title: The interleukin-2 antagonizing antibody MT204 delays allogeneic skin graft rejection in non-human primates and is well tolerated.
abstract: MT204 is a humanized IgG1 antibody specific for interleukin-2 (IL-2) of human and rhesus monkey origin. It potently antagonizes IL-2 signaling in both CD25(+) and CD25(-) cells by a unique mode of action. MT204 can not only prevent soluble IL-2 from binding to the intermediate affinity IL-2 receptors but can also antagonize IL-2 that is already bound to the CD25 subunit of high affinity IL-2 receptors on the cell surface. As initial steps toward development of a therapeutic antibody, pharmacokinetics (PK) and tolerability of MT204, as well as efficacy were investigated in rhesus monkeys. MT204 was infused by single escalating (2, 10 and 50mg/kg) or repeat dose administrations (50mg/kg, 1 ×/week for 3 weeks). Over the course of the experiment, the animals were regularly observed for clinical adverse reaction and bled for laboratory investigations (PK, hematology, chemical chemistry and leukocyte subset analysis). For the efficacy study, six rhesus monkeys were grafted with MHC-mismatched rhesus skin and infused with MT204 (50mg/kg), on the day of transplantation and again on days 5 and 12 post grafting. Efficacy was determined by assessment of graft necrosis at different time-points. No obvious adverse effects were observed clinically after single infusion, or after three repeated infusions of 50mg/kg and no MT204-related toxic effects were revealed by hematology or clinical chemistry. In the efficacy study, MT204-treated animals showed a significant delay in graft rejection versus control animals (p=0.025 by Log-rank test). The characteristics of MT204, displaying linear pharmacokinetics, half-life in the range expected for a human IgG, benign safety profile and signs of efficacy, warrant further development of this antibody for therapy.
authors.affiliation: Micromet Inc. 6707 Democracy Blvd., Bethesda, MD 20817, USA. christine.plater-zyberk@micromet.de
authors.forename: Christine
authors.initials: C
authors.lastname: Plater-Zyberk
authors.forename: Dave M
authors.initials: DM
authors.lastname: Lopes Estêvão
authors.forename: Sandrine
authors.initials: S
authors.lastname: d'Argouges
authors.forename: Krista G
authors.initials: KG
authors.lastname: Haanstra
authors.forename: Ivanela
authors.initials: I
authors.lastname: Kondova
authors.forename: Michel
authors.initials: M
authors.lastname: Vierboom
authors.forename: Thomas
authors.initials: T
authors.lastname: Boehm
authors.forename: Ruediger
authors.initials: R
authors.lastname: Neef
authors.forename: Eva M
authors.initials: EM
authors.lastname: Vieser
authors.forename: Benno
authors.initials: B
authors.lastname: Rattel
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Margeet
authors.initials: M
authors.lastname: Jonker
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D006084:Graft Rejection / Q000188:drug therapy* / Q000517:prevention & control*; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008253:Macaca mulatta; D016038:Skin Transplantation; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; C517847:MT204 antibody, human