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

抗体-药物偶联物（ADC）是一种将毒素直接递送至癌细胞的靶向治疗技术，也是一类快速增长的肿瘤治疗药物，目前已有8种ADC获批用于临床。大多数临床可用的ADC通过赖氨酸e-氨基的化学反应产生，其产生异质产物，或通过还原链间二硫键活化的半胱氨酸巯基缀合产生，这可能损害抗体稳定性。我们将在抗体上引入位点特异性半胱氨酸突变，用于与毒性药物的位点特异性缀合。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，功能和功效特征。

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.