title: Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3.
abstract: The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse.
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: McDonagh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Huhalov
authors.forename: Brian D
authors.initials: BD
authors.lastname: Harms
authors.forename: Sharlene
authors.initials: S
authors.lastname: Adams
authors.forename: Violette
authors.initials: V
authors.lastname: Paragas
authors.forename: Shinji
authors.initials: S
authors.lastname: Oyama
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Lia
authors.initials: L
authors.lastname: Luus
authors.forename: Ryan
authors.initials: R
authors.lastname: Overland
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nguyen
authors.forename: Jinming
authors.initials: J
authors.lastname: Gu
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kohli
authors.forename: Matt
authors.initials: M
authors.lastname: Wallace
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Feldhaus
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Kudla
authors.forename: Birgit
authors.initials: B
authors.lastname: Schoeberl
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D019938:Cyclin D1; D046912:Multiprotein Complexes; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C573311:MM-111