PMID- 23700410 OWN - NLM STAT- MEDLINE DCOM- 20131224 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 5 DP - 2013 TI - Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates. PG - e62616 LID - 10.1371/journal.pone.0062616 [doi] LID - e62616 AB - Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to the regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity in both mice and humans. It has previously been reported that peripheral administration of the endogenous TrkB agonist ligand neurotrophin-4 (NT-4) profoundly decreases food intake and body weight in rodents, while paradoxically increasing these same parameters in monkeys. We generated a humanized TrkB agonist antibody, TAM-163, and characterized its therapeutic potential in several models of type 2 diabetes and obesity. In vitro, TAM-163 bound to human and rodent TrkB with high affinity, activated all aspects of the TrkB signaling cascade and induced TrkB internalization and degradation in a manner similar to BDNF. In vivo, peripheral administration of TAM-163 decreased food intake and/or body weight in mice, rats, hamsters, and dogs, but increased food intake and body weight in monkeys. The magnitude of weight change was similar in rodents and non-human primates, occurred at doses where there was no appreciable penetration into deep structures of the brain, and could not be explained by differences in exposures between species. Rather, peripherally administered TAM-163 localized to areas in the hypothalamus and the brain stem located outside the blood-brain barrier in a similar manner between rodents and non-human primates, suggesting differences in neuroanatomy across species. Our data demonstrate that a TrkB agonist antibody, administered peripherally, causes species-dependent effects on body weight similar to the endogenous TrkB ligand NT-4. The possible clinical utility of TrkB agonism in treating weight regulatory disorder, such as obesity or cachexia, will require evaluation in man. FAU - Perreault, Mylene AU - Perreault M AD - Cardiovascular and Metabolic Diseases Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA. mylene.perreault@pfizer.com FAU - Feng, Guo AU - Feng G FAU - Will, Sarah AU - Will S FAU - Gareski, Tiffany AU - Gareski T FAU - Kubasiak, David AU - Kubasiak D FAU - Marquette, Kimberly AU - Marquette K FAU - Vugmeyster, Yulia AU - Vugmeyster Y FAU - Unger, Thaddeus J AU - Unger TJ FAU - Jones, Juli AU - Jones J FAU - Qadri, Ariful AU - Qadri A FAU - Hahm, Seung AU - Hahm S FAU - Sun, Ying AU - Sun Y FAU - Rohde, Cynthia M AU - Rohde CM FAU - Zwijnenberg, Raphael AU - Zwijnenberg R FAU - Paulsen, Janet AU - Paulsen J FAU - Gimeno, Ruth E AU - Gimeno RE LA - eng PT - Journal Article DEP - 20130520 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Monoclonal) RN - 0 (Appetite Depressants) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Administration, Intravenous MH - Animals MH - Antibodies, Monoclonal/administration & dosage/pharmacokinetics/*pharmacology MH - Appetite Depressants/administration & dosage/pharmacokinetics/*pharmacology MH - Body Weight/*drug effects MH - Cricetinae MH - Diet, High-Fat/adverse effects MH - Dogs MH - Drug Evaluation, Preclinical MH - Energy Intake/drug effects MH - Female MH - HEK293 Cells MH - Humans MH - Hypothalamus/metabolism MH - Macaca fascicularis MH - Macaca mulatta MH - Male MH - Mesocricetus MH - Mice MH - Mice, Inbred C57BL MH - Obesity/etiology/pathology MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Zucker MH - Receptor, trkB/*agonists/metabolism MH - Tissue Distribution PMC - PMC3659094 COIS- Competing Interests: Mylene Perreault, Guo Feng, Sarah Will, Tiffany Gareski, David Kubasiak, TJ Unger, Juli Jones, Ariful Qadri, Seung Hahm, and Ruth E. Gimeno were employees in the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Inc, Cambridge (MA), USA. Kim Marquette, Ying Sun, and Janet Paulsen were employees in Global Biological Technologies (GBT), Pfizer Inc, Cambridge (MA), USA. Yulia Vugmeyster is with PDM, Pfizer Inc, Andover (MA), USA. Cynthia M. Rohde is in DSRD, Pfizer Inc, Andover (MA), USA. Raphael Zwijnenberg was with Fort Dodge Animal Health, Pfizer Inc, Princeton, NJ, USA. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2013/05/24 06:00 MHDA- 2013/12/25 06:00 PMCR- 2013/05/20 CRDT- 2013/05/24 06:00 PHST- 2012/12/04 00:00 [received] PHST- 2013/03/23 00:00 [accepted] PHST- 2013/05/24 06:00 [entrez] PHST- 2013/05/24 06:00 [pubmed] PHST- 2013/12/25 06:00 [medline] PHST- 2013/05/20 00:00 [pmc-release] AID - PONE-D-12-40522 [pii] AID - 10.1371/journal.pone.0062616 [doi] PST - epublish SO - PLoS One. 2013 May 20;8(5):e62616. doi: 10.1371/journal.pone.0062616. Print 2013.