Modulation of neurotrophin signaling by monoclonal antibodies.

The neurotrophin family is comprised of the structurally related secreted proteins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophine-4 (NT-4). They bind and activate the tyrosine kinase receptors Trk A, B, and C in a ligand-specific manner and additionally bind a shared p75NTR receptor. The neurotrophins were originally defined by their ability to support the survival and maturation of embryonic neurons. However, they also control important physiological functions of the adult nervous system including learning and memory, sensation, and energy homeostasis. For example, NGF/trkA signaling is critical for normal and pathological sensation of pain. Likewise, the BDNF/trkB pathway controls feeding and metabolism, and its dysfunction leads to severe obesity. Antibodies can modulate neurotrophin signaling. Thus, NGF blocking agents can attenuate pain in several animal models, and a recombinant humanized NGF blocking antibody (Tanezumab) has shown promising results in human clinical trials for osteoarthritic pain. On the other hand trkB agonist antibodies can modulate food intake and body weight in rodents and nonhuman primates. The power of monoclonal antibodies to modulate neurotrophin signaling promises to turn the rich biological insights into novel human medicines.