Selective and Concentrated Accretion of SN-38 with a CEACAM5-Targeting Antibody-Drug Conjugate (ADC), Labetuzumab Govitecan (IMMU-130).

Abstract

Labetuzumab govitecan (IMMU-130), an antibody-drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130-treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196-203. ©2017 AACR.

• Authors: Robert M Sharkey, Serengulam V Govindan, Thomas M Cardillo, Jennifer Donnell, Jing Xia, Edmund A Rossi, Chien-Hsing Chang, David M Goldenberg
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 1 Pg. 196-203 (01 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29079710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• CEACAM5 protein, human
• Carcinoembryonic Antigen
• GPI-Linked Proteins
• Immunoconjugates
• labetuzumab govitecan

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Carcinoembryonic Antigen (metabolism)
• Cell Line, Tumor
• Female
• GPI-Linked Proteins (metabolism)
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• Mice
• Mice, Nude