Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 3, pp 577–590

Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice

  • Selwyn J. Hurwitz
  • Hongzheng Zhang
  • Sujin Yun
  • Thil D. Batuwangala
  • Michael Steward
  • Steve D. Holmes
  • Daniel Rycroft
  • Lin Pan
  • Mourad Tighiouart
  • Hyung Ju C. Shin
  • Lydia Koenig
  • Yuxiang Wang
  • Zhuo (Georgia) Chen
  • Dong M. Shin
Original Article

DOI: 10.1007/s00280-011-1713-x

Cite this article as:
Hurwitz, S.J., Zhang, H., Yun, S. et al. Cancer Chemother Pharmacol (2012) 69: 577. doi:10.1007/s00280-011-1713-x

Abstract

Purpose

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 (IC50) and variations in tumor growth.

Results

The PD models adequately described tumor responses for the antibody dose regimens. In vivo IC50 values varied with EGFR and K-ras status. DT-IgG had a similar serum t1/2 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 IC50 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.

Keywords

DT-IgG Targeted antibody EGFR VEGF Bevacizumab Cetuximab Pharmacokinetics NONMEM Tumor population pharmacodynamic model 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Selwyn J. Hurwitz
    • 5
  • Hongzheng Zhang
    • 1
  • Sujin Yun
    • 1
  • Thil D. Batuwangala
    • 2
  • Michael Steward
    • 2
  • Steve D. Holmes
    • 2
  • Daniel Rycroft
    • 2
  • Lin Pan
    • 3
  • Mourad Tighiouart
    • 3
  • Hyung Ju C. Shin
    • 4
  • Lydia Koenig
    • 1
  • Yuxiang Wang
    • 1
  • Zhuo (Georgia) Chen
    • 1
  • Dong M. Shin
    • 1
  1. 1.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory University School of MedicineAtlantaUSA
  2. 2.Domantis LimitedCambridgeUK
  3. 3.Department of Biostatistics, School of Public HealthEmory UniversityAtlantaUSA
  4. 4.Quest DiagnosticsAtlantaUSA
  5. 5.Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of PediatricsEmory University School of Medicine/VA Medical CenterDecaturUSA

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