Key Factors in ADC Target Selection

Antibody-drug conjugate (ADC) target selection is a core aspect of drug design that directly impacts efficacy and safety. Current strategies emphasize achieving a balance between innovation and risk control, primarily focusing on two paths: optimization of established targets and exploration of new targets.

Pharmaceutical companies tend to select established targets that are lowly expressed in normal tissues and highly expressed in tumor tissues, to enhance tumor selectivity and reduce off-target toxicity. For example, the HER2 target has been successfully validated in breast cancer treatment. ADC drugs based on trastuzumab (such as trastuzumab-emtansine and trastuzumab-deruxtecan) have significantly improved efficacy for metastatic breast cancer patients through payload and linker optimization, becoming a "successfully replicable" development paradigm. The advantage of such targets lies in the substantial clinical data support, which reduces development uncertainty.

The proportion of new target development in ADC pipelines is relatively modest, with current hotspots including immune checkpoint CD276 (B7-H3), which shows potential in refractory solid tumors such as small cell lung cancer. However, monoclonal antibodies targeting CD276 have failed multiple times. ADC technology, through precise delivery of highly active payloads, may reactivate the value of such targets. New target selection requires priority evaluation of antigen heterogeneity and intratumoral distribution to avoid efficacy limitations caused by uneven target expression.

1. Specificity

The target is highly expressed in tumor cells but lowly expressed or not expressed in normal tissues, ensuring that ADCs can precisely recognize and bind to tumor cells, reducing non-specific binding and toxicity to normal tissues. Ideal targets have significantly higher expression levels in tumor tissues compared to normal tissues, such as HER2, Trop-2, etc., enabling ADCs to accurately recognize and enter tumor cells. The lower the target expression in normal tissues, the better, or it should only be expressed in non-critical, regenerative tissues (such as hair follicles), which can reduce off-target toxicity. The target needs to be effectively internalized (enter the cell), but too rapid internalization may also affect drug release. Some ADCs also rely on the "bystander effect" (drugs can penetrate adjacent cells), so target selection should also consider this. The target itself should not trigger excessive immune responses, which could otherwise affect efficacy or increase side effects.

Specificity is the core principle for ADCs to exert targeted therapeutic effects, significantly reducing off-target toxicity and improving treatment safety and selectivity. If the target is widely expressed in normal tissues, ADCs may mistakenly damage normal cells, causing severe side effects. For example, HER2 is highly expressed in certain breast cancers, gastric cancers, and other tumors, while having very low expression in normal tissues, making it an ideal ADC target; whereas CD44 is also expressed in normal keratinocytes, requiring careful evaluation of off-target risks when developing ADCs targeting CD44.

2. Expression Level

Refers to the expression level of the target on the tumor cell surface or inside the cell, including antigen density and expression intensity. Targets with high expression levels can bind to more ADCs, promoting ADC internalization and cytotoxic drug release, thereby improving therapeutic efficacy; low-expression targets may result in insufficient ADC binding, failing to reach effective cytotoxic doses, and affecting efficacy. For example, in HER2-positive breast cancer, tumor cells with high HER2 expression show higher sensitivity to ADC drugs (such as T-DM1) and better efficacy; for HER2-low expressing tumors, more efficient ADCs or combination therapy strategies need to be developed.

3. Internalization

The process by which the target, after binding to the ADC, transports the ADC into the cell through endocytosis mechanisms to lysosomes and other intracellular compartments, releasing cytotoxic drugs. Internalization is a critical step for ADCs to exert cytotoxic effects. If the target cannot be internalized or has low internalization efficiency, cytotoxic drugs cannot effectively function inside the cell, leading to poor efficacy. For example, CD22 is expressed in B-cell malignancies and can rapidly internalize after binding to ADCs, enabling ADC drugs to release cytotoxic drugs inside cells and exert anti-tumor effects; whereas CD30, although expressed on the surface of tumor cells, mainly undergoes proteolytic cleavage and shedding rather than internalization, limiting its efficacy as an ADC target.

4. Target Heterogeneity

Refers to the variability in target expression within tumor cell populations, including heterogeneity in target expression levels within tumor cells and differences in target expression between different patients. Target heterogeneity may affect ADC therapeutic efficacy. If there are large numbers of target-negative or low-expression cells within the tumor, ADCs cannot effectively kill these cells, leading to tumor recurrence or resistance. For example, in breast cancer, HER2 expression exhibits heterogeneity, with some tumor cells having high HER2 expression while others have low or no HER2 expression. HER2-targeted ADCs may not completely eliminate tumor cells; developing linkers with bystander effects or combining with other treatment modalities can overcome challenges posed by target heterogeneity.

5. Accessibility

Refers to the ease with which ADC drugs can reach tumor targets, influenced by tumor type, tumor microenvironment, vascular distribution, and other factors. Accessibility is a prerequisite for ADCs to exert their effects. If ADCs cannot effectively penetrate tumor tissues, even with good target specificity and expression levels, therapeutic effects cannot be achieved. For example, in hematological malignancies (such as leukemia, lymphoma), tumor cells exist in circulating systems like blood and bone marrow, making it easier for ADC drugs to reach targets; whereas in solid tumors (such as lung cancer, liver cancer), due to complex tumor tissue structure and uneven vascular distribution, ADC drug penetration is poorer, requiring optimized drug design or combination therapy strategies to improve accessibility.

Reference

Cuthbertson J, Paliouras S, Kolesnikova T. Trends in target novelty in oncology R&D. Nature Reviews Drug Discovery, 2025.