Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Animal cell – per se – expressing immunoglobulin – antibody – or...
Reexamination Certificate
1995-05-16
2003-07-22
Schwadron, Ronald B. (Department: 1644)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Animal cell, per se, expressing immunoglobulin, antibody, or...
C424S133100, C424S143100, C424S144100, C424S154100, C424S173100, C424S178100, C424S183100, C424S809000, C435S326000, C435S334000, C435S346000, C530S387100, C530S388220, C530S388750, C530S389600, C530S391100, C530S391300, C530S391700, C530S808000, C530S866000
Reexamination Certificate
active
06596536
ABSTRACT:
The present invention relates to new nucleptide sequences coding for variable regions of &agr; chain T-cell receptors, corresponding peptide segments and the diagnostic and therapeutic uses.
It is known that the receptors recognizing antigens at the surface of mature T lymphocytes (hereafter designated T-cell receptors) possess a structure having a certain similarity with those of immunoglobulins. Therefore, they contain heterodimeric structures containing &agr; and &bgr; glycoprotein chains or &ggr; and &dgr; glycoprotein chains (see Meuer et al. (1), Moingeon et al. (2), Brenner et al. (3), Bank et al. (4)).
The directory of T-cell receptors must be able to address the immense diversity of antigenic determinants. This is obtained by genetic recombination of different discontinuous segments of genes which code for the different structural regions of T-cell receptors. Thus, the genes contain V segments (variable segments), optionally D segments (diversity segments), J segments (junction segments) and C segments (constant segments). During the differentiation of T-cells, specific genes are created by recombination of V, D and J segments for the &bgr; and &dgr; loci and V and J segments for the &agr; and &ggr; loci. These specific combinations as well as the pairing of two chains create the combinational diversity. This diversity is highly amplified by two supplementary mechanisms, namely the imprecise recombination of V-D-J or V-J segments and the addition of nucleotides corresponding to the N region (Davis et al. (5).
A certain number of genetic V segments are already known. These segments have been grouped into subfamilies as a function of the similarity of sequences. By definition, the segments which have more than 75% similarity in the nucleotide sequence have been considered as members of the same subfamily (Crews et al. (6)). The known V&agr; nongenetic segments have also been classified into 22 subfamilies, 14 of which have only one member (see Concannon et al. (7), Kimura et al. (8), Wilson et al. (9)).
Moreover, about 60 J genetic segments have been described (9).
Furthermore, monoclonal antibodies directed against specific segments of the variable parts of T-cell receptors, in particular the &bgr; or &dgr; chains, were recently described in WO 90/06758. These monoclonal antibodies are useful not only as diagnostic tools but also as therapeutic tools, for example, vis-à-vis rheumatoid athritis.
The use of synthetic peptides corresponding to the variable regions of the &agr; or &bgr; chains in the treatment of auto-immune diseases is also described (23 and 24).
It is also known that variations exist from one individual to another in the expression of different variable segments of the T-cell receptor in man (27 and 28).
The present inventions aims to enrich the directory of genetic segments coding for the variable regions of the chains of T-cell receptors by providing on the one hand new V&agr; genetic segments belonging to new subfamilies or belonging to subfamilies of which at least one member is already known, and on the other hand, new J&agr; genetic segments.
Therefore a subject of the present invention is nucleotide sequences coding for the variable regions of &agr; chains of human T lymphocyte receptors, corresponding to cDNA's containing nucleotide sequences chosen from any one of the following:
a—V&agr; segments corresponding to one of the sequences SEQ ID No. 1 to 11, and
b—J&agr; segments corresponding to one of the sequences SEQ ID No. 12, 13 and 15 to 20, and the sequences which differ from them by one or more nucleotides.
