Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies

摘要: We have previously described anti-epidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) which can block binding of transforming alpha (TGF-alpha) and EGF to receptors inhibit activation tyrosine kinase. Studies with these MAbs involving cell cultures nude mouse xenografts demonstrated their capacity the a variety tumor lines, express TGF-alpha appear depend upon for proliferation. To explore mechanism(s) by anti-EGF 225 MAb inhibits proliferation, we compared activity native response bivalent F(ab')2 monovalent Fab' fragments. Both its fragments could 125I-EGF receptors. Scatchard analysis revealed that Kd is comparable (1 nM), whereas 5 nM. were able completely TGF-alpha-induced kinase activation, as assayed autophosphorylation residues on MCF10A nonmalignant human mammary cells, MDA468 breast adenocarcinoma A431 vulvar squamous carcinoma cells. The forms proliferation stimulated endogenous (autocrine) in three lines. They also blocked stimulation added exogenous cells growth-inhibitory effect cultures. Monovalent had weaker inhibitory effects determine whether vivo antiproliferative occur without participation Fc portion MAb, capacities s.c. compared. Equimolar amounts either or administered at intervals equivalent half-lives molecules, attempt maintain plasma levels. inhibited xenograft dose-dependent manner, more sustained case intact antibody.(ABSTRACT TRUNCATED AT 400 WORDS)