Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.
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Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM
Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.
Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3.
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- 21372224 [ View in PubMed]
- Abstract
PURPOSE: Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans. EXPERIMENTAL DESIGN: Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys. RESULTS: The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution ( approximately 6), cell binding (K(d) approximately 1.2 nmol/L), cytotoxicity (IC(50) approximately 2.2 nmol/L), and serum stability in vitro (t/((1/2)) approximately 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P
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Drug Target Kind Organism Pharmacological Action Actions Sacituzumab govitecan Tumor-associated calcium signal transducer 2 Protein Humans YesAntibodyDetails