Enzyme-Based Strategies to Generate Site-Specifically Conjugated Antibody Drug Conjugates

摘要: Antibody Drug Conjugates (ADCs) exploit the specificity of monoclonal antibodies for targeting highly potent small molecular weight toxins to cancer cells in order selectively effect their destruction. It is expected that due ADCs tumor, these drugs will be associated with less side effects and a higher therapeutic index than standard chemotherapy. However, so far this promise has only poorly translated into clinic. Despite fact therapy have been developed many decades, field experienced number failures clinical development, an unfavorable benefit safety relationship. The first ADC, Mylotarg®, anti-CD33 approved treatment acute myeloid leukemia (AML) eventually had taken off market 10 years post approval. To date two ADCs, anti-CD30 ADC brentuximab vedotin (Adcetris®) anti-HER-2 trastuzumab-emtansine (Kadcyla®), are therapy. In fact, Kadcyla® as second-line breast limited comparison first-line There increasing body evidence first-generation including marketed products, generated by chemical conjugation, liabilities connected conjugation technologies employed, which negative impact on efficacy ADCs. Here, we describe novel approaches, specific focus enzymatic aim at overcoming limitations namely heterogeneity chemically conjugated insufficient linker stability. While site-specific can also achieved using while it possible employ improved linkers technologies, there additional compelling arguments toxin payloads antibodies. New developments data related preclinical evaluation such next-generation discussed.