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.
Highlights
The development of antibody–drug conjugates (ADC) can be traced back to early studies in the 1970s through the 1990s [1,2,3,4], when the typical drugs in clinical use were conjugated to various antibodies, and even studied in limited cases clinically (BR96; ref. 5)
Because labetuzumab govitecan is intended for further clinical development, this study addresses its pharmacodynamics in two colonic cancer xenograft models that express copious amounts of CEACAM5, comparing the accretion of SN-38 derived from the ADC with that from its parental drug, irinotecan
As illustrated by the similar dissociation constants for labetuzumab and labetuzumab govitecan, is unaffected by the coupling procedure (Supplementary Fig. S4). This coupling procedure does not appear to have an appreciable impact on the clearance of the hMN-14 IgG, which is consistent with studies comparing sacituzumab govitecan (IMMU-132) and hRS7 IgG in mice [29, 33]
Summary
The development of antibody–drug conjugates (ADC) can be traced back to early studies in the 1970s through the 1990s [1,2,3,4], when the typical drugs in clinical use were conjugated to various antibodies, and even studied in limited cases clinically (BR96; ref. 5). The development of antibody–drug conjugates (ADC) can be traced back to early studies in the 1970s through the 1990s [1,2,3,4], when the typical drugs in clinical use were conjugated to various antibodies, and even studied in limited cases clinically Each facet of the ADC, the antibody, the drug, and the linker, received attention to overcome the limitations of the early ADCs developed [6,7,8]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Prior presentation: This work was presented at the 2017 Annual Meeting of the American Association for Cancer Research, Washington, D.C., and is published in the Proceedings for this meeting (April 2017, Vol 58, pp 1042, abstract 4081)
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