Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-03-29
2004-09-14
Fredman, Jeffrey (Department: 1636)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S455000, C536S023100, C536S023500
Reexamination Certificate
active
06790637
ABSTRACT:
The present invention is broadly directed to therapeutic molecules capable of inter alia modulating apoptosis in mammalian cells. The therapeutic molecules of the present invention encompass genetic sequences and chemical entities capable of regulating expression of a novel mammalian gene belonging to the bcl-2 family and which promotes cell survival. The therapeutic molecules of the present invention may have further utility in delaying cell cycle entry. In addition, the present invention extends to chemical entities capable of modulating activity and function of the translation product of said novel gene of the bcl-2 family. The present invention also extends to the translation product of the novel gene of the bcl-2 family and its use in, for example, therapy, diagnosis, antibody generation and as a screening tool for therapeutic molecules capable of modulating physiological cell death or survival and/or modulating cell cycle entry.
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. A summary of the SEQ ID NOs. is provided before the Examples
Throughout this specification, 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 dement or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
The increasing sophistication of recombinant DNA technology is greatly facilitating research and development in the medical and allied health fields. This technology is becoming particularly important in research into the treatment and diagnosis of both proliferative cell disorders such as caners and sarcomas and in degenerative diseases such as some autoimmune conditions. There is a need to identify and characterise at the genetic level the elements involved in cell survival and physiological cell death (apoptosis).
Apoptosis is accomplished by a process that is conserved between organisms as diverse as nematodes and man. Positive and negative regulation of cell survival is essential for the proper development and differentiation of the embryo and for ensuring homeostasis in adult tissues. Cell survival can be promoted by the binding of growth factors to their receptors or by interaction of cellular adhesion molecules. A range of cytotoxic agents can counteract these signals and activate apoptosis, a process initially defined by specific morphologic criteria, such as chromatin condensation, cell compaction, membrane blebbing and, often, internucleosomal cleavage of DNA.
The biochemical details of the intracellular pathways governing cell survival and death remain largely undefined. However, several key regulators have emerged. The first to be discovered was Bcl-2, a 26 kD cytoplasmic protein encoded by the bcl-2 gene translocated to the IGH locus in human follicular lymphoma. High levels of Bcl-2 greatly enhance the ability of cells to survive cytokine deprivation and a wide variety of other cytotoxic conditions, including DNA damage.
The mammalian genome contains other genes homologous to bcl-2 but which differ in function. For example, bcl-x blocks apoptosis (Boise et al, 1993) whereas bar and bak inhibit the survival function of bcl-2 and bcl-x (Oltvai et al, 1993; Chittenden et al, 1995; Farrow et al., 1995; Kiefer et al, 1995). Due to the potential importance of cell apoptosis controlling genes in the treatment of cancers and sarcomas and in the treatment of degenerative disorders, there is a need to identify new genes homologous to bcl-2 in structure and function.
In accordance with the present invention, the inventors have identified a novel gene from mammals designated herein “bcl-w”. Gene transfer studies show that bcl-w enhances cell survival and belongs to the bcl-2 family of apoptosis-controlling genes. The identification of this new gene will lead to the generation of a range of therapeutic molecules capable of acting as either antagonists or agonists of bcl-w expression or activity and will be useful in cancer or degenerative disease therapy. The identification of the gene will also permit the production of vast quantities of recombinant translation products for use in therapy, diagnosis, antibody generation and as a screen for therapeutic molecules capable of modulating physiological cell deaths or survival including modulating cell cycle entry.
Accordingly, the present invention is directed to a nucleic acid molecule comprising a nucleotide sequence encoding or complementary to a sequence encoding a novel mammalian gene from the bcl-2 family and comprising an amino acid sequence substantially as set forth in SEQ ID NO:7 or SEQ ID NO:9 or having 47% or greater similarity to either of SEQ ID NO:7 or SEQ ID NO:9.
Another aspect of the present invention is directed to a nucleic acid molecule comprising a nucleotide sequence encoding or complementary to a sequence encoding the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:9 or a derivative thereof or encoding an amino acid sequence having 47% or greater similarity to either SEQ ID NO:7 or SEQ ID NO:9.
The term “similarity” as used herein includes em identity between compared sequences at the nucleotide or amino acid level. Where there is non-identity at the nucleotide level, “similarity” includes differences between sequences which result in different amino acids that are nevertheless related to each other at the structural, functional, biochemical and/or conformational levels. Where there is non-identity at the amino acid level “similarity” includes amino acids that are nevertheless related to each other at the structural, functional, biochemical and/or conformational levels.
Preferably, the percentage similarity is between 48% and 100% inclusive such as approximately 50% or 55%, 59% or 65%, 70% or 75%, 80% or 85%, 90% or 95% or greater than 96% or a percentage similarity therebetween.
Another aspect of the present invention provides a nucleic acid molecule comprising a sequence of nucleotides substantially as set forth in SEQ ID NO:6 or SEQ ID NO:8 or a nucleotide sequence encoding an amino acid sequence having 47% or greater similarity to SEQ ID NO:7 or SEQ ID NO:9.
The nucleic acid molecule according to this aspect of the present invention corresponds herein to “bcl-w”. This gene has been determined by the inventors in accordance with the present invention to enhance cell survival. The product of the bcl-w gene is referred to as Bcl-w. Human Bcl-w is defined by the amino acid sequence set forth in SEQ ID NO:7 and mouse Bcl-w is defined in SEQ ID NO:9. The respective nucleotide sequences from human bcl-w and mouse bcl-w are shown in SEQ ID NO:6 and SEQ ID NO:8 respectively. Reference herein to “bcl-w” includes reference to derivatives thereof includes single or multiple nucleotide substitutions, deletions and/or additions. Similarly, reference herein to “Bcl-w” includes all derivatives including amino acid substitutions, deletions and/or additions. The gene is preferably from a human, primate, livestock animal (sheep, pig, cow, horse, donkey), laboratory test animal (eg. mouse, at, rabbit, guinea pig), companion animal (eg. dog, cat) or captive wild animal (eg. fox, kangaroo, deer).
Although the present invention relates to a mammalian homologue of Bcl-w having an amino acid sequence of 47% or greater similarity to SEQ ID NO:7 or SEQ ID NO:8, the subject invention does extend to novel Bcl-w homologues from any animal including a mammal previously undisclosed.
Accordingly, another aspect of the present invention provides a nucleic acid molecule comprising a sequence of nucleotides encoding human Bcl-w or a derivative thereof, said human Bcl-w having an amino acid sequence substantially as set forth in SEQ ID NO:7 or is a mammalian homologue thereof having an amino acid sequence of substantially 47
Adams Jerry McKee
Cory Suzanne
Gibson Leonie M.
Holmgreen Shaun P.
Cerylid Pty., Ltd.
Fredman Jeffrey
Kaushal Sumesh
Scully Scott Murphy & Presser
LandOfFree
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