Clinical Cancer esearch cer Therapy : Preclinical ineered Thio-Trastuzumab-DM 1 Conjugate with an roved Therapeutic Index to Target Human Epidermal R wth Factor Receptor 2 – Positive Breast Cancer

nloaded pose: Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytorugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antir activity. Successful ADC development for a given target antigen depends on optimization of dy selection, linker stability, cytotoxic drug potency, andmode of linker-drug conjugation to the antiHere, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety s of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC hat of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate. erimental Design and Results: To generate thioTMAb-mpeo-DM1, one drug maytansinoid 1 ) molecule was conjugated to an engineered cysteine residue at Ala114 (Kabat numbering) on each zumab-heavy chain, resulting in two DM1 molecules per antibody. ThioTMAb-mpeo-DM1 retained r in vitro anti–cell proliferation activity and human epidermal growth factor receptor 2 (HER2) g properties to that of the conventional ADC. Furthermore, it showed improved efficacy over nventional ADC at DM1-equivalent doses (μg/m) and retained efficacy at equivalent antibody (mg/kg). An improved safety profile of >2-fold was observed in a short-term target-independent fety study. In cynomolgus monkey safety studies, thioTMAb-mpeo-DM1 was tolerated at higher dy doses (up to 48 mg/kg or 6,000 μg DM1/m) compared with the conventional ADC that ose-limiting toxicity at 30 mg/kg (6,000 μg DM1/m). clusions: The engineered thioTMAb-mpeo-DM1 with broadened therapeutic index represents Con a promising antibody drug conjugate for future clinical development of HER2-positive targeted breast cancer therapies. Clin Cancer Res; 16(19); 4769–78. ©2010 AACR.