Method of targeting a therapeutic agent to cells expressing the

Details Method of targeting a therapeutic agent to cells expressing the Method of targeting a therapeutic agent to cells expressing the

1995-06-07

1998-10-13

Walsh, Stephen

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Monoclonal antibody or fragment thereof

4241381, 4241391, 4241811, 4241831, A61K 39395, C07K 1630

Patent

active

058208593

ABSTRACT:
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 DNA. 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, gp180.sup.erbB-3. The intrinsic catalytic function of gp180.sup.erbB-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, gp180.sup.EGFR/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 gp180.sup.erbB-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 procedures for targeting a therapeutic drug to cells having a high level of the receptor protein.

REFERENCES:
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Drebin et al., Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo, Oncogene, 2:3878-394, 1988.

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