Unlocking the full potential of antibody-drug conjugates (ADCs)

Antibody-drug conjugates(ADCs) have revolutionized oncology, yet their full potential remains untapped

The field is at a turning point, with developers pushing past the limits of historic therapeutic windows including enhancing drug-to-antibody ratios (DAR) for greater potency, adopting multispecific approaches to address tumor heterogeneity, and expanding payloads beyond traditional cytotoxics.

But innovation alone is not enough. Higher DARs can increase hydrophobicity and accelerate systemic clearance, multispecific ADCs introduce design complexity, and novel payloads demand optimized delivery strategies. Beyond the science, success hinges on manufacturability, scalability, regulatory acceptance, and commercial viability.

This report explores how advancements in high-DAR ADCs, multispecific designs, and novel payloads are pushing boundaries while also introducing new challenges. The future of ADCs is not just about innovation but about ensuring these breakthroughs lead to viable products.

DAR: Helping unlock ADC potential

The DAR is a critical determinant of an ADC’s therapeutic profile, influencing the intrinsic potency of the payload warhead. Striking the right balance is essential: a low DAR may lead to insufficient potency, while a high DAR can increase hydrophobicity, causing ADC aggregation, faster systemic clearance, and increased off-target toxicity - ultimately narrowing the therapeutic index

The case for high DARs

For years, ADCs were largely constrained to DARs of 2 to 4, balancing efficacy and tolerability. In fact, before 2020, approximately 85% of ADCs entering the pipeline fell within this range (see Figure 1)(1). However, this paradigm is shifting. While only 13% of ADCs had a DAR ≥5 before 2020, that number has since surged to 46%.⁽¹⁾

This shift has been largely driven by the success of high-DAR ADCs like Enhertu (DAR 8) and Trodelvy (DAR 7.6), approved in 2019 and 2020, respectively. These approvals demonstrated that high-DAR ADCs could achieve exceptional clinical outcomes, catalyzing innovation in conjugation strategies. Advances such as engineered cysteines, non-canonical amino acids, and glycoengineering have expanded the ADC toolbox, making higher DARs more viable than ever. One example is GlycoConnect, a technology that enables stable, non-genetic conjugation with high DAR capabilities, allowing for drug loads of DAR 8+ while preserving homogeneity and therapeutic performance.^(2-3)

The success of high-DAR ADCs underscores the impact of optimized DAR strategies, with the ceiling continuing to rise. Developers like Sutro Biopharma are pushing DARs as high as 16, and more high-DAR ADCs are advancing through the pipeline (see Figure 2)^(1,4).

As these candidates enter the clinic, emerging data is shaping the next frontier of development.

Fig 1. Each bar represents the percentage of traditional ADCs within each DAR category, encompassing both active and inactive / discontinued programs. “Before 2020” includes all ADCs introduced into the pipeline up to that year, while “Since 2020” reflects only those added from 2020 onward. Data source: Beacon ADC⁽¹⁾

Fig 2. Number of traditional ADC assets in each active stage of development, categorized by DAR range. Data source: Beacon ADC.⁽¹⁾

Challenges of ADCs with higher DAR

High-DAR ADCs present both opportunities and risks. Beyond the scientific challenges associated with hydrophobicity, the commercial and manufacturing hurdles are equally critical.

From a commercial standpoint, proprietary conjugation platforms are valuable but can also limit flexibility and create barriers to innovation. Companies developing high-DAR ADCs must decide between building their own technology or licensing existing platforms. Licensing often offers access to validated methods and regulatory precedent but comes with financial costs, contractual restrictions, and potential competitive dependencies. This creates a strategic trade-off between accelerating development timelines and maintaining long-term control over manufacturing and intellectual property (IP).

From a CMC standpoint, high-DAR ADCs present significant challenges due to their increased hydrophobicity and heterogeneity, which complicate conjugation, purification, and formulation. Purification is particularly demanding, often requiring additional chromatography steps to remove unconjugated species. These challenges are further amplified for CDMOs without the specialized infrastructure to handle complex ADC manufacturing. Additionally, high-DAR ADCs tend to clear rapidly from circulation, which may necessitate higher dosing to maintain efficacy. This, in turn, increases bulk drug substance requirements and drives up production costs, adding another layer of complexity to their development and commercialization.

