A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors

Abstract

ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu di erentiation factor (NDF/ neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 e ectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classi®ed epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor e ect correlated with its accelerated endocytic degradation. One group of tumor-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 their direct receptors. The inhibitory e ect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results 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.

The EGF receptor family as targets for cancer therapy

“…Antibody-induced downregulation of ErbB2 has been shown to induce reversion of the transformed phenotype in ErbB2-transformed cells (Drebin et al, 1985). A relationship between receptor degradation and antitumor e ects of anti-ErbB2 MAbs is supported by a recent study using a large battery of anti-ErbB2 antibodies (Klapper et al, 1997). In that study, stimulation of ErbB2 receptor phosphorylation was found to be uncoupled from the growth inhibitory e ects of the antibodies (Klapper et al, 1997).…”

“…A relationship between receptor degradation and antitumor e ects of anti-ErbB2 MAbs is supported by a recent study using a large battery of anti-ErbB2 antibodies (Klapper et al, 1997). In that study, stimulation of ErbB2 receptor phosphorylation was found to be uncoupled from the growth inhibitory e ects of the antibodies (Klapper et al, 1997). Since ErbB2 is the preferred co-receptor for EGFr, ErbB3 and ErbB4, targeting ErbB2 with MAbs or speci®c tyrosine kinase inhibitors is also likely to impair signaling through the other three ErbB receptors of the family.…”

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

“…These di erences raised the possibility that the interaction of the two ErbB-1 ligands with ErbB-2 and ErbB-3 was mediated by sites disparate from those that transmit NDF actions. To examine this proposition we used panels of monoclonal antibodies (mAbs) speci®c to each ErbB protein Klapper et al, 1997). Two di erent types of mAbs to each receptor were used: antibodies that interfere with ligand binding and those that exert only a small e ect on NDF binding.…”

Insertion of the DNA for the 163–171 peptide of IL1β enables a DNA vaccine encoding p185neu to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice

“…An issue not directly addressed in this paper but raised by the significant evidence in the literature is whether anti-p185 neu antibodies induce a functional block of p185 neu receptor function, 20 down-regulate its expression on the cell surface, 20,21 impede the formation of p185 neu homo-or heterodimers that spontaneously transduce proliferative signals to the cells, 21,22 and block its ability to bind ligands. 23 These antibodies also significantly suppress the growth of transplantable p185 neu + tumors, 24,25 the natural onset of mammary carcinomas in Her-2/neu transgenic mice, 21 and delay tumor growth in patients with Her-2/neu positive tumors.…”