Antibody-drug conjugates (ADCs) comprise monoclonal antibodies covalently coupled to cytotoxic agents through engineered chemical linkers, targeting tumor cells by targeting antigens recognized by the antibody and minimizing off-target effects in healthy tissues. ADCs represent a novel class of biopharmaceuticals that deliver high-efficacy and low-toxicity therapies for various oncologic diseases, including hematological malignancies, solid tumors, and lymphoid disorders.

The future of antibody research of ADCs has been primarily driven by advancements in antibody-drug conjugation technology and the optimization of target selection and drug delivery mechanisms. However, several factors continue to limit ADC clinical efficacy, including off-target toxicity, heterogeneous drug distribution, and aggregation or rapid clearance of uncoupled antibodies in systemic circulation.

Custom Monoclonal Antibodies in Biomedical Research: Advancing Precision Science

Moreover, ADCs with an imbalanced hydrophilic-lipophilic balance and excessive steric crowding may exhibit poor stability and aggregation in vivo, hampering the release of the therapeutic payload at tumor sites [24].

Therefore, future of antibody research should focus on addressing these limitations by exploring site-specific coupling methods such as engineered cysteine (Thio-mab) coupling and unnatural amino acid coupling. By introducing specific chemical groups or unnatural amino acids at designated positions on mAbs, site-specific conjugation achieves a more homogenous drug-to-antibody ratio (DAR) distribution and significantly enhances the therapeutic window of ADCs.

In addition, leveraging bispecific antibodies (BsAbs) and advanced cytotoxic agent chemotypes may further increase ADC efficacy. In particular, combining BsAbs targeted to different tumor targets such as an anti-EGFR Fab and an anti-HER3 scFv has been shown to maximize internalization and degradation of complexes in lysosomes and enhance overall antitumor activity.