Linker Technologies in ADCs: How They Impact Efficacy & Stability

Catch up on our ADC development series on YouTube to hear more expert insights.

Antibody-drug conjugates (ADCs) have revolutionized targeted cancer therapy, but discussions often focus on the antibody and the cytotoxic payload, leaving linker technology as an overlooked component. In reality, linker technology is a pivotal aspect that significantly influences ADC efficacy, selectivity and stability. Let’s take a closer look at why linkers matter and how they contribute to the overall performance of ADCs.

The Importance of Linker Characteristics

One of the fundamental considerations in ADC design is the linker’s biophysical properties, as they directly impact the molecule’s stability, manufacturability and half-life. For instance, more hydrophobic linkers tend to reduce half-life and can cause biophysical complications such as aggregation and solubility, while more hydrophilic linkers can limit the impact on the biophysical and developability profile of the ADC.

Another critical factor is the choice between cleavable and non-cleavable linkers. Cleavable linkers are generally preferred when targeting intracellular mechanisms, as they facilitate the controlled release of the cytotoxic payload at the intended site of action. However, they must be carefully designed to avoid non-specific or systemic cleavage, which can lead to off-target side-effects. Non-cleavable linkers do have other benefits as enhance stability ensures that the payload remains intact until the ADC is internalized and degraded within the lysosome. Yet this can have an adverse effect on efficacy as a small proportion of ADC reaching target cells will ‘drop’ payload is the molecule has to be degraded, ADCs that only reach endosomal pathway (as with receptor recycling) won’t release payload.

Conjugation Strategies and Their Impact

The nature of the conjugation technology also plays a significant role in the overall stability and homogeneity of ADCs. Techniques such as site-specific conjugation using non-canonical amino acid insertion, engineered reactive handles or enzymatic methods can better control the drug-to-antibody ratio (DAR), reducing heterogeneity and minimizing the impact on biophysical properties. Achieving homogeneity ensures that every molecule performs predictably, improving consistency of effect despite inherent variability among patients.

The conjugation position itself can also drastically affect half-life and stability. For example, the use of improper conjugation sites can result in over five-fold reductions in half-life, underscoring the importance of precise ADC engineering. site-specific conjugation methods offer more rational approaches to maintaining consistency in DAR and reducing heterogeneity.

The Future of Linker Technology in ADCs

Looking ahead, the integration of innovative conjugation techniques and deeper understanding of linker characteristics and increasing cleavage selectivity will undoubtedly shape the next generation of ADCs. By addressing the interplay between the linker, payload, and conjugation strategies, we can develop more efficient and stable ADCs, ultimately improving therapeutic outcomes and quality of life for patients.

Linkers are no longer the unsung heroes of ADCs. They are now seen as integral to achieving the desired therapeutic effect and will continue to evolve as an essential component of next-generation antibody-drug conjugates.

Catch up on the previous parts in our ADC development blog series:

Part 1: Exploring new paths in ADC development

Part 2: What’s the Evolving Role of Medicinal Chemistry in ADC Development?

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