The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain.
Nerve growth factor (NGF) is involved in pain transduction mechanisms and plays a key role in many persistent pain states, notably those associated with inflammation. On this basis, both the NGF ligand and its receptor TrkA (tyrosine kinase A) represent an eligible target for pain therapy. Although the direct involvement of NGF in pain modulation is well established, the effect of a direct functional block of the TrkA receptor is still unknown. In this study, we have demonstrated that MNAC13, the only anti-TrkA monoclonal antibody for which function neutralizing properties have been clearly shown both in vitro and in vivo, induces analgesia in both inflammatory and neuropathic pain models, with a surprisingly long-lasting effect in the latter. The formalin-evoked pain licking responses are significantly reduced by the MNAC13 antibody in CD1 mice. Remarkably, treatment with the anti-TrkA antibody also produces a significant antiallodynic effect on neuropathic pain: repeated i.p. injections of MNAC13 induce significant functional recovery in mice subjected to sciatic nerve ligation, with effects persisting after administration. Furthermore, a clear synergistic effect is observed when MNAC13 is administered in combination with opioids, at doses that are not efficacious per se. This study represents a direct demonstration that neutralizing antibodies directed against the TrkA receptor may display potent analgesic effects in inflammatory and chronic pain.
Ugolini
Gabriele
G
Lay Line Genomics, Via di Castel Romano 100, 00128 Rome, Italy.
Marinelli
Sara
S
Covaceuszach
Sonia
S
Cattaneo
Antonino
A
Pavone
Flaminia
F
D016475:3T3 Cells; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001666:Binding Sites, Antibody / Q000187:drug effects; D004195:Disease Models, Animal; D005557:Formaldehyde; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020932:Nerve Growth Factor / Q000378:metabolism; D009500:Neutralization Tests; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D020917:Receptor, trkA / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
D000701:Analgesics, Opioid; D000911:Antibodies, Monoclonal; C518608:MNAC13 monoclonal antibody; D005557:Formaldehyde; D020932:Nerve Growth Factor; D020917:Receptor, trkA