title: MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors.
abstract: Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR-mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation.
authors.affiliation: Corresponding Authors: Alexey A. Lugovskoy, Merrimack Pharmaceuticals, One Kendal Square, Suite B7201, Cambridge, MA 02139. alugovskoy@merrimackpharma.com.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Fitzgerald
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Johnson
authors.forename: Jason
authors.initials: J
authors.lastname: Baum
authors.forename: Sharlene
authors.initials: S
authors.lastname: Adams
authors.forename: Sergio
authors.initials: S
authors.lastname: Iadevaia
authors.forename: Jian
authors.initials: J
authors.lastname: Tang
authors.forename: Victoria
authors.initials: V
authors.lastname: Rimkunas
authors.forename: Lihui
authors.initials: L
authors.lastname: Xu
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kohli
authors.forename: Rachel
authors.initials: R
authors.lastname: Rennard
authors.forename: Maja
authors.initials: M
authors.lastname: Razlog
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: Brian D
authors.initials: BD
authors.lastname: Harms
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Olivier
authors.forename: Birgit
authors.initials: B
authors.lastname: Schoeberl
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lugovskoy
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D000068338:Everolimus; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000077143:Docetaxel; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D043823:Taxoids; D000093542:Gemcitabine; C546842:MTOR protein, human; C581292:ERBB3 protein, human; C000595155:Istiratumab