Antibody-drug conjugates (ADCs) benefit from an elegant design. When functioning to their full potential, they entrust an antibody to guide a therapeutic payload directly to tumor cells, while avoiding unwanted effects on healthy tissue. This combination of selectivity and potency creates treatment options which are transforming oncology therapeutics.
ADC design has evolved rapidly over the past decade as researchers seek to extract the full potential from this drug type, but concerns over toxicity have limited its broader potential. In recent years, ADC development has shifted from prioritizing target selection to addressing the adverse effects of payload activity in normal tissues. This increased scrutiny of the payload ensures that testing properly examines not just the ADC’s target, but what happens when the payload gets there.
These three pointers can help researchers navigate the complexity of ADC toxicity, enabling safer, more efficient development.
1. Remember Toxicity Often Follows the Payload
Researchers can sometimes focus too heavily on an ADC’s antibody when evaluating toxicity, but the payload should not be overlooked. ADCs containing the same payload but targeting different tumor antigens can still cause adverse effects, demonstrating that toxicity can follow the payload.
This is evident in two of the most popular payload types used in ADCs.
- Microtubule inhibitors: this type of payload disrupts the cell division mechanism, making it highly effective against growing tumors. But they can also affect healthy tissues that rely on continuous cell turnover. ADCs with these payloads are often associated with toxicities in the gastrointestinal tract, peripheral nerves, bone marrow, and other sensitive tissues.
- DNA-damaging payloads: these compounds impair DNA to prevent cancer cells from surviving and growing. However, rapidly dividing healthy cells can be caught in the crossfire, leading to off-target toxicity across multiple organ systems.
Both examples show that many ADC toxicities can be traced to biological consequences of the payload’s mechanism of action and suggest that payload pharmacology often influences toxicity more than target expression alone.
2. Navigate the Balancing Act of Linker Design
In ADCs, linkers bind the payload to antibodies. Ideally, they remain stable in circulation and release the payload only after the ADC has been internalized into the target cell. But when payload release occurs prematurely, ADCs can suffer from increased systemic exposure and cause toxicity in healthy tissues.
This creates a delicate balancing act scientists must overcome. If a linker releases the payload too early, healthy tissues can be exposed to a cytotoxic agent before the ADC reaches the target. If it’s too stable, the payload may not achieve the desired therapeutic effect. Tweaking the linker length, hydrophilicity, and stereochemistry can alter how an ADC behaves in the body, significantly affecting its efficacy and safety.
3. Treat Tissue Susceptibility as a Key Factor
Recent ADC development has shown that toxicity cannot be explained solely by target expression and that some tissues appear particularly vulnerable to injury associated with ADCs, regardless of whether they express the intended antigen.
These tissues are often those that rely on continuous cell renewal, such as bone marrow, the gastrointestinal tract, and certain reproductive tissues. Their rapidly dividing cell populations are especially sensitive to mechanisms that make ADCs effective against tumors, and can become unintended casualties.
Other toxicities, such as interstitial lung disease, are less straightforward. This example is a recognized concern for certain ADC classes and underscores how tissue-specific biology can influence safety outcomes in ways that target expression alone cannot predict.
A Final Word
ADC development is evolving quickly, and developers are learning that the same antibody can produce different outcomes depending on the payload type, how the payload is released, and how normal tissues respond to exposure. To ensure the very highest standards of safety are upheld, scientists must take a broader view of ADC design that considers chemistry and biology in tandem.
In the future, ADC innovations including new payload classes, bispecific ADCs, and dual-payload approaches, will drive the need for thorough preclinical evaluation.
All this underlines the importance of exhaustive preclinical evaluation. Through proper testing, researchers can distinguish between toxicities driven by the target and those originating from the payload itself. This can help guide decisions around advancing candidates and where design modifications can improve the balance between safety and efficacy.
