Effect of tyrosine kinase inhibitor treatment of renal cell carcinoma on the accumulation of carbonic anhydrase IX-specific chimeric monoclonal antibody cG250.

Abstract

OBJECTIVE:

To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC.

MATERIALS AND METHODS:

Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 µg (125) I-cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250.

RESULTS:

While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible.

CONCLUSIONS:

Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed.

• Authors: Jeannette C Oosterwijk-Wakka, Gürsah Kats-Ugurlu, William P J Leenders, Lambertus A L M Kiemeney, Lloyd J Old, Peter F A Mulders, Egbert Oosterwijk
• Journal: BJU international (BJU Int) Vol. 107 Issue 1 Pg. 118-25 (Jan 2011) ISSN: 1464-410X [Electronic] England
• PMID: 20346054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Benzenesulfonates
• G250 monoclonal antibody
• Indoles
• Phenylurea Compounds
• Piperidines
• Protein Kinase Inhibitors
• Pyridines
• Pyrroles
• Quinazolines
• Niacinamide
• Sorafenib
• Protein-Tyrosine Kinases
• Carbonic Anhydrases
• Sunitinib
• vandetanib

Topics

• Animals
• Antibodies, Monoclonal (metabolism)
• Antineoplastic Agents (therapeutic use)
• Benzenesulfonates (therapeutic use)
• Carbonic Anhydrases (metabolism)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Drug Synergism
• Female
• Humans
• Immunohistochemistry
• Indoles (therapeutic use)
• Kidney Neoplasms (drug therapy, pathology)
• Mice
• Neoplasm Transplantation
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Piperidines (therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyridines (therapeutic use)
• Pyrroles (therapeutic use)
• Quinazolines (therapeutic use)
• Sorafenib
• Sunitinib