Nucleic acids, vectors and host cells encoding heregulin

DETAILED DESCRIPTION In accordance with the objects of this invention, we have identified and isolated novel ligand families which bind to p185.
sup.
HER2.
These ligands are denominated the heregulin (HRG) polypeptides, and include HRG-.
alpha.
, HRG-.
beta.
1, HRG-.
beta.
2, HRG-.
beta.
3 and other HRG polypeptides which cross-react with antibodies directed against these family members and/or which are substantially homologous as defined infra.
A preferred HRG is the ligand disclosed in FIG.
4 and its fragments, further designated HRG-.
alpha.
.
Other preferred HRGs are the ligands and their fragments disclosed in FIG.
8, and designated HRG-.
beta.
1, HRG-.
beta.
2 disclosed in FIG.
12, and HRG-.
beta.
3 disclosed in FIG.
13.
In another aspect, the invention provides a composition comprising HRG which is isolated from its source environment, in particular HRG that is free of contaminating human polypeptides.
HRG is purified by absorption to heparin sepharose, cation (e.
g.
polyaspartic acid) exchange resins, and reversed phase HPLC.
HRG or HRG fragments (which also may be synthesized by in vitro methods) are fused (by recombinant expression or an in vitro peptidyl bond) to an immunogenic polypeptide and this fusion polypeptide, in turn, is used to raise antibodies against an HRG epitope.
Anti-HRG antibodies are recovered from the serum of immunized animals.
Alternatively, monoclonal antibodies are prepared from cells in vitro or from in vivo immunized animals in conventional fashion.
Preferred antibodies identified by routine screening will bind to HRG, but will not substantially cross-react with any other known ligands such as EGF, and will prevent HRG from activating p185.
sup.
HER2.
In addition, anti-HRG antibodies are selected that are capable of binding specifically to Individual family members of the HRG family, e.
g.
HRG-.
alpha.
, HRG-.
beta.
1, HRG-.
beta.
2, HRG-.
beta.
3, and thereby may act as specific antagonists thereof.
HRG also is derivatized in vitro to prepare immobilized HRG and labeled HRG, particularly for purposes of diagnosis of HRG or its antibodies, or for affinity purification of HRG antibodies