Synthesis, characterization and targeting chemotherapy for ovarian cancer of trastuzumab-SN-38 conjugates

Antibody-drug conjugates (ADCs), combining monoclonal antibody with high cytotoxicity chemotherapeutic drug (warhead), have been successfully applied for clinical cancer therapy. Linker technology to select and design linker connecting warhead with antibody, is critical to the success of therapeutic ADCs. In this study, three kinds of linkers were designed to connect SN-38, the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100–1000 times more potent than CPT-11, with the anti-HER2 antibody trastuzumab to prepare three different ADC conjugates (T-SN38 A, B and C). Meanwhile, we compared the anti-ovarian cancer effect of these three T-SN38 conjugates with trastuzumab in vitro and in vivo. Our in vitro results showed that T-SN38 A, B and C (drug-to-antibody ratio, DAR=3.7, 3.2, 3.4) were 2 to 3 times as cytotoxic as SN-38, and the IC50 for these three conjugates on SKOV-3 cell line at 72h were 5.2±0.3, 4.4±0.7, and 5.1±0.4nM respectively. In our in vivo studies, T-SN38 conjugates had well targeting ability for tumor tissue and all three of them had much higher anti-ovarian cancer potency than trastuzumab. Among of them, T-SN38 B, which coupled SN-38 with trastuzumab by a carbonate bond, has the best anti-ovarian cancer potency. In conclusion, the novel HER2-targeting ADCs T-SN38 have great potential for HER2-positive ovarian cancer. Moreover, the SN-38-Linkers designed in this study can also be used to connect with other antibodies for the therapy of other cancers. Schematic displays the structures of three HER2-targeting antibody-drug conjugates (ADCs): T-SN38 A, T-SN38 B and T-SN38 C. T-SN38 A prepared with the hydrophobic ester linkage linker A which contained ester bond cleavage site; T-SN38 B contains hydrophobic linker B with carbonate cleavage site; T-SN38 C contains linker C with hydrophilic PEG4 fragment and carbonate cleavage site. Results of in vitro and in vivo showed T-SN38 A, B and C (Drug Antibody Rate, DAR=3.7, 3.2, 3.4) have great potential for HER2-positive ovarian cancer. [Display omitted]