Antibodies as Magic Bullets

The concept of a “magic bullet” as first formulated by Paul Ehrlich can perhaps most readily be applied to antibodies “armed” with toxic substances or radionuclides. Most of the toxins from plants and bacteria are enzymes, a single molecule of which can catalyze thousands of reactions. In contrast, non-enzymatic reagents must be potent enough that only a few molecules are able to damage vital structures such as DNA and microtubules. Most of the current ADCs bind to the tubulin subunit of microtubules, which are the major components of the mitotic spindle, and inhibit their function in the process of cell division. Rapidly dividing cells such as tumor cells become stranded in the pre-mitotic phase of the cell cycle and eventually die. To equip antibodies with a radioactive payload, they are conjugated with cage-like complexes (chelators) that bind the positively charged ions of radioactive metals. In more recent approaches to diminish side effects, the antibody-chelate conjugates have been loaded with radionuclides after binding their target molecules in the tumor tissue.