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US 2004/0063140 A1Published application
Methods for diagnosis of cancer using erbB-3
OwnerMatthias H. Kraus, Stuart A. Aaronsoninventors
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OwnerMatthias H. Kraus, Stuart A. Aaronsoninventors
Estimating the term…
A DNA fragment distinct from the epidermal growth factor receptor (EGFR) and erbB-2 genes was detected by reduced stringency hybridization of v-erbB to normal genomic human DNk Characterization of the cloned DNA fragment mapped the region of v-erbB homology to three exons with closest homology of 64% and 67% to a contiguous region within the tyrosine kinase domains of the EGFR and erbB-2 proteins, respectively. cDNA cloning revealed a predicted 148 kd transmembrane polypeptide with structural features identifying it as a member of the erbB family, prompting designation of the new gene as erbB-3. It was mapped to human chromosome 12q11-13 and was shown to be expressed as a 6.2 kb transcript in a variety of normal tissues of epithelial origin. Markedly elevated erbB-3 mRNA levels were demonstrated in certain human mammary tumor cell lines. These findings indicate that increased erbB-3 expression, as in the case of EGFR and erbB-2, plays a role in some human malignancies. Using erbB-3 specific antibodies (polyclonal or monoclonal), the erbB-3 protein was identified as a 180 kDa glycoprotein, gp180erbB-3. The intrinsic catalytic function of gp180erbB-3 was uncovered by its ability to autophosphorylate in vitro. Ligand-dependent signaling of its cytoplasmic domain was established employing transfectants which express a chimeric EGFR/erbB-3 protein, gp180EGFR/erbB-3. EGF induced tyrosine phosphorylation of the chimera and promoted soft agar colony formation of such transfectants. These findings, combined with the detection of constitutive tyrosine phosphorylation of gp180erbB-3 in 4 out of 12 human mammary tumor cell lines, implicate the activated erbB-3 product in the pathogenesis of some human malignancies. Thus, this invention also relates to a method for detecting a receptor ligand capable of either activating or down-regulating the receptor protein, as well as procedures for purifying the resultant ligand; a method of screening potential ligand analogs for their ability to activate the receptor protein; and procedures for targeting a therapeutic drug to cells having a high level of the receptor protein.
An isolated polypeptide having the amino acid sequence as given by SEQ ID NO:
An isolated polypeptide having an amino acid sequence encoded by the DNA isolate consisting essentially of a nucleotide sequence that encodes an amino acid sequence differing in at least one amino acid from the amino acid sequence of human erbB-3, or a unique portion thereof, and having greater overall similarity to the amino acid sequence of human erbB-3 than to that of any other polypeptide.
A purified antibody specific for a unique portion of SEQ ID NO:
A bioassay for determining the amount of erbB-3 mRNA in a biological sample comprising the steps of:
A bioassay for screening potential analogs of ligands of erbB-3 receptors for the ability to affect an activity mediated by the erbB-3 receptors, comprising the steps of:
A method for detecting the presence of an erbB-3 activating ligand in a source containing a potential erbB-3 ligand, comprising the steps of:
A method for detecting the presence of an erbB-3 blocking ligand in a source containing a potential erbB-3 ligand, comprising the steps of:
A purified erbB-3 activating ligand.
A purified erbB-3 blocking ligand.
A method of decreasing a biochemical or biological activity mediated by the erbB-3 receptor, comprising blocking the binding of an erbB-3 activating ligand with the erbB-3 receptor.
A method of promoting a biochemical or biological activity mediated by the erbB-3 receptor, comprising contacting an erbB-3 activating ligand with the erbB-3 receptor.
A method of detecting the overexpression of erbB-3 in a sample from a subject, comprising detecting the amount of erbB-3 in the sample and comparing the amount in the sample to the amount in an equivalent sample having normal expression, the presence of erbB-3 in a greater amount indicating overexpression of erbB-3.
A method of detecting the activation of erbB-3 in a test sample from a subject, comprising detecting the presence of phosphorylation of erbB-3, the presence of phosphorylation of erbB-3 indicating the presence of erbB-3 activation in the sample.
Dependencies are inferred from the claim text.