TrkA ligands : development and uses

Neurotrophins are dimeric polypeptides responsible for the survival, differentiation and maintenance of specific neuronal populations that express cell surface receptors termed tropomyosin receptor kinases (Trks). Trks possess intrinsic tyrosine kinase activity and are thought to mediate most neurotrophic effects. Recently, non-neuronal cells as well as certain human neoplasias, such as neuroblastoma have also been shown to express Trks. The prototype neurotrophin, Nerve Growth Factor (NGF) binds to the first identified Trk, TrkA causing its dimerization, auto- and trans-phosphorylation and subsequent cascade of signaling events. NGF also binds to a receptor with less well characterized biological activity termed p75. The production of novel ligands which can either mimic or inhibit the signaling of the NGF-TrkA ligand-receptor system holds much promise for the development of therapeutics and diagnostics in pathologies ranging from neurodegenerative disease to cancer.Prior to this work no "artificial" ligands had been reported to bind the extracellular domain of TrkA and to sufficiently affect TrkA-mediated signaling. In my work, I designed and synthesized small peptidic cyclic analogs of NGF beta-turn regions. A competitive antagonist termed C(92-96) which structurally mimics NGF beta-turn C-D was obtained (LeSauteur et al., 1995). In addition, the monoclonal antibody (mAb) 5C3, a naturally dimeric molecule which is specific for human TrkA, was produced and characterized. MAb 5C3 is a structural and functional mimic of NGF and an artificial receptor agonist (LeSauteur et al., 1996a). The in vivo targeting efficacy of two novel ligands; the NGF analog C(92-96) and mAb 5C3, was evaluated and compared (LeSauteur et al. 1996b). Both TrkA ligands were radiolabelled with technicium and used to specifically image TrkA-expressing tumors. The pharmacokinetics of targeting was better for the NGF analog C(92-96) than for mAb 5C3. MAb 5C3 has been shown to be a useful diagnostic and prognostic factor for neuroblastoma (Kramer et al., 1996)