Conclusion

The evolution of ADCs is redefining the ‘optimal’ DAR by balancing potency, stability, and safety through controlled DAR distributions. As higher-DAR ADCs become more viable, overcoming manufacturing and IP challenges will be crucial for sustaining innovation. Advances in linker design, site-specific conjugation, purification, and CDMO partnerships will shape the future of ADCs, ensuring both clinical and commercial success.

Multispecific ADCs: The next evolution or unnecessary complexity?

ADCs have reshaped oncology, offering a precision-driven alternative to traditional chemotherapy. Yet, their Achilles’ heel remains - tumor heterogeneity. Cancer cells evolve, adapt, and escape, which can render single-antigen ADCs ineffective. This raises the question: If one target isn’t enough, why not engage multiple?

The case for multispecific ADCs

Inspired by the success of bispecific antibodies, Nineteen of which have been approved, multispecific ADCs aim to enhance efficacy and overcome resistance by targeting multiple antigens simultaneously.⁽¹⁾ Their potential advantages include:

• Broader tumor targeting and resistance prevention
  • Targeting multiple antigens overcomes tumor heterogeneity and reduces antigen escape, making treatment more durable
  • Improved efficacy with lower toxicity
  • More efficient internalization increases drug delivery, allowing for lower doses and reduced off- target effects in healthy tissues
  • ADCs can modulate the tumor microenvironment by inducing immunogenic cell death, enhancing antigen presentation, and promoting T-cell activation, potentially converting immunosuppressive (‘cold’) tumors into pro-inflammatory (‘hot’) ones. Multispecific ADCs may amplify these effects by targeting multiple tumor-associated or immune- regulatory molecules, further improving efficacy

Beyond targeting multiple antigens, multivalency—binding multiple epitopes on the same antigen—is emerging as a strategy to enhance ADC internalization.

Some bivalent ADCs achieve this by targeting two distinct epitopes, improving specificity and uptake. A key example is JSKN003, a HER2- targeting ADC from Alphamab Oncology, which binds HER2 domains II and IV⁽⁵⁾. Preclinical data suggest JSKN003 enables faster and more extensive internalization than Enhertu, potentially due to its bispecific design, reinforcing the potential of multispecific ADCs for enhanced drug delivery⁽⁵⁾.

The recent approval of Ziihera, a bispecific antibody that also targets HER2 domains II and IV, further validates this approach⁽⁶⁾. By enhancing receptor clustering and internalization, Ziihera demonstrates that multivalent HER2 targeting is clinically impactful⁽⁶⁾. This strengthens the case for developing multivalent ADCs as a next-generation strategy to improve drug delivery efficiency and therapeutic outcomes

Fig 3. Number of multispecific ADC assets entering the pipeline each year, categorized by their current drug status. The 65% CAGR (2020-2024) highlights the rapid growth of multispecific ADCs. Analysis focuses on traditional ADCs. Data source: Beacon ADC.⁽¹⁾

The advantages of multispecific ADCs are driving strong developer interest, reflected in a rapidly growing pipeline with over 150 active assets in development and nearly 90 new additions in 2024 alone (see figure 3)⁽¹⁾. While their full clinical impact is still being validated, promising signs are emerging—such as Bristol-Myers Squibb’s Izalontamab Brengitecan (EGFR/HER3), having progressed to Phase 3 trials⁽¹⁾. As late-stage data emerge and the first approvals approach, the true potential of these next-generation ADCs will come into focus.

Multispecific ADC challenges

Multispecific ADCs offer exciting therapeutic potential but their complexity comes with major challenges. At the outset, creating these therapies demands sophisticated antibody scaffolds, specialized linker chemistries, and complex conjugation strategies. This may result in longer early-stage validation timelines and increased costs. Manufacturing adds another hurdle, as novel designs demand new workflows, making it difficult to find experienced partners. At the same time, evolving regulatory frameworks create further uncertainty, complicating approval pathways.

Adding to these challenges are pharmacokinetic issues such as altered distribution patterns, clearance rates, and payload release kinetics, which can affect dosing strategies and therapeutic windows.

Finally, patient selection is a significant barrier, as tumors must express all target antigens at clinically relevant levels, often requiring companion diagnostics, which further adds regulatory complexity and narrows the patient population.

Conclusion

Multispecific ADCs are a logical next step in targeted oncology, but their complexity must deliver clear benefits. The key question is whether they will outperform traditional ADCs or offer diminishing returns. Their success will depend on late-stage clinical validation and the ability of manufacturers to make them a scalable reality—ultimately determining whether they redefine ADC therapy or remain an unproven innovation.

