BioProcess International: Bridging Innovation & Clinical Reality in ADC and AOC Development

Abzena’s regulatory & bioconjugation experts, Jeffrey Mocny & Nicolas Camper, outline the priorities developers should address early to reduce downstream risk and improve clinical readiness.

Antibody-drug conjugates (ADCs) and antibody-oligonucleotide conjugates (AOCs) are advancing rapidly beyond oncology into areas such as rare diseases and neuromuscular disorders. However, ensuring these innovative therapies reach patients relies on developers bridging the gap between early innovation and the realities of scalable manufacturing, analytical control, and regulatory readiness. Success now depends on early identification of hidden chemistry, manufacturing, and controls (CMC) risks and robust conjugation strategies, as well as processes designed with clinical and commercial scalability in mind.

Expanding modalities are increasing development complexity

ADC and AOC therapeutics are advancing quickly, but from very different starting points. ADCs are now a more established modality, with over a dozen US Food and Drug Administration (FDA) approvals and a clearer body of regulatory experience. AOCs, on the other hand, are earlier in their development, but interest is growing as developers explore applications beyond oncology, including rare diseases and neuromuscular disorders.

As ADCs and AOCs move from promising concepts toward clinical development, the pressure shifts from what can be designed to what can be manufactured, characterized, and controlled at scale. Despite their relative maturity as a modality, ADCs can still present complex manufacturing demands, especially when newer conjugation strategies introduce multiple processing steps and specialist chemistries. AOCs bring additional uncertainty around analytical characterization, formulation, and regulatory expectations. 

In both cases, demonstrating control over product quality and manufacturing consistency is central to clinical readiness and meeting regulatory expectations, making early alignment between molecular design and CMC strategy essential.

Early development decisions can have consequences far beyond candidate selection. For complex conjugates, choices around conjugation chemistry, linker-payload design, analytical strategy, and formulation all influence how easily a program can move from laboratory success to controlled, reproducible manufacture. When these CMC considerations are addressed too late, developers may find that a promising molecule introduces unexpected complexity into scale-up, characterization, or process control. 

Glycan remodeling strategies in ADC development are a prime example of how early choices around conjugation chemistry can shape the complexity of later scale-up and process control. These approaches modify specific sugar structures on the antibody to create more uniform and stable conjugates, enabling a level of control that can be highly attractive during early research. However, such choices often come with added manufacturing complexity. Preparing these ADCs can involve multiple sequential enzymatic steps, specialist linker-payload synthesis, and complex carbohydrate chemistry. This process may look efficient at small scale, but can become far more difficult to control, reproduce, and scale in a manufacturing environment.

Characterization must keep pace with complexity

A similar disconnect between early design and later development can emerge through limitations in analytical capabilities during characterization. 

In AOC development, oligonucleotides introduce extraordinary molecular complexity. A single oligonucleotide sequence can exist in an enormous number of conformations, creating challenges in controlling conjugatable impurities and understanding product heterogeneity. Developers must therefore consider how the antibody and oligonucleotide behave independently, as well as how the combined conjugate population can be characterized and controlled as an integrated product. 

Although existing analytical tools can assess certain ADC and AOC product attributes individually, fully characterizing the aggregate conjugate population remains difficult. As these molecules become more complex, gaps in analytical understanding can make it harder to establish robust control strategies, assess product consistency and support scalability.

Building CMC into early development decisions

Early CMC alignment starts with defining what the program is trying to build and what success needs to look like from a manufacturing perspective. For complex conjugates, this means looking beyond activity at small scale and asking whether the molecule, process and analytical strategy can support reproducible clinical manufacture. In some cases, this may require developers to reconsider or modify promising molecular designs if the associated manufacturing complexity introduces excessive risk, cost or scalability limitations.

Several priorities can help guide these early development decisions:

A clear quality target product profile (QTPP) gives teams a practical reference point for development. It helps define the physical and chemical characteristics the molecule needs to achieve, as well as the level of control required to support quality, safety and future scalability. 

Once the intended QTPP is clear, developers can evaluate which conjugation routes are realistic and whether they can support larger-scale manufacture. This process includes considering whether the chemistry, purification approach and analytical strategy can deliver the desired molecule without creating unnecessary process complexity, difficult-to-control impurities or scalability limitations.

A control strategy should reflect where the program is susceptible to variability, whether in conjugation efficiency, impurity formation, product heterogeneity, or purification. Identifying these pressure points early helps teams focus development work where it can have the greatest impact. This is particularly important in demonstrating manufacturing control and reproducibility, which remain central regulatory expectations for complex conjugates.

With this approach, CMC becomes part of the program’s direction from the beginning rather than a set of issues to solve later.

Securing future success for ADC and AOC development 

The continued expansion of ADCs and AOCs is pushing conjugate development into increasingly complex territory. As these modalities evolve beyond their original applications, developers face growing pressure to balance innovation with manufacturability, analytical control, and scalability. 

As conjugate modalities become more sophisticated, the programs most likely to succeed will be those that connect molecular design, CMC strategy, and process control from the earliest stages of development, with close coordination between discovery, analytical, and manufacturing teams.

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