A novel engineered antibody fragment ADC that is not dependent on intracellular degradation for drug

In this article titled "Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumor activity in mice" the authors mostly from Tagworks Pharmaceuticals and Radboud University develop a very novel ADC. The approach is based on the authors rationale that current ADCs are reliant on internalizing tumor antigens. These types of antigens have inherent limitations such as limited tumor receptor availability (with solid tumors) and poor intratumoral distribution. Thus, this paper engineers a diabody (50 kDa) from the mAb CC49 that targets tumor-associated glycoprotein 72 (TAG72) that is non-internalizing and overexpressed in several tumor types. A second major approach is that this is pretargeting. The diabody is engineered to contain 4 cysteines for attaching the microtubule inhibitor MMAE. The innovation is the use of a novel linker based on transcyclotene (TCO) that can be cleaved by the chemical tetrazine. The approach is to inject the diabody-TCO-MMAE, which clears rapidly from the blood and normal organs and has strong uptake in the tumor by two days post-injection. This is followed by injection of a tetrazine-Dota molecule that localizes to the tumor and liberates the MMAE. Although, this approach is highly innovative the anti-tumor results were less than spectacular. Anti-tumor results only came with the largest does (5 mg/kg) and 4 cycles within a two-week period. There still needs much optimization and its not clear if this approach will be better than the current intracellular drug release/delivery system.