Anti-ACVR2B monoclonal antibody, clone 2D22

Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from our laboratory and others have shown that the use of ACVR2B/Fc, a soluble form of the activin receptor 2B (ACVR2B), can mitigate muscle wasting induced by chemotherapy, although the underlying mechanisms responsible for such protective effects are unclear. In order to understand the biochemical mechanisms through which ACVR2B/Fc functions, we employed a comprehensive, multi-platform metabolomics approach. Using both nuclear magnetic resonance (NMR) and mass-spectrometry (MS), we profiled the metabolome of both serum and muscle tissue from four groups of mice including (1) vehicle, (2) the chemotherapeutic agent, Folfiri, (3) ACVR2B/Fc alone, and (4) combined treatment with both Folfiri and ACVR2B/Fc. The metabolic profiles demonstrated large effects with Folfiri treatment and much weaker effects with ACVR2B/Fc treatment. Interestingly, a number of significant effects were observed in the co-treatment group, with the addition of ACVR2B/Fc providing some level of rescue to the perturbations induced by Folfiri alone. The most prominent of these were a normalization of systemic glucose and lipid metabolism. Identification of these pathways provides important insights into the mechanism by which ACVR2B/Fc protects against chemotherapy-induced cachexia.

Initiation of BMP signaling is dependent upon activation of Type I BMP receptor by constitutively active Type II BMP receptor. Three Type II BMP receptors have been identified; Acvr2a and Acvr2b serve as receptors for BMPs and for activin-like ligands whereas BMPR-II functions only as a BMP receptor. As BMP signaling is required for endochondral ossification and loss of either Acvr2a or Acvr2b is not associated with deficits in limb development, we hypothesized that BMPR-II would be essential for BMP signaling during skeletogenesis. We removed BMPR-II from early limb mesoderm by crossing BMPR-II floxed mice with those carrying the Prx1-Cre transgene. Mice lacking limb expression of BMPR-II have normal skeletons that could not be distinguished from control littermates. From these data, we conclude that BMPR-II is not required for endochondral ossification in the limb where loss of BMPR-II may be compensated by BMP utilization of Acvr2a and Acvr2b. genesis 49: 719-724, 2011. (C) 2011 Wiley-Liss, Inc.