Antibody-drug conjugates (ADCs) are targeted bioconjugate pharmaceuticals that combine the benefits of monoclonal antibodies (mAbs) and cytotoxic drugs. Regrettably, the technology still has some flaws which haven’t been solved. For example, the attach mode restricts its sphere of influence and action pattern. Also, its generally poor tumor penetration and immune system responses via Fc interactions are still great concerns.(2)
In order to enhance and perfect ADCs, we designed a “weakened” antigenic determinate helper which has weaker interactions with the antibody using genetic-engineering methods. The weakened antigenic determinate, which we call “Key” during our research, won’t completely cover up the antibody binding site. As a result, antibodies with Key still offer the potential of targeting the normal antigens. When the Key-antibody complex meets the original antigens, Key will be squeezed out of the binding site because of its lower affinity. With an effector protein fused to Key by a linker, it would be able to release the effector protein whenever an original antigen appears.
Key will activate the scFv-effector complex when it comes to the system like a switching signal activating the inductive switch. The system acts as a switch and that’s where the name Switchgen came from. We chose p185her2/neu as the antigen to be mutated and weakened. Corresponding to the antigen, we chose the antibody chA21 as the antibody in the system mentioned above.