Antibody drug conjugates (ADCs) are emerging as a promising class of cancer therapeutics. The strategy of conjugating potent cytotoxic compounds to highly specific antibodies has already been proven effective with two FDA approved ADCs and &gt;60 in clinical trials. Although ADC development has progressed rapidly, a major challenge has been the production of homogeneous, site-specific ADCs that have defined drug loading. Site-specific ADCs are expected to have well defined pharmacokinetic and pharmacodynamic properties and should translate more quickly from preclinical to clinical investigations. Even though there are several strategies to produce site-specific ADCs, they all rely on mutations or inefficient conjugation chemistries. Here we present a novel strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, our strategy affords to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and Non-Hodgkin lymphoma, respectively.

Harnessing a catalytic lysine residue for the rapid, one-step preparation of homogeneous antibody-drug conjugates

254th National Meeting (2017)

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