A SUBCLASS OF TUMOR-INHIBITORY MONOCLONAL-ANTIBODIES TO ERBB-2 HER2 BLOCKS CROSSTALK WITH GROWTH-FACTOR RECEPTORS/

ErbB-2 is an orphan receptor that belongs to a family of tyrosine kina se receptors for either epidermal growth factor (EGF) or Neu different iation factor (NDF/ neuregulin), Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical co urse of certain human adenocarcinomas, the encoded protein is an attra ctive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely unde rstood. To study this question, we generated a large battery of mAbs t o ErbB-2, that were classified epitopically, Whereas most antibodies s timulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation, One group of tu mor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to thei r direct receptors. The inhibitory effect was due to acceleration of l igand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF, These r esults identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.