As the field of antibody-drug conjugates (ADCs) has matured in recent years, these novel agents have become an increasingly popular modality, particularly in oncology. Their popularity has been driven by several transformative developments in the category over the past 25 years, including increased and optimized linker stability, new payloads, and optimized and more site-specific conjugation strategies.[1][2][3]
Those transformations have enabled an increase in the number and types of molecules packaged as bioconjugates – including ADCs – in preclinical and clinical phases. Today’s bioconjugate landscape is more diverse than ever, with an abundance of possible combinations of modalities, antibody formats, and linker technologies resulting in novel bioconjugates (Figure 1).
However, the large diversity in molecules makes it difficult to establish a standard chemistry, manufacturing, and controls (CMC) development path. At the same time (and somewhat counter-intuitively), as the ADC field matures, many programs in the clinical pipeline are converging on the same established payload classes, notably a limited set of small-molecule cytotoxins.[1][2][3] While these molecules have demonstrated strong efficacy, the lack of payload diversity increasingly limits follow-up treatment options once resistance emerges and tumors rebound. To the uninitiated, those limitations would appear to threaten the continued growth of the ADC category.
Meeting the challenges of payload innovation
Fortunately, the ADC field has proven quite adept at devising innovative solutions to those challenges. In particular, the field is turning toward payloads with novel modes of action and more sophisticated dual-payload ADCs. By combining warheads with synergistic mechanisms (e.g., simultaneously inducing DNA damage while inhibiting DNA repair), these innovative therapeutics present tumors with multiple, parallel barriers to escape. Those mechanisms significantly increase the time required for resistance to develop, ultimately affording clinicians a longer and more viable window for treating patients.
However, such advances in conjugate design come with substantial CMC complexity. Novel payload classes and dual-payload architectures place new demands on analytical strategies, impurity and clearance control, and downstream processing. Successfully translating these innovations into the clinic requires scientific creativity as well as deep manufacturing and development expertise. That is where contract development and manufacturing organizations (CDMOs) can step in. CDMOs with broad experience across ADCs and emerging conjugate formats can help drug innovators design and implement tailored solutions to derisk and accelerate an ADC’s path to Investigational New Drug (IND) application, while also ensuring reliable supply for the clinic.
Anticipating and mitigating early-phase CMC challenges
Engaging with an experienced CDMO at an early stage can facilitate development of novel conjugate formats by front-loading crucial elements of the development program, including:
- Defining the conjugation strategy: This is particularly important for novel modalities such as oligo conjugates, dual-payload ADCs, and peptide conjugates.
- Delineating a scalable manufacturing process
- Conducting comprehensive developability studies to inform lead selection
Such early engagement can mitigate the main developability and manufacturability liabilities even prior to the CMC stage, which presents its own set of challenges. Unlike classic ADCs, novel conjugate formats often require multiple downstream processing unit operations. For example, several tangential flow filtration (TFF) steps may be required to clear reactants in multistep conjugations. Additionally, oligo-, protein-, or polymer-conjugates often require one or more chromatography steps to remove complex and larger impurities. Novel payload classes that are harder to clear on TFF, or reactants that can interfere with subsequent chemical steps, require delicate clearance solutions to limit residual levels.
Compared with standard monoclonal antibodies (mAbs) or classic ADCs, the stability of novel formats is harder to predict and requires more extensive studies. Moreover, analytics methods may need to be developed from scratch, as there may not be a suitable platform starting point that only requires some tweaking. Some novel formats incorporate less-toxic or non-toxic payloads, resulting in more tolerable ADCs that enable much higher dosing and higher concentration formulations. These factors drive high material demand for tox studies and formulation development early in the CMC stage, necessitating proactive and integrated planning of material flows.
Addressing residual clearance challenges
At the World ADC London Summit 2026, we outlined our approach to CMC development of an innovative antibody-protein conjugate. This project entailed a multistep reaction culminating with a dibenzocyclooctyne (DBCO)-mediated conjugation to the protein payload. The project’s complexity was reflected in a process that required multiple unit operations, including two chromatography steps and five TFF steps. As an additional challenge, the linker needed to be decapped prior to conjugation (Figure 2A).
