Generation of site-specific multiple-payload carrying peptidic linker (MPP) ADC delivering MMAD.

<p>(A) Schematic showing generation of a double-MMAD carrying peptidic linker ADC generated on trastuzumab A114C. (B) <i>In vitro</i> cytotoxicity of peptidic linked MMAD trastuzumab A114C ADC against various levels of Her2 expressing cancer cell lines, reported in Mean IC₅₀ values of conjugated payload in nM. Data are the mean of multiple experiments. MAL = malemide; DBCO = Dibenzocyclooctyne.</p

In vitro cytotoxicity of single-cysteine mutant thailanstatin trastuzumab ADCs against various levels of Her2 expressing cancer cell lines, reported in Mean IC₅₀ values of conjugated payload in nM.

<p>In vitro cytotoxicity of single-cysteine mutant thailanstatin trastuzumab ADCs against various levels of Her2 expressing cancer cell lines, reported in Mean IC₅₀ values of conjugated payload in nM.</p

Double-cysteine mutant thailanstatin trastuzumab ADCs.

<p>(A) <i>In vitro</i> cytotoxicity of double-cysteine mutant thailanstatin trastuzumab ADCs against various levels of Her2 expressing cancer cell lines, reported in Mean IC₅₀ values of conjugated payload in nM. Data are the mean of multiple experiments. (B) <i>In vivo</i> efficacy of double-cysteine mutant thailanstatin trastuzumab <b>ADC16</b> in N87 gastric cancer xenograft model dosed at 0.5, 1.56 and 3 mg/kg (q4d x 4). (C) <i>In vitro</i> cytotoxicity of double-cysteine mutant thailanstatin trastuzumab <b>ADC16</b> against T-DM1 resistant N87 (N87-TDM1) and 361 (361-TDM1) as well as MDR1 overexpressing N87 (N87-MDR1-CL3) cancer cell lines, reported in IC₅₀ values of conjugated payload in nM.</p

Potency of hinge-cysteine thailanstatin trastuzumab ADC.

<p>(A) Structure of iodoacetamide derivatized non-cleavable thailanstatin linker-payloads (LPs). (B) <i>In vitro</i> cytotoxicity of hinge-cysteine thailanstatin trastuzumab ADCs against cancer cell lines expressing various levels of Her2, reported in half-maximal inhibitory concentration (IC₅₀) values of conjugated payload in nM. Data are the mean of multiple experiments. (C) <i>In vivo</i> efficacy of hinge-cysteine thailanstatin trastuzumab <b>ADC1</b> in an N87 gastric cancer xenograft model dosed at 3 mg/kg (q4d x 4). Arrows indicate the day(s) on which intravenous dosing was carried out. DAR = Drug Antibody Ratio; 361 = MDA-MB-361-DYT2; 468 = MDA-MB-468.</p