NIE 2024 | Dr. Xiangyang Tan, Chief Scientific Officer of Cobiota: Challenges and Next-Generation Development Directions for ADC Drugs

Here are the key points of Dr. Tan's speech:

Dr. Tan pointed out that there are currently more than 1,400 ADC drug projects in development globally, including over 300 clinical projects. In the first half of 2024, ADC projects showed explosive growth, with a 21% increase in number compared to the end of 2023, indicating a rapid development momentum in the ADC drug field. There are a total of 82 globally active clinical targets for ADCs, with more than 200 preclinical targets. Hot targets such as HER2 and TROP2 are competing fiercely in homogeneity. In the first half of 2024, new ADC targets formed a parallel trend where dual-targets are emerging and new targets are emerging one after another, indicating that there is much potential to be explored in the future.

The key to current ADC drug development is no longer simply pursuing toxicity but seeking a balance between toxicity and efficacy. In the first half of 2024, the new ADC toxins mainly included toxic topoisomerase I inhibitors. In addition, new conjugated drugs are emerging rapidly. Currently, there are more than 2,400 XDC drug projects globally. In the first half of 2024, preclinical projects of different technical types such as multi-target ADCs and radioactive drug conjugates grew rapidly.

The indications for global ADC clinical projects are mainly tumors, especially solid tumors. Breast cancer, non-small cell lung cancer, and gastric cancer are the tumor types with the most clinical trials conducted. China has disclosed more preclinical ADC projects in 2024 than the United States. The target layout is gradually transforming from following to innovation, showing the vitality and potential of domestic ADC drug research and development.

The clinical research and development success rate of ADC drugs is 10.8%, higher than the entire tumor field but lower than CAR-T, small nucleic acid, and monoclonal antibody drugs. The main reasons for ADC development failures include intolerable toxicity, insufficient efficacy, and commercial considerations. The clinical efficacy of ADCs depends on the correct combination and selection of target antigens, targeting antibodies, conjugation linkers, and cytotoxic payloads. These core components interact with each other and jointly determine the effectiveness and safety of ADCs. Therefore, the complexity of ADC drug design is much higher than that of individual antibody drugs or cytotoxic chemotherapy drugs.

Dr. Tan pointed out that generally speaking, targets with good internalization, low expression in normal tissues but high expression in tumors are the first choice for developing ADCs. However, in actual preclinical development and clinical applications, it is difficult to predict ADC activity and clinical toxicity based solely on target properties. It is necessary to comprehensively determine according to different tumor types and ADC development technical experience. In addition, the toxicity of ADC drugs includes target-mediated toxicity and target-independent toxicity. Years of ADC clinical experience have shown that most of the clinical toxicity of ADCs is target-independent toxicity. The free toxin in normal tissues may be the main cause of toxic reactions.

Dr. Tan also mentioned that the efficacy of ADCs is often limited by resistance. The potential resistance mechanisms of ADCs are complex and affected by various factors including molecular structure, mechanism of action, and cellular environment. At the same time, the currently approved solid tumor indications for ADCs are relatively concentrated, mostly adopting a patient selection strategy without biomarker screening. The mechanism of action of toxins is relatively single. The limitations of available ADC clinical indications may be related to the restricted distribution and expression level of targets, tumor insensitivity to toxins, and tumor heterogeneity.

Finally, Dr. Tan looked ahead to the development directions of next-generation ADCs. He proposed that the design and optimization of ADCs need to combine clinical needs and target characteristics, comprehensively consider each part of the ADC, and continuously personalize adjustments according to needs during the research and development process. The discovery of next-generation ADC targets will use multi-omics data design algorithms, compile comprehensive cell surface antigen annotation datasets, and comprehensively evaluate the feasibility of ADC development from multiple dimensions.

Driven by basic research in oncology and immunology, the selection range of ADC targets will expand from traditional tumor cell antigens to the tumor microenvironment, including tumor blood vessels and matrix targets. In addition, by engineering antibodies to reduce molecular weight or change their affinity for antigen binding, the toxicity of ADCs to non-target tissues can be reduced and tumor-specific exposure can be increased, with the potential to expand the therapeutic window of ADCs and treat patients with lower target expression levels. Next-generation ADCs will explore toxins with new mechanisms of action, such as new immunomodulators, RNA inhibitors, PROTAC degraders, etc. It is also possible to integrate two toxins with different mechanisms into a single antibody to develop dual-toxin ADCs. In terms of linker technology, next-generation ADC linkers will focus on achieving controllable toxin release without relying on endogenous enzyme-mediated cleavage. Next-generation conjugation technology will obtain site-fixed, DAR value uniform ADCs through methods such as engineering modification, metabolic labeling, or chemical enzyme modification. New conjugated drugs such as bispecific ADCs and radionuclide-conjugated antibody RDC will open up new tracks in the ADC field to overcome the clinical challenges faced by traditional ADCs.