More particularly a subject of the present invention is:
sequences coding for the variable regions of &agr; chains of human T lymphocyte receptors, corresponding to cDNAs containing nucleotide sequences chosen from any one of the V&agr; segments corresponding to one of the sequences SEQ ID No. 1 to 10 and the sequences which differ from them by one or more nucleotides,
sequences coding for the variable regions of &agr; chains of human T lymphocyte receptors, corresponding to cDNAs containing nucleotide sequences chosen from any one of the J&agr; segments corresponding to one of the sequences SEQ ID No. 12, 13 and 15 to 20 and the sequences which differ from them by one or more nucleotides.
The expression “and sequences which differ from them by one or more nucleotides”, encompasses alleles which differ by up to 8 nucleotides, but more often differ by 1 or 2 nucleotides or which can differ by the deletion or addition of one or two codons.
Also a more particular subject of the invention is: nucleotide sequences coding for the variable regions of &agr; chains of human T lymphocyte receptors, corresponding to cDNAs corresponding to all or part of the nucleotide sequences chosen from any one of the V&agr; segments corresponding to one of the sequences SEQ ID No. 2 to 5, and the sequences which differ from them by one or two nucleotides,
nucleotide sequences coding for the variable regions of the &agr; chains of human T lymphocyte receptors, corresponding to cDNAs corresponding to all or part of the nucleotide sequences chosen from any one of the V&agr; segments corresponding to one of the sequences
1 to 200 of SEQ ID No. 1
1 to 467 of SEQ ID No. 6
1 to 77 of SEQ ID No. 7
1 to 151 of SEQ ID No. 8
291 to 386 of SEQ ID No. 9
1 to 260 of SEQ ID No. 10
and the sequences which differ from them by one or two nucleotides,
nucleotide sequences coding for the variable regions of the &agr; chains of human T lymphocyte receptors, corresponding to cDNAs corresponding to all or part of the nucleotide sequence corresponding to SEQ ID No. 11 and which contain the 108 nucleotide,
nucleotide sequences coding for the variable regions of the &agr; chains of human T lymphocyte receptors, corresponding to cDNAs corresponding to all or part of the nucleotide sequences chosen from any one of the J&agr; segments corresponding to one of the sequences SEQ ID No. 12, 13 and 15 to 20 and the sequences which differ from them by one or two nucleotides.
By the expression “nucleotide sequences corresponding to cDNAs corresponding to all or part of the nucleotide sequences” is also designated the complete sequences as well as fragments of these sequences including short fragments (oligonucleotides) which can be used as probes (generally containing at least 10 nucleotides) or as primers (generally containing at least 15 nucleotides). In a general fashion, the invention encompasses the group of new oligonucleotides which are fragments of V&agr; and J&agr; sequences according to the invention.
As to the sequences which differ by one or two nucleotides, they correspond to variations which are observed experimentally at the time of determination of the nucleotide sequence of several cDNAs.
Also a subject of the present invention is the peptides coded by the nucleotide sequences according to the invention as well as the alleles and the derivatives of the latter which have the same function.
Also a subject of the present invention is the peptides constituted by or composed of a peptide sequence coded by all or part of the sequence 108 to 364 of SEQ ID No. 11.
In a general fashion, the present invention encompasses the peptides constituted by or composed of a peptide sequence coded by the nucleotide sequences according to the invention as well as fragments of these peptides. It also encompasses the peptides which differ from the latter by one or more amino acids and which have the same function. These peptides can correspond to modifications such as those known with muteins or to allelic variations. In fact it has been shown in particular that certain genetic segments coding for the variable regions of chains of T receptors in man were subjected to a phenomenon of genetic polymorphism called allelic variation (25). The present invention encompasses the peptides resulting from this phenomenon.
The nucleotide sequences according to the invention have been obtained according to the following stages:
isolation of the RNA's of peripheral lymphocytes of an individual;
obtaining t
Ferradini Laurent
Hercend Thierry
Roman-Roman Sergio
Triebel Frederic
Aventis Pharma S.A.
Muserlian Lucas and Mercanti
Schwadron Ronald B.
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