title: Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis.
abstract: Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone.
authors.affiliation: Zyngenia, Inc., Gaithersburg, MD, USA. pkanakaraj@zyngenia.com
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Kanakaraj
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Puffer
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Yao
authors.forename: Spandana
authors.initials: S
authors.lastname: Kankanala
authors.forename: Ernest
authors.initials: E
authors.lastname: Boyd
authors.forename: Rutul R
authors.initials: RR
authors.lastname: Shah
authors.forename: Geping
authors.initials: G
authors.lastname: Wang
authors.forename: Dimki
authors.initials: D
authors.lastname: Patel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishnamurthy
authors.forename: Shashi
authors.initials: S
authors.lastname: Kaithamana
authors.forename: Rodger G
authors.initials: RG
authors.lastname: Smith
authors.forename: David W
authors.initials: DW
authors.lastname: LaFleur
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
authors.forename: David M
authors.initials: DM
authors.lastname: Hilbert
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: Viktor V
authors.initials: VV
authors.lastname: Roschke
mesh_terms: D000068879:Adalimumab; D042702:Angiopoietin-2 / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D042702:Angiopoietin-2; D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab