Ciliary neurotrophic factor encyclopedia topics

Satiety effects

In 2001, it was reported that in a human study examining the usefulness of CNTF for treatment of motor neuron disease, CNTF produced an unexpected and substantial weight loss in the study subjects. Further investigation revealed that CNTF could reduce food intake without causing hunger or stress, and is believed to operate by a non-leptin, but 'leptin-like' pathway.

Axokine

Axokine is a modified version of human Ciliary neurotrophic factor with a 15 amino acid truncation of the C terminus and two amino acid substitutions, which is three to five times more potent than CNTF in in vitro and in vivo assays and has improved stability properties. Like CNTF it is a neurotrophic factor, and may stimulate nerve cells to survive. It was tested in the 1990s as a treatment for amyotrophic lateral sclerosis. It did not improve muscle control as much as expected, but trial participants did report a loss of appetite.

Phase III clinical trials for the drug against obesity were conducted in 2003 by Axokine's maker, Regeneron, demonstrating a small positive effect in some patients, but the drug was not commercialized. According to a March 31, 2003 Regeneron press release , a major problem with the treatment was that in nearly 70% of the subjects tested, antibodies against Axokine were produced after approximately three months of treatment. In the minority of subjects who did not develop the antibodies, weight loss averaged 12.5 pounds in one year, versus 4.5 pounds for placebo-treated subjects. In order to obtain this benefit, subjects needed to receive daily subcutaneous injections of one microgram Axokine per kilogram body weight.

Xencor patent application 20050064555 raises the disturbing idea that subjects producing antibodies against CNTF analogues may eventually suffer severe side effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF. The application claims methods of designing CNTF analogues with lower immunogenicity than Axokine based on analysis of affinity of each modified epitope for each of 52 class II MHC alleles, and provides specific examples of such modifications. As of November 2006, no such analogues were listed in Xencor's product pipeline.