Generation of Antibody Drug Conjugate (ADC) technologies for site specific conjugation to toxins

抗体-药物结合物(ADC)是一种将毒素直接输送到癌细胞的靶向治疗技术，是一类快速增长的肿瘤治疗药物，已有8种ADC获准临床使用。大多数临床上可用的ADC要么是通过赖氨酸e-氨基的非化学反应产生异类产物，要么是通过减少链间二硫键激活的半胱氨基结合产生的，这可能会影响抗体的稳定性。我们将在抗体上引入位点特异性半胱氨酸突变，以实现与有毒药物的位点特异性结合。我们将在功能模型中比较不同的突变抗体作为ADC，以确定最佳的稳定性、功能和疗效特征。

Antibody-Drug Conjugates (ADCs) are a targeted treatment technology for delivery of toxinsdirectly to cancer cells and a fast-growing class of oncology therapeutics, with eight ADCsapproved for clinical use. Most clinically-available ADCs are produced through either achemical reaction of lysine e-amino groups which produces heterogeneous products, orconjugation through cysteine sulfhydryl groups activated by reducing the interchain disulfidebonds, which may compromise antibody stability. We will introduce site-specific cysteinemutations on antibodies for site-specific conjugation with toxic drugs. We will comparedifferent mutant antibodies as ADCs in functional models, to identify optimal stability,function and efficacy characteristics.