Abstract 2904: SN-38 antibody-drug conjugates as a novel platform for solid cancer therapy: preclinical science
Authors: Goldenberg David M. , Cardillo Thomas M. , Sharkey Robert M. , McBride William J. , Rossi Edmund A. , Chang Chien-Hsing , Govindan Serengulam V. 
Published: May 2015

Abstract
SN-38 is the active metabolite of the camptothecin prodrug, CPT-11 (irinotecan), which is a solid cancer therapeutic, particularly colorectal cancer (CRC). SN-38 is highly potent (low nM), but its bioavailability is hampered by a low rate of CPT-11 conversion to SN-38 (e.g., &lt;5%), as well as its subsequent detoxification, mainly by UGT1A1 glucoronidation. In an attempt to improve SN-38's bioavailability and therapeutic index, we conjugated it to tumor-targeting humanized monoclonal antibodies (mAbs) using a novel pH-sensitive linker and a maleimide attachment to the mAb's interchain SH groups, achieving a drug-antibody ratio of 7.6. Linker coupling on the 20th position of SN-38 helps maintain SN-38 in the more active lactone form. In human serum, SN-38 is released from the linker with a half-life of ∼24 h, providing ample time for the ADC to localize in tumors. The pH-sensitive linker has the potential to release of SN-38 in the acidic tumor microenvironment by the targeted ADC in the absence of its direct internalization. Studies using two different SN-38-conjugated mAbs targeting CEACAM5 (IMMU-130) and Trop-2 (IMMU-132) show growth inhibition and regression of diverse human solid cancer xenografts in mice given repeated doses (cumulative ≤ 50 mg/kg in mice, or ∼ 4 mg/kg human equivalent dose [HED]), without defining an MTD (CPT-11 conversion is more active in mice, but mice are more tolerant to SN-38 than humans). Dosing regimens using the same total amount of the ADC given once or twice weekly for at least 2 weeks appears to be preferred over the same total amount given once every other week (2 doses). IMMU-130 is a poorly-internalizing mAb that shows good ADC activity in human CRC models expressing CEACAM5, while IMMU-132 internalizes rapidly and is active against CRC, gastric, breast, pancreatic, and prostatic cancers expressing Trop-2; both targets have antigen receptors in the 1 x 10*5 range in most cancer cell lines. Studies to assess tumor and tissue concentrations of SN-38 in xenograft models given the ADC or CPT-11 are ongoing. Toxicity studies performed in relevant animal species found the ADCs were tolerated at HED of up to 60 mg/kg, limited by neutropenia and diarrhea (also dose-limiting for CPT-11 therapy), and with no evidence of selective toxicity to antigen-expressing normal tissues. These results with an ADC having relatively modest toxicity suggest a high therapeutic index. Ongoing Phase I/II clinical trials confirm anticancer activity with a high therapeutic window (less neutropenia and GI toxicity than CPT-11) in cancers expressing the target antigens.
Citation Format: David M. Goldenberg, Thomas M. Cardillo, Robert M. Sharkey, William J. McBride, Edmund A. Rossi, Chien-Hsing Chang, Serengulam V. Govindan. SN-38 antibody-drug conjugates as a novel platform for solid cancer therapy: preclinical science. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2014-2904