title: Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA. mylene.perreault@pfizer.com
authors.forename: Mylène
authors.initials: M
authors.lastname: Perreault
authors.forename: Guo
authors.initials: G
authors.lastname: Feng
authors.forename: Sarah
authors.initials: S
authors.lastname: Will
authors.forename: Tiffany
authors.initials: T
authors.lastname: Gareski
authors.forename: David
authors.initials: D
authors.lastname: Kubasiak
authors.forename: Kimberly
authors.initials: K
authors.lastname: Marquette
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Unger
authors.forename: Juli
authors.initials: J
authors.lastname: Jones
authors.forename: Ariful
authors.initials: A
authors.lastname: Qadri
authors.forename: Seung
authors.initials: S
authors.lastname: Hahm
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rohde
authors.forename: Raphael
authors.initials: R
authors.lastname: Zwijnenberg
authors.forename: Janet
authors.initials: J
authors.lastname: Paulsen
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Gimeno
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001067:Appetite Depressants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects*; D006224:Cricetinae; D059305:Diet, High-Fat / Q000009:adverse effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D001067:Appetite Depressants; D020813:Receptor, trkB