title: Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer.
abstract: OBJECTIVE
  Vascular endothelial growth factor receptor-1 (VEGFR-1) plays important roles in promotion of tumor growth by mediating cellular functions in tumor vascular endothelium and cancer cells. Blockade of VEGFR-1 activation has been shown to inhibit pathologic angiogenesis and tumor growth, implicating VEGFR-1 as a potential therapeutic target for the treatment of cancer. We have thus developed a VEGFR-1 antagonist human monoclonal antibody designated as IMC-18F1 and evaluated its antitumor activity in preclinical experimental models to show the therapeutic potential of the antibody for cancer treatment in clinic.
  
  
  METHODS
  Human IgG transgenic mice were used for generation of anti-VEGFR-1 antibodies. Anti-VEGFR-1-specific blocking antibodies were identified using solid-phase binding and blocking assays. Inhibitory antitumor cell activity of IMC-18F1 was assessed in cell-based kinase and growth assays. Pharmacokinetic/pharmacodynamic studies were done to determine the association of antibody blood level with antitumor efficacy of the antibody in vivo. Antitumor efficacy of the anti-VEGFR-1 antibodies as monotherapy and in combination with cytotoxic agents was evaluated in human breast cancer xenograft models.
  
  
  RESULTS
  A fully human neutralizing antibody, IMC-18F1, was shown to be a high-affinity (KD=54 pmol) inhibitor of VEGFR-1 ligand binding (VEGF-A, VEGF-B, and placental growth factor). IMC-18F1 inhibited ligand-induced intracellular activation of VEGFR-1 and mitogen-activated protein kinase signaling and prevented ligand-stimulated in vitro growth of breast cancer cells. In vivo, IMC-18F1 suppressed the growth of human breast tumor xenografts in association with reduced mitogen-activated protein kinase and Akt activation, reduced tumor cell proliferation, and increased tumor cell apoptosis. Pharmacokinetic/pharmacodynamic studies established a plasma elimination half-life of 5 days for IMC-18F1 and a steady-state trough plasma therapeutic threshold of 88 microg/mL. Importantly, inhibition of mouse and human VEGFR-1 with MF1 and IMC-18F1, respectively, enhanced the antitumor efficacy of cytotoxic agents commonly used to treat breast cancer.
  
  
  CONCLUSIONS
  Based on preclinical validation studies, IMC-18F1 anti-VEGFR-1 has potential to provide clinical benefit to cancer patients.
authors.affiliation: Department of Experimental Therapeutics, ImClone Systems, Inc., New York, New York 10014, USA. Yan.Wu@imclone.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Zhong
authors.forename: James
authors.initials: J
authors.lastname: Huber
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bassi
authors.forename: Bridget
authors.initials: B
authors.lastname: Finnerty
authors.forename: Erik
authors.initials: E
authors.lastname: Corcoran
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Navarro
authors.forename: Paul
authors.initials: P
authors.lastname: Balderes
authors.forename: Xenia
authors.initials: X
authors.lastname: Jimenez
authors.forename: Henry
authors.initials: H
authors.lastname: Koo
authors.forename: Venkata R M
authors.initials: VR
authors.lastname: Mangalampalli
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000097:blood / Q000627:therapeutic use*; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000970:Antineoplastic Agents; D040262:Receptors, Vascular Endothelial Growth Factor; D020928:Mitogen-Activated Protein Kinases