ADCs Against Cancer: Clinical Landscape and Challenges
Release date：2019/11/14 17:30:23
As a new frontier in the battle against cancer, an increased number of antibody-drug conjugations in clinical trials brings us a new wave of potent immunotherapeutics against over 30 different types of cancers in almost all major organs and tissues. The current status put over 80 ADCs in active clinical trials among which 6 candidates have gained FDA approval, which includes ado-trastuzumab emtansine (Kadcyla™), brentuximab vedotin (Adcetris™), inotuzumab ozogamicin (Besponsa™), gemtuzumab ozogamicin (Mylotarg™) , moxetumomab pasudotox-tdfk (Lumoxiti®) and polatuzumab vedotin-piiq (POLIVY, Genentech, Inc.). Approved ADCs show promising market share among other immunotherapeutics with increased annual sales, a driving force for the investment in other ADCs. As a brief summary, we are in an age of an “ADC boom” and with the hope that more ADCs to survive and thrive in clinical evaluations, they could add powerful weapons into the arsenal of immunotherapies.
The technology is based on the concept of delivering a cytotoxic payload selectively to cancer cells by attaching it to an antibody targeted to antigens on the cell surfaces. This approach has several advantages including the ability to select patients as likely responders based on the presence of antigen on the surface of their cancer cells and a wider therapeutic index, given that ADC targeting enables a more efficient delivery of cytotoxic agents to cancer cells than can be achieved by conventional chemotherapy, thus minimizing systemic toxicity.
The clinical landscape of ADCs in both heme and solid cancers has grown to nearly 600 clinical trials incorporating nearly 60 ADCs using payload-warhead of various mechanisms such as tubulin inhibitors, damaging DNA, topoisomerase inhibitors, and inhibitors of ENA polymerase II. While the predominant targets of most ADCS are heme cancers, including leukemias and lymphomas, the solid cancers of breast, colorectal, lung, prostate, ovarian, urothelial system is increasingly targeted by next-generation ADCs. In late-stage clinical trials, there has been an increased progression of ADCs in 2018, which has increased the possibility of more ADCs obtaining FDA approval and reaching cancer patients.
Although there are many examples of antibodies that have been developed for this purpose, along with numerous linker technologies used to attach the cytotoxic agent to the antibody. Challenges, however, still remain:
1) The full-size antibody, based on which all current ADCs are constructed, is a limitation for tumor penetration against solid tumors and as a result, might have a significant impact on the efficacy of those ADCs.
2) There is a limited number of available payloads and a lack of ingenuity and creativity in the linking mechanisms. With the majority of the ADCs in clinical trials formulated around vc-auristatin and maytansinoids-ester linkages, complications might soon surface when the efficacy of those payloads fail to efficiently eliminate corresponding tumors.
3) Over 68% of the active ADCs are in Phase I, a stage where most of the ADC trial suspensions take place. Thus, it is still too early to draw any conclusions regarding the fate of the majority of ADCs.
With the emerging of new targets, antibodies, as well as payload-linkers, we anticipate an expanding number of ADCs to reach the clinical trials and FDA approval to benefit us all.
Biochempeg giving full support to make their research in ADC more convenient and diverse, which has developed a series of peptides with discrete PEG chain which mitigates aggregation & immunogenicity in ADC.