We found that the reagent used for decapping interfered with the subsequent conjugation step, and that the reaction required a large amount of excess reagent. Consequently, extreme removal, in relative terms, was required to avoid a significant reduction in yield. We therefore employed TFF to remove the excess residual reagent. Yet despite the expected exponential decay of residual impurities, reagent levels increased again after recirculation and even more so after emptying the TFF system, reaching levels above the in-process controls (IPC) specification, which were set to ensure successful downstream conjugation (Figure 2B).
We hypothesized that the residual spikes were caused by minor deadleg pockets in the TFF system that were released during recirculation and emptying. We tested this hypothesis at lab scale by introducing several recirculation steps after every few diavolumes (DV) to release and subsequently clear the deadleg pockets. Although this appeared to be a promising approach, it was poorly reproducible and system-dependent, posing risk for scale-up to Good Manufacturing Practices (GMP).
Using DMSO as a surrogate, we tested an improved clearance strategy directly at scale. This process included recirculation and flush-and-wash steps, resulting in reproducible removal of residuals below the IPC specification and the level of quantification, and confirming the feasibility and success of the procedure (Figure 2C).
In addition to derisking the chemical conjugation steps via a robust residual-clearance strategy, we tackled some of the typical CMC development challenges for novel conjugate formats. Notably, to isolate the target molecule from a heterogeneous mixture post-conjugation, we adjusted the chromatographic purification step to improve robustness for scale-up. We also established tailored analytical methods to characterize the novel construct adequately for clinical release. All told, addressing this program’s technical challenges resulted in a successful IND filing and ample, on-time supply for clinical studies with a 100% batch success rate. The customer lauded our team’s breadth of capabilities across biologics, linkers, small molecules, and bioconjugation, an offering that “allows the realization of virtually any bioconjugate and their seamless assembly,” while enabling creation of “truly novel biotherapeutics.”
Key takeaways
The case illustrates how early-stage development of novel conjugates is a delicate balancing act, one that weighs acceptance of a program’s risks and limitations against the imperative to expedite patient access to novel therapies. It featured cumbersome clearance procedures that would likely not be viable for routine commercial production but are feasible for first clinical supply.
A holistic view of the product life cycle enabled the CDMO and the customer to determine jointly which challenges needed to be addressed. Prior to IND, challenges can be mitigated through adequate control strategies, and in later stages after clinical success is established, targeted process and analytical development can be implemented to ensure commercial readiness.
More broadly, an early focus on developability and manufacturability can help drug developers identify and mitigate liabilities that can cause major setbacks during CMC development. Considering liabilities in the selection of the lead candidate and process design can save a lot of time down the line. Such a focus is particularly important with novel conjugates, where traditional platform approaches often fail, and in-depth expertise is required to overcome CMC challenges. An experienced CDMO with scientific expertise can help the customer maintain the pace of early-phase development of novel products and can facilitate risk-balanced decision-making to inform phase-appropriate setup to move the molecule as fast as possible to the clinic. For novel ADCs, such collaboration can be crucial to eventual commercial success.
References
[1] Antibody Drug Conjugates Market Size & Share Analysis – Growth Trends and Forecast (2026-2031). Mordor Intelligence; 2026.
[2] Conilh L, Sadilkova L, Viricel W, Dumontet C. Payload diversification: a key step in the development of antibody-drug conjugates. J Hematol Oncol. 2023 Jan 17;16(1):3. doi: 10.1186/s13045-022-01397-y. PMID: 36650546; PMCID: PMC9847035.
[3] Wang Z, Li H, Gou L, Li W, Wang Y. Antibody-drug conjugates: Recent advances in payloads. Acta Pharm Sin B. 2023 Oct;13(10):4025-4059. doi: 10.1016/j.apsb.2023.06.015. Epub 2023 Jun 30. PMID: 37799390; PMCID: PMC10547921.
Featured image courtesy © 2026 Lonza. Used with permission.
DOI: 10.14229/jadc.2026.22.04.001
