title: Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871.
abstract: OBJECTIVE
  The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor.
  
  
  METHODS
  By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (K(d) = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties.
  
  
  RESULTS
  This antibody blocks binding of IGF-1 to its receptor (IC(50) 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC(50) 0.42 nmol/L) and induced the down-regulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L.
  
  
  CONCLUSIONS
  These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.
authors.affiliation: Pfizer Global Research and Development, Inc., Eastern Point Road, Groton, CT 06340, USA. bruce_d_cohen@groton.pfizer.com
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cohen
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Baker
authors.forename: Catherine
authors.initials: C
authors.lastname: Soderstrom
authors.forename: George
authors.initials: G
authors.lastname: Tkalcevic
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Rossi
authors.forename: Penny E
authors.initials: PE
authors.lastname: Miller
authors.forename: Mark W
authors.initials: MW
authors.lastname: Tengowski
authors.forename: Faye
authors.initials: F
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
authors.forename: Jean S
authors.initials: JS
authors.lastname: Beebe
authors.forename: James D
authors.initials: JD
authors.lastname: Moyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D007074:Immunoglobulin G / Q000276:immunology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1