Neutralizing antibodies targeting NGF-mediated pain.



Neutralizing antibodies targeting NGF-mediated pain.


A. Cassetta, D. Lamba


PM.P06: Enabling technologies for drug discovery
PM.P06.001: Crystallography of biomolecules and functional studies


Neutralizing antibodies, NGF, TrkA, Neuropathic pain

Scuola Internazionale Superiore di Studi Avanzati, Trieste (Italy); Lay Line Genomics S.p.A., Roma (Italy); European Brain Research Institute, Roma (Italy); Scuola Normale Superiore, Pisa (Italy)

Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs.
Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1). Administration of either antibodies has been shown to be effective in a number of preclinical models of pain, including interstitial cystitis, non-bacterial prostatitis and osteoarthritis.
The monoclonal antibodies MNAC13 (anti-TrkA) and aD11 (anti NGF) are potent antagonists that prevent the NGF-TrkA interaction in vivo systems. In order to gain deeper insights into the molecular basis of their observed high affinities a structural and functional characterization of these antibodies and of their complexes with TrkA and NGF are actively being pursued. A detailed structural information on their antigenic recognition is expected to aid in the development of analogs as antagonists or agonists of neurotrophins that may have greater affinity or specificity for further experimental and therapeutic applications.

Covaceuszach S, Cattaneo A, Lamba D. Neutralization of NGF-TrkA receptor interaction by the novel antagonistic anti-TrkA monoclonal antibody MNAC13: a Structural insight. Proteins: Structure, Function and Bioinformatics (2005) 58, 717.
Cattaneo A, Covaceuszach S, Lamba D. Method for the humanization of antibodies and humanized antibodies thereby obtained. Patent n° WO/2005/061540.

Covaceuszach S, Cassetta A,  Konarev PV, Gonfloni S,  Ibañez C, Rudolph R, Svergun DI, Lamba D, Cattaneo A. Dissecting NGF interactions with TrkA and p75 receptors by structural and functional studies of an anti-NGF neutralizing antibody. J Mol Biol (2008)381, 881.




Doriano Lamba
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Tel : +39-040-3758514


Last Updated (Monday, 25 October 2010 10:27)