Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1997-08-12
2001-07-17
Allen, Marianne P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S184100, C424S185100, C424S188100, C424S190100, C424S191100, C424S208100, C424S225100, C424S227100, C424S228100, C424S236100, C530S300000, C530S332000, C530S403000, C530S806000, C530S825000, C530S826000, C514S002600
Reexamination Certificate
active
06261569
ABSTRACT:
TECHNICAL FIELD
The invention relates to synthetic peptide antigen analogues of native peptide antigens with partial or complete retro, inverso or retro-inverso modifications. When administered as an immunogen to an immunocompetent host the synthetic peptide antigen analogues induce the production of antibodies which recognize the native peptide antigen. The invention also relates to uses of these analogues, to vaccines and methods of preparing vaccines comprising these antigen analogues, and to antibodies generated using these antigen analogues.
BACKGROUND ART
The stereochemistry of polypeptides can be described in terms of the topochemical arrangement of the side chains of the amino acid residues about the polypeptide backbone which is defined by the peptide bonds between the amino acid residues and the &agr;-carbon atoms of the bonded residues. In addition, polypeptide backbones have distinct termini and thus direction.
The majority of naturally occurring amino acids are L-amino acids. Naturally occurring polypeptides are largely comprised of L-amino acids.
D-amino acids are the enantiomers of L-amino acids and form peptides which are herein referred to as inverso peptides, that is, peptides corresponding to native peptides but made up of D-amino acids rather than L-amino acids.
Retro peptides are made up of L-amino acids in which the amino acid residues are assembled in opposite direction to the native peptide sequence.
Retro-inverso modification of naturally occurring polypeptides involves the synthetic assemblage of amino acids with &agr;-carbon stereochemistry opposite to that of the corresponding L-amino acids, i.e. D- or D-allo-amino acids, in reverse order with respect to the native peptide sequence. A retro-inverso analogue thus has reversed termini and reversed direction of peptide bonds while approximately maintaining the topology of the side chains as in the native peptide sequence.
Partial retro-inverso peptide analogues are polypeptides in which only part of the sequence is reversed and replaced with enantiomeric amino acid residues. Since the retro-inverted portion of such an analogue has reversed amino and carboxyl termini, the amino acid residues flanking the retro-inverted portion are replaced by side-chain-analogous &agr;-substituted geminal-diaminomethanes and malonates, respectively.
Processes for synthesis of retro-inverso peptide analogues (Bonelli et al., 1984; Verdini and Viscomi, 1985) and some processes for the solid-phase synthesis of partial retro-inverso peptide analogues have been described (Pessi et al., 1987).
It has been observed that due to the stereospecificity of enzymes with respect to their substrates, replacement of L-amino acid residues with D-amino acid residues in peptide substrates generally abolishes proteolytic enzyme recognition and/or activity, although exceptions are known.
Peptide hormones have been of particular interest as targets for retro-inversion, presumably because their analogues would have potential use as therapeutic agents.
Partial, and in a few cases complete, retro-inverso analogues of a number of peptide hormones have been prepared and tested (see, for example, Goodman and Chorev, 1981).
Complete or extended partial retro-inverso analogues of hormones have generally been found to be devoid of biological activity. The lack of biological activity has been attributed to possible complex structural changes caused by extended modification, the presence of reversed chain termini or the presence of proline residues in the sequences. Some partial retro-inverso analogues, that is peptides in which only selected residues were modified on the other hand, have been shown to retain or enhance biological activity. Retro-inversion has also found application in the area of rational design of enzyme inhibitors.
The fact that retro-inversion of biologically active peptides has met with only limited success in retaining or enhancing the activity of the native peptide is probably due to several reasons. Although structurally very similar, it was realized early that peptides and their retro-enantiomers are topologically not identical and crystal structure and solution conformation studies have borne this out. Biological activity of a peptide hormone or neurotransmitter depends primarily on its dynamic interaction with a receptor, as well as on transduction processes of the peptide-receptor complex. It is now clear that such interactions are complex processes involving multiple conformational and topological properties. Consequently it is not surprising that a retro-inverso analogue may not be able to mimic all of these properties.
The development of synthetic peptide vaccines has been a very active field of research over the past two decades (Arnon, 1991; Steward and Howard, 1987). Unfortunately, not much is known about the chemistry of antigen-antibody binding; only very few X-ray crystal structures of antibody-antigen complexes have been solved to date (Davies et al., 1988). As a result, prior to the present invention, it was not possible to predict if antibodies could be elicited against an inverso, retro or retro-inverso peptide and if such antibodies would be capable of recognizing the native peptide antigen from which the peptide sequence was derived. Lerner and co-workers (Lerner, 1984) report the synthesis of native, retro-, inverso- and retro-inverso forms of an influenza virus haemagglutinin peptide. They claim that antibodies raised against these peptides are not cross-reactive and that only antibodies against the native form peptide bind to the native peptide antigen.
Oral immunization, with the production of secretory immunoglobulin A (IgA) antibodies in various mucosae, has been used for many years, particularly for gastrointestinal infections. Successful induction of a systemic immune response to an orally administered polypeptide antigen requires that at least some of the antigen is taken up into the circulation. It is now known that intestinal peptide transport is a major process, with the terminal stages of protein digestion occurring intracellularly after non-specific transport of peptides into the mucosal absorptive cells. There is also irrefutable evidence that small amounts of intact peptides and proteins do enter the circulation from the gut under normal circumstances. Due to inefficient is intestinal absorption and due to proteolytic degradation of ‘native’ polypeptide antigens, the amount of antigen required for oral immunization generally far exceeds that required for parenteral induction of systemic immunity. Furthermore, oral presentation of such large quantities of antigen often leads to the simultaneous induction of IgA/suppressor T-cell-mediated systemic tolerance which acts to reduce the production of immunoglobulin G (IgG) antibodies. Therefore, a need exists for non-tolerogenic effective oral vaccines which can withstand proteolytic attack.
DISCLOSURE OF THE INVENTION
Definitions
Throughout the specification and claims “retro modified” refers to a peptide which is made up of L-amino acids in which the amino acid residues are assembled in opposite direction to the native peptide with respect the which it is retro modified.
Throughout the specification and claims “inverso modified” refers to a peptide which is made up of D-amino acids in which the amino acid residues are assembled in the same direction as the native peptide with respect to which it is inverso modified.
Throughout the specification and claims “retro-inverso modified” refers to a peptide which is made up of D-amino acids in which the amino acid residues are assembled in the opposite direction to the native peptide with respect to which it is retro-inverso modified.
Throughout the specification and claims the term “native” refers to any sequence of L amino acids used as a starting sequence for the preparation of partial or complete retro, inverso or retro-inverso analogues.
The term “peptide” as used throughout the specification and claims is to be understood to include peptides of any length.
Throughout the specification and claims the
Comis Alfio
Fischer Peter
Tyler Margaret Isabel
Allen Marianne P.
Deakin Research Limited
Howson and Howson
Zeman Mary K.
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