POTENT HUMAN P40-TRKA AGONISTS DERIVED FROM AN ANTIRECEPTOR MONOCLONAL-ANTIBODY

Monoclonal antibody (mAb) 5C3 directed against human p140 TrkA is a st ructural and functional mimic of nerve growth factor (NGF) and an arti ficial receptor agonist. mAb 5C3 binds in the NGF-docking site and, li ke NGF, it promotes TrkA internalization, TrkA and phosphatidylinosito l-3 kinase tyrosine phosphorylation, and increased transformation of T rkA-expressing fibroblasts. More important, mAb 5C3 protects human Trk A-expressing cells from apoptotic death in serum-free media. Interesti ngly, agonistic activity is observed with monomeric F-ab 5C3 fragments . mAb 5C3 (K-d similar to 2 nM) was used to study features of ligand b inding by TrkA and the distribution of TrkA protein in normal human br ain.