ADC-positive drugs: Role analysis from R&D controls to quality control standards

Definition and Classification of ADC Positive Drugs

ADC positive drugs generally refer to antibody-drug conjugates or their functional mimetic molecules that are known to have well-defined target-binding activity, internalization efficiency, and cytotoxic activity. In industry practice, such reagents can be divided into two categories: first, reference substances sharing the same target and the same linker-payload format as the target ADC, commonly used for batch consistency evaluation in process development; second, control antibodies that retain only target-binding function without a toxic payload, used to distinguish target specificity from additional effects introduced by the conjugation process. Common specifications include lyophilized powder or liquid forms, generally requiring purity greater than 95% and endotoxin levels meeting routine standards for biological reagents.

Use as a Positive Control in Early-Stage Research and Development

During the screening stage of ADC candidate molecules, ADC positive drugs are widely used as positive control groups. For example, in target-binding ELISA, internalization assays, or in vitro cytotoxicity experiments, using ADC positive drugs with confirmed activity can validate the effectiveness of the experimental system. Researchers assess the relative activity of candidate molecules by comparing their EC50 or IC50 with those of the positive drug. It should be noted that the selection of positive drugs should be as close as possible to the test molecule in chemical structure (such as linker type and drug-to-antibody ratio, DAR) to avoid misjudgment caused by mechanistic differences.

Use as a Standard in Process Quality Control

Upon entering clinical or commercial production stages, ADC positive drugs are often used as quality control standards for process scale-up to test batch-to-batch consistency. Specific applications include: using the positive drug as a reference peak when determining DAR distribution by high-performance liquid chromatography; assessing aggregate proportion in hydrophobic interaction chromatography or size exclusion chromatography; and monitoring batch potency in cell activity assays. According to the Chinese Pharmacopoeia and relevant ICH guidelines, quality control standards require a complete calibration report, including content, purity, activity, and stability data, and must be periodically re-calibrated. ADC positive drugs play the role of a "gold standard" in this process.

Precautions and Regulatory Considerations

When using ADC positive drugs, it is necessary to comply with the Drug Administration Law and relevant regulations for in vitro diagnostic reagents. Promotional terms such as "or" must never be used. In research-use statements, it should be clearly indicated that they are "for research use only, not for clinical diagnosis or treatment." In addition, the storage conditions of positive drugs must be strictly validated, typically recommending storage at -80°C or -20°C protected from light, with no more than three freeze-thaw cycles. For ADCs with different linkers (such as enzyme-cleavable or non-cleavable), the corresponding type of positive control should be selected to avoid cross-interference.