Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Patent
1994-12-05
1999-10-26
Scheiner, Laurie
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
4241911, 530328, A61K 39015, A61K 3900, A61K 3804
Patent
active
059723513
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
Human leucocyte antigens (HLA) play a pivotal role in cellular immune responses. They present peptides derived from various proteins to T lymphocytes: HLA class I molecules present peptides derived from intracellular, cytoplasmic, antigens to (CD8 positive) HLA class I restricted cytotoxic T cells [1], whereas HLA class II molecules present peptides derived from exogenous antigens to (CD4 positive) regulatory T lymphocytes [2].
2. Description of the Related Art
The precise definition of such peptide epitopes is of interest for understanding variation in immune responses between individuals, for identifying the pathogenic mechanisms of autoimmune disorders and for designing subunit vaccines. Recently, by eluting peptides from purified class I molecules, Rammensee and colleagues [3] and others [4] showed that particular HLA class I types bind short peptides of 8-10 amino acids in length. Furthermore, they found conserved amino acids at certain positions in the peptides bound to particular class I molecules which are characteristic of the individual HLA, and thereby defined "motifs" for the type of peptide that binds to a given HLA type. This suggests a means of identifying epitopes within previously known protein antigens by selecting short peptide sequences from that antigen that fit the peptide "motif" for a given HLA. However, it is likely that only a small proportion of peptides fitting such a motif are actually epitopes [5].
We have recently developed a novel assay [6], termed an HLA assembly assay, which provides a means of testing whether particular peptides will bind at high affinity to a particular HLA class I molecule, such as HLA-A2. Peptides which act as epitopes would be expected to bind to their particular class I molecule with high affinity, and we found that known HLA-A2 epitopes did so [6]. This suggested to us that combining the techniques of Rammensee et al. to identify conserved residue(s) in peptides binding a particular HLA class I with the HLA assembly assay to screen such peptides for high-affinity binding, would provide a rapid and novel approach to identifying peptides presented by HLA class I molecules that should include most or all HLA class I restricted T cell epitopes in that antigen. Then cytotoxic T cell assays may be undertaken using lymphocytes from individuals exposed to the micro-organism to identify which of the binding peptides are recognised as cytoxic T cell epitopes.
SUMMARY OF THE INVENTION
Thus the invention provides in one aspect a method of identifying peptides of an antigen of interest which are capable of recognition by or induction of cytotoxic T lymphocytes, which method comprises the steps of: one particular position of the peptide) of peptides which bind to a chosen human leucocyte class I antigen, sequence of the antigen of interest, cytotoxic T lymphocytes.
Step a) involves ascertaining a motif of peptides which bind to the chosen human leucocyte class I antigen. A motif is any feature common to most or all of the peptides sequenced; for example, a particular position of the peptide, e.g. position 2, may be often or always occupied by a particular amino acid. This step may be performed by sequencing peptides derived from the HLA and screening the sequences for a motif. As described below, for HLA-B53 and HLA-B35, proline was found to be predominant at position 2. For other class I molecules different amino acids have been found to be predominant at this position in eluted peptides: arginine in HLA-B27 peptides [22], and leucine or isoleucine in HLA-A2 peptides [3]. The predominance of a single amino acid at position 2 of the peptide in various different HLA types, supports the view that the peptide is anchored in the HLA molecule cleft by high affinity interaction of the sidechain of residue 2 of the peptide with a pocket in the floor of the HLA molecule near to residue 45 of the HLA heavy chain [22].
Step b) involves providing, e.g. by buying or synthesising, peptides which are present in the know
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Elvin John
Gotch Frances Margaret
Hill Adrian Vivian Sinton
McMichael Andrew James
Whittle Hilton Carter
Isis Innovation Limited
Parkin Jeffrey S.
Scheiner Laurie
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