Antibody-Drug Conjugate (ADC) Preclinical DMPK and Bioanalysis Research Strategies

Antibody-drug conjugates (ADCs) are a novel therapeutic that combines highly targeted monoclonal antibodies with cytotoxic small molecule drugs, and have become a rising trend due to their precise and powerful mode of action. ADCs have the characteristics of both small molecule and macromolecular therapeutics, and are often present in vivo as complex and dynamically changing mixtures resulting from biotransformation and DAR changes. These bring unique challenges to ADC DMPK and bioanalytical research. This blog will summarize the marketed ADC drugs and introduce the comprehensive DMPK and bioanalytical strategies for ADC drugs.

Summary of 15 approved ADCs by 2024

As of July 2024, 15 ADC drugs have been approved by regulatory authorities worldwide, covering multiple indications such as hematologic tumors and solid tumors.

Table 1. Summary of 15 approved ADCs

DMPK research contents of ADCs

ADCs feature a complex structure and diverse dynamic processes in vivo, and their ADME characteristics are highly correlated with their pharmacological efficacy and toxicity. Carrying out the following DMPK studies for ADC drugs is recommended.

Table 2. Recommended DMPK studies for ADC drugs

Integrated bioanalytical strategies for ADC drugs

The absorption, distribution, metabolism, and excretion of ADC drugs in various tissues directly affect the efficacy and safety of ADCs, making their bioanalysis more challenging than other drugs. Not only large molecules (total antibodies and conjugated antibodies) but also small molecule components (free and conjugated payloads) need to be taken into consideration. Bioanalysis of total antibodies, conjugated antibodies, free payloads, and related metabolites is essential throughout all stages, including early discovery/screening, preclinical, and clinical development of ADC drugs. A comprehensive bioanalytical approach is required to properly assess the ADME properties of ADC drugs.

Figure 1. Bioanalytical considerations for ADC drugs

By utilizing multiple analytical platforms and employing a combination of small molecule/large molecule and hybrid analysis methods, suitable analysis strategies can be devised to tackle specific challenges in ADC drug development effectively.

Table 3. ADC bioanalytical platform and applications

Figure 2. DMPK integrated bioanalytical platform of ADC drugs

In recent years, ADC drugs have gone through multiple iterations to improve efficacy and safety, and have been updated to fourth-generation ADC drugs. ADC drugs' stability, safety, and efficacy require a combination of multiple biological analysis platforms. As more innovative conjugation strategies, antibody scaffolds, and novel warheads are used in next-generation ADCs, bring more challenges to ADC bioanalysis.

Summary

With extensive experience in ADC drug bioanalysis, WuXi AppTec DMPK has established integrated bioanalytical platforms (LBA, LC-MS, LC-HRMS, hybrid LBA/LC-(HR)MS, and QWBA), developed and validated bioanalytical methods to evaluate the components of ADCs, to provide customers with one-stop ADC bioanalysis services. We have supported hundreds of ADC projects, including dozens of ADC IND applications. 

Table 4. DMPK studies to support ADC preclinical discovery and development

Committed to accelerating drug discovery and development, we offer a full range of discovery screening, preclinical development, and clinical drug metabolism and pharmacokinetic (DMPK) platforms and services. With research facilities in the United States (New Jersey) and China (Shanghai, Suzhou, Nanjing, and Nantong), 1,000+ scientists, and over fifteen years of experience in Investigational New Drug (IND) application, our DMPK team at WuXi AppTec are serving 1,600+ global clients, and have successfully supported 1,500+ IND applications.  

Talk to a WuXi AppTec expert today to get the support you need to achieve your drug development goals.

Authors: Maotian Zhou, Huijuan Qian