Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lymphokines – e.g. – interferons – interlukins – etc.
Reexamination Certificate
1996-12-20
2001-08-14
Mertz, Prema (Department: 1635)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lymphokines, e.g., interferons, interlukins, etc.
C530S350000, C435S069100, C435S069520, C435S252300, C435S320100
Reexamination Certificate
active
06274708
ABSTRACT:
The present invention relates generally to novel haemopoietin receptors, or components or parts thereof and to a method for cloning genetic sequences encoding same. More particularly, the subject invention is directed to recombinant or synthetic haemopoietin receptors or components or parts thereof. The receptor molecules or components or parts thereof and their genetic sequences of the present invention are used in the development of a wide range of agonists, antagonists and therapeutics and diagnostic reagents based on ligand interaction with its receptor.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide and amino acid sequences referred to in the specification are defined following the bibliography.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
The proliferation, differentiation and function of a wide variety of cells are controlled by secreted regulators, known as cytokines. One such cytokine is interleukin (IL)-11 which is a functionally pleiotropic molecule (1,2), initially characterized by its ability to stimulate proliferation of the IL-6dependent plasmacytoma cell line, T11 65 (3). Other biological actions of IL-11 include induction of multipotential haemopoietin progenitor cell proliferation (4,5,6), enhancement of megakaryocyte and platelet formation (7,8,9,10), stimulation of acute phase protein synthesis (11) and inhibition of adipocyte lipoprotein lipase activity (12, 13). The diverse and pleiotropic function of IL-11 makes it an important haemopoietin molecule to study, especially at the level of its interaction with its receptor.
The structure of the IL-11 receptor is not well known. It is known that neutralizing antibodies to gp130 inhibit IL-11-dependent proliferation of TF-1 cells (14) and, hence, it is likely that gp130 forms part of the receptor.
Members of the haemopoietin receptor family generally comprise &agr;- and &bgr;-chains (15,16,17). However, until the advent of the present invention, there was no information on the existence of IL-11 receptor chains. In work leading up to the present invention, the inventors developed a cloning procedure for haemopoietin receptors which does not require prior knowledge of their ligands. The cloning procedure has been successful in cloning the IL-11 receptor &agr;-chain permitting, for the first time, a detailed molecular analysis of the IL-11 receptor. The present invention provides, therefore, a generalized method for cloning haemopoietin receptors and in particular component chains thereof which provides a basis for developing a range of agonists, antagonists, therapeutic and diagnostic agents based on the IL-11 receptor.
Accordingly, one aspect of the present invention provides a genetic molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a haemopoietin receptor or a mutant, derivative, component, part, fragment, homologue, analogue or a peptide or polypeptide equivalent thereof wherein said receptor comprises an amino acid sequence set forth in SEQ ID NO: 1:
Trp—Ser—Xaa—Trp—Ser,
wherein Xaa is any amino acid.
More particularly, the present invention contemplates a genetic molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding an IL-11 receptor or a mutant, derivative, component, part, fragment, homologue, analogue or a peptide or polypeptide equivalent thereof wherein said receptor comprises an amino acid sequence set forth in SEQ ID NO: 1:
Tip—Ser—Xaa—Trp—Ser,
wherein Xaa is any amino acid.
Another aspect of the present invention contemplates a method of identifying and/or cloning a genetic sequence encoding or complementary to a sequence encoding a haemopoietin receptor and in particular an IL-11 receptor or a component or part thereof, said method comprising screening a source of genetic material with one or more degenerate oligonucleotides designed from the sequence of amino acids comprising the sequence set forth in SEQ ID NO: 1:
Trp—Ser—Xaa—Trp—Ser
wherein Xaa is any amino acid residue.
The sequence defined in SEQ ID NO: 1 has been identified in both &agr; and &bgr; chains of haemopoietin receptors and in particular IL-11 receptor. Accordingly, the method of the present invention is applicable to the cloning of genetic sequences encoding an &agr;-chain, a &bgr;-chain or a combination of both &agr;- and &bgr;-chains such as in a full length receptor.
Preferably, the genetic molecule is of mammalian origin such as but not limited to humans, livestock animals (e.g. sheep, cows, pigs, goats, horses), laboratory test animals (e.g. mice, rats, guinea pigs), companion animals (e.g. cats, dogs) or captive wild animals. Most preferred organs are from humans and murine species (e.g. mice). The source of genetic material may be a genomic library or a cDNA library obtained from mRNA from a particular cell type such as would not limit to liver cells, bone marrow cells, placenta cells and heptatoma cells. A cDNA library is preferred and may also be an expression library. Furthermore, for the generation of mutants the CDNA library may be prepared by high error rate polymerase chain reaction (PCR) resulting in a mutant library.
The term “screening” includes any convenient means to identify target clones. For example, colony hybridization may be employed with oligonucleotide probes or if an expression library is prepared, screening may be, for example, enzyme activity or antibody interactivity. Terms such as “components”, “parts” or “fragments” include separately an &agr;-chain and a &bgr;-chain or parts thereof. Preferably, the “components”, “parts” and “fragments” are functional and more preferably a functional &agr;- or &bgr;-chain.
The genetic molecule may be single or double stranded, linear or closed circle DNA (e.g. genomic DNA), cDNA or mRNA or combinations thereof The genetic molecule may also include a vector such as an expression vector component to facilitate expression of the IL-11 receptor genetic sequence.
In a particular aspect, the genetic sequence encodes the &bgr;-chain of IL-11 receptor and in one preferred embodiment is murine IL-11 receptor &agr;-chain encoded by a nucleotide sequence as set forth in SEQ ID NO: 2 or comprises an amino acid sequence as set forth in SEQ ID NO: 3, or comprises a part, derivative, fragment, portion, derivative, homologue, analogue or peptide equivalent thereof. In an alternative preferred embodiment, the genetic sequences encodes the &agr;-chain of human IL-11 receptor and comprises the nucleotide sequence as set forth in SEQ ID NO: 4 or an amino acid sequence as set forth in SEQ ID NO: 5 or comprises a part, derivative, fragment, portion, derivative, homologue, analogue or peptide or polypeptide equivalent thereof. Accordingly, the genetic sequence may include a molecule capable of encoding a fill length IL-11 receptor or a fragmented portion thereof such as an &agr;-chain or a &bgr;-chain whether functional or not or may correspond to a portion thereof characterized by the amino acid sequence Trp-Ser-Xaa-Trp-Ser wherein Xaa is any amino acid residue. Additionally, the genetic sequence or part thereof may act as an antisense molecule or molecules to mRNA encoding the &agr;- or &bgr;-chain of the IL-11 receptor. Such antisense molecules may be useful in genetic therapy or in the rational design of agonistic or antagonistic agents.
In a related embodiment, there is provided a genetic sequence which encodes an IL-11 receptor or a component, part or fragment thereof wherein said genetic sequence comprises a sequence of nucleotides to which SEQ ID NO: 2 or 4 may hybridize under stringency conditions. In a further related embodiment, the genetic sequence is defined by the ability
Amrad Operations Pty Ltd.
Mertz Prema
Scully Scott Murphy & Presser
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