present at the surface of numerous pathogenic microorganisms. Some of these polysaccharide molecules have been depicted to protect the infecting pathogenic organism from the immune system of the infected mammalian host.
The initial immunologic response to administration of a capsular polysaccharide is the production of antibodies of the IgM class, which persist for relatively short periods (Beuvery et al., 1982; Beuvery et al., 1983). A similar response is manifested after the same capsular antigen is injected a second time (Käyhty et al., 1984). Absence of a booster response indicates the lack of “immunologic memory”, attributes of a thymus-independent antigen.
The production of polysaccharides by bacteria has been recognized for a long time and a number of bacteria, including pneumococci, streptococci, staphylococci, menigococci, ASalmonella, Shigella,
Haemophilus influenza, Escherichia coli, Kilebsiella pneumoniae
and
Bacteroides fragilis
, are frequent causes of illness in man.
The bacterial cell wall is not the sole pathogenic organism component that contains polysaccharide antigens that are considered important determinants for inducing an immune response. A lot of viruses, such as rotaviruses (Hoshino et al., 1994), parainfluenza viruses (Ray et al., 1986; Tsurudome et al., 1989, Henrickson, 1991; Kasel et al., 1984), influenza viruses (Murphy et al., 1990; Tamura et al., 1996; Ada et al., 1986; Tamura et al., 1990; Tamura et al., 1991) or immunodeficiency viruses (FIV, HIV etc.) and fungi also express polysaccharide antigens at their surface, notably under the form of highly glycosylated proteins.
Immunodeficiency viruses, like FIV or HIV, all express envelope glycoproteins (gp 120 for HIV-1, gp 125 for HIV-2) at their surfaces. These envelope glycoproteins have been shown to be deeply involved in virus entry into target cells of the host, specifically the V3 loop domain of these external glycoproteins.
Pathogenic fungi, like some strains of
Candida albicans
or
Neurospora crassa
, also express polysaccharide antigenic determinants involved in the immune response of the host (Reiss, 1986).
The main targets of the protective immune response against bacterial infection are the capsular polysaccharide as well as the O—Ag carbohydrate moiety of the LPS (for a review, see Austrian, 1985). Carbohydrate antigens are T-cell independent, inducing weak antibody responses associated with the lack of a strong B cell memory response (Bondada et al., 1994). Vaccine strategies have thus been mainly focused on the development of either polysaccharide-protein conjugates or anti-idiotype vaccines based on mimicking the carbohydrate structure (Lucas, 1994). The difficult steps of the former approach are the purification of the polysaccharide (especially-when starting from LPS, which must be devoid of any residual lipid A-related endotoxic activity), and the loss of immunogenicity of the carbohydrate moiety during coupling to the protein carrier. Carbohydrate synthesis may diminish the problems associated with antigen purification, but nonetheless remains a limited solution due to the overall difficulties of carbohydrate chemistry.
The fact that the surface polysaccharide antigens of pathogenic microorganisms, and in particular the antigenic capsular polysaccharide of bacteria, seem to induce predominantly a T cell independent immune response renders these isolated or chemically synthesized antigens less valuable to use for inducing a protective immune response in the infected host.
Moreover, the synthesis of such polysaccharide antigen molecules at an industrial and commercial scale is difficult and very costly as compared with the synthesis of protein and peptide antigen compounds that are the active principals of the conventional vaccine compositions.
Thus, there is a need in the art to design protein or peptide molecules that are able to immunologically mimic the antigenic polysaccharide, specifically that are able to induce a strong and protective immune response to the corresponding pathogenic organism.
One strategy, based on the mimicry of carbohydrate antigens by anti-idiotype antibodies, is not a simple alternative to the use of the polysaccharide antigen itself, since obtaining these antibodies is relatively time-consuming, and their use in humans is still a matter of debate. Therefore, polysaccharide-protein conjugates remain, despite difficulties, the only viable strategy for human vaccination against bacterial polysaccharidic antigens investigated until now.
As the anti-idiotype antibody molecule in its entirety is unsuitable for repeated immunization, the characterization and use of its CDRs as immunogenic peptides to elicit anti-carbohydrate antibodies has recently been reported (Weternick et al., 1995), representing an additional complication. In comparison, obtaining peptide mimics using phage display technology is quite straightforward.
Over the last few years phage-displayed peptide libraries have been widely screened with antibodies as well as non-antibody molecules leading to the identification of new ligands that do not necessarily resemble the natural ones, but display similar binding capacity (for reviews see Scott et al., 1994; Cortese et al., 1995; Felici et al., 1995; Daniels et al., 1996).
The identification of peptides that mimic carbohydrate structures has also been reported (Oldenburg et al., 1992; Scott et al., 1992, Hoess et al., 1993, Bianchi et al., 1995; Bonnycastle et al., 1996; Valadon et al., 1996). This approach might be an alternative to the use of anti-idiotypic antibodies as mimics (Westerinck et al., 1995).
In particular, Valadon et al (1996) have used phage-displayed hexa- or deca-peptide libraries in order to select peptides binding to a monoclonal antibody, Mab 2H1, directed against the glucuronoxylomannan (GXM) capsular polysaccharide from
Cryptococcus neoformans
. These authors have selected about 35 different peptides that bind to the 2H1 anti-GXM monoclonal antibody. These peptides gathered in four different motifs, the peptides belonging to one specific motif exhibiting a significant homology (Tables 1 and 3). Further, these authors have immunized mice with some of the selected peptides (namely PA1, P601E, and P514), but have elicited only a small anti-GXM response, although they have stimulated the production of antibodies that have the 2H1 idiotype (unpublished results of the authors). There is no need to say that Valadon et al., in failing to obtain antibodies to the initial polysaccharide antigen with the selected hexa- or deca-peptides, have also failed to obtain any protective antibody against glucuronoxylomannan of
Cryptococcus neoformans.
One explanation for the failure of Valadon et al. to select random peptides inducing a significant immune response against glucuronoxylomannan of
C. neoformans
lies-probably in the weak specificity of the initial anti-GXM monoclonal antibody (2H1) used by these authors, which did not confer good selectivity properties in the screening steps of the candidate peptides expressed by the phage clones of the hexa- or decapeptide libraries, although this particular point is not discussed in Valadon et
Cortese Riccardo
Felici Franco
Kraehenbuhl Jean Pierre
Phalipon Armelle
Sansonetti Philippe
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Hines Ja'Na
Minnifield Nita
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