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01.03.2012 | Original Article | Ausgabe 3/2012

Cancer Chemotherapy and Pharmacology 3/2012

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

Cancer Chemotherapy and Pharmacology > Ausgabe 3/2012
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
Wichtige Hinweise
Selwyn J. Hurwitz and Hongzheng Zhang contributed equally to this work.
Domantis Limited is a wholly owned subsidiary of GlaxoSmithKline.



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.


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.


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 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.


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.

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