title: Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice.
abstract: OBJECTIVE
  DT-IgG is a fully humanized dual-target therapeutic antibody being developed to simultaneously target epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), important signaling molecules for tumor growth. The antitumor pharmacodynamics (PD) of DT-IgG was studied in nude mice bearing human tumor xenografts with different EGFR and VEGF expressions and K-ras oncogene status and compared with bevacizumab, cetuximab and bevacizumab + cetuximab.
  
  
  METHODS
  Mice bearing human oral squamous cell carcinoma (Tu212), lung adenocarcinoma (A549), or colon cancer (GEO) subcutaneous xenografts were administered with the antibodies intraperitoneally (i.p.), and tumor volumes were measured versus time. Nonlinear mixed effects modeling (NONMEM) was used to study drug potencies (IC(50)) and variations in tumor growth.
  
  
  RESULTS
  The PD models adequately described tumor responses for the antibody dose regimens. In vivo IC(50) values varied with EGFR and K-ras status. DT-IgG had a similar serum t                            (1/2) as cetuximab (~1.7 vs. 1.5 day), was more rapid than bevacizumab (~6 day), and had the largest apparent distribution volume (DT-IgG > cetuximab > bevacizumab). The efficacy of DT-IgG was comparable to bevacizumab despite lower serum concentrations, but was less than bevacizumab + cetuximab.
  
  
  CONCLUSIONS
  A lower IC(50) of DT-IgG partially compensated for lower serum concentrations than bevacizumab and cetuximab, but may require higher doses for comparable efficacy as the combination. The model adequately predicted variations of tumor response at the DT-IgG doses tested and could be used for targeting specific tumor efficacies for future testing.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine/VA Medical Center, Medical Research # 151H, 1670 Clairmont Road, Decatur, GA, 30300, USA. shurwit@emory.edu
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Hongzheng
authors.initials: H
authors.lastname: Zhang
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
authors.forename: Thil D
authors.initials: TD
authors.lastname: Batuwangala
authors.forename: Michael
authors.initials: M
authors.lastname: Steward
authors.forename: Steve D
authors.initials: SD
authors.lastname: Holmes
authors.forename: Daniel
authors.initials: D
authors.lastname: Rycroft
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.forename: Lydia
authors.initials: L
authors.lastname: Koenig
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab