In 1913, the renowned German chemist Paul Ehrlich introduced the concept of the “magic bullet”, which is considered the earliest description of ADC drugs. In 2000, the FDA approved Mylotarg, the first ADC drug to enter the market. It was believed that ADC drugs would come flourish, but it was eventually withdrawn due to its limited efficacy and off-target toxicity, plunging ADC into darkness once again.
Since then, with the advancement of antibody drugs, progress in conjugation technology and the continuous progress of the concept of ADC, among other factors, ADC has undergone several generations of exploration and validation, eventually leading to a glorious era. The original “magic bullet” has also been upgraded to a “magic missile”.
In fact, the targeting effect of ADC drugs expands the treatment window of traditional chemotherapy, allowing ADCs to carry a higher cytotoxic payload. Gosatuzumab, for instance, carries a load of SN-38 that is over 100 times greater than that of irinotecan, while the DXD carries a load of DXD that is approximately 9 times greater than that of SN-38. Additionally, due to their targeting effect, ADCs can be released in high concentrations around tumor cells, even exerting a bystander effect to kill the adjacent tumor cells, thereby achieving the synergistic effect of “1 + 1 > 2”.
However, balancing efficacy and safety has always been a challenge in the development of ADC drugs and remains a bottleneck limiting their progress.
Faced with the ongoing clinical impact of Detrozumab, the development of theoretically safer ADC drugs has been halted due to the influence of competition patterns. Blenrep, the first ADC therapy targeting BCMA, became the second ADC drug to be withdrawn due to its poor efficacy in confirmatory clinical studies. These occurrences once again demonstrate that the iterative development of innovative drugs is never a smooth journey.
Nevertheless, the future of ADC holds great promise. Continuous efforts are needed to strike the delicate balance between efficacy and safety, overcome challenges, and navigate the complex landscape of drug development. With each step forward, ADCs have the potential to revolutionize cancer treatment, leading to improved outcomes for patients in need.