Payloads: Beyond cytotoxicity

Traditional ADC payloads, such as microtubule inhibitors and DNA-damaging agents, have been instrumental to the modality’s clinical success. However, resistance mechanisms and narrow therapeutic windows necessitate innovation. The clinical and commercial success of topoisomerase 1 inhibitors has fueled interest in expanding the payload landscape, driving diversification beyond traditional cytotoxic chemotherapy.

The case for emerging ADC payloads

Emerging payloads are transforming ADCs into next- generation XDCs, expanding their therapeutic potential. Below are key innovative payload classes and their distinct advantages:

Immunomodulatory payloads:

ADCs conjugated to immune-modulating agents—such as TLR agonists, STING agonists, or glucocorticoid receptor modulators—aim to enhance anti-tumor immunity or induce immunomodulatory effects.

Since 2021, the number of immune-modulating ADCs has increased, notably, many of these programs extend beyond oncology, reflecting ADCs broader therapeutic potential. However, 36% of pipeline assets have been discontinued, often due to safety and efficacy challenges, specifically raising questions about their risk-benefit differentiation from existing treatments.⁽¹⁾

Antibody-oligonucleotide conjugates (AOCs):

AOCs leverage siRNAs and ASOs to modulate gene expression, enabling precision targeting of intracellular RNA pathways beyond traditional cytotoxics. Their therapeutic promise is proven beyond oncology,

As demonstrated by Avidity Biosciences’ Myotonic dystrophy type 1 program, which has reached phase 3(1). However, ensuring intracellular delivery and preventing premature degradation before reaching the target RNA remain key obstacles.

Degrader-antibody conjugates (DACs):

DACs conjugate antibodies with PROTACs or molecular glue degraders, hijacking the ubiquitin-proteasome system to selectively degrade disease-driving proteins. This approach circumvents resistance mechanisms observed in traditional ADCs. However, with 19% of pipeline assets already inactive, key challenges remain, including optimizing intracellular delivery and linker design to ensure efficient target degradation.⁽¹⁾

Fig 4. Distribution of drug status across payload types, including active and discontinued programs. Data source: Beacon ADC.⁽¹⁾

Novel ADC challenges

Developing ADCs with novel payloads introduces unique challenges beyond typical payload-related issues. The testing and optimization phases are extended due to the need for detailed characterization, toxicity profiling, and stability assessments. Once these obstacles are cleared, manufacturing becomes a key challenge, as next- generation ADCs often require specialized synthesis and conjugation methods. Identifying the right partner for scale-up, ensuring reproducibility, and maintaining cost-effectiveness is no easy feat.

Moreover, regulatory hurdles are heightened by the lack of standardized workflows and clear approval pathways. These challenges are even more significant in non-oncology applications, where industry expertise and regulatory frameworks are still developing.

Conclusion

Next-generation ADC payloads promise to extend beyond traditional cytotoxics, enabling broader therapeutic applications. However, their success hinges on overcoming key challenges, including payload stability, targeted delivery, scalable manufacturing, and regulatory approval. Addressing these hurdles will be critical to realizing their full potential.

Summary

The evolution of ADCs is shifting from incremental refinements to broader therapeutic advancements. Progress in high DARs, multispecific strategies, and novel payloads is expanding their potential.

Yet, with innovation comes complexity. Scientific, manufacturing, and regulatory hurdles continue to complicate commercialization. The real test is no longer whether ADCs can innovate, but whether the entire ecosystem—developers, manufacturers, and regulators— can evolve alongside these innovations. Will these hurdles slow progress, or will they drive smarter, more adaptable solutions?

One thing is certain: the ceiling for ADCs is still rising. The next breakthrough is already taking shape, and its impact will be determined not only by clinical outcomes but also by the industry’s ability to navigate the challenges ahead.

REFERENCES

1. Beacon ADC, by Hanson Wade
2. Wijdeven, M.A., Remon Van Geel, Hoogenboom, J., Jorge, Janssen, B.D., Hurkmans, I., Laureen de Bever, Berkel, van and Delft, van (2022). Enzymatic glycan remodeling– metal free click (GlycoConnectTM) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. 14(1). doi: https://doi.org/10.1080/19420862.2022.2078466.
3. Synaffix.com. (2023). Synaffix to Launch 2 New ADC Technologies at the World ADC San Diego – Synaffix. [online] Available at: https://synaffix.com/synaffix-to-launch-new-adc-technologies-at-the-world-adc-conference-in-san-diego/ [Accessed 11 Feb. 2025].
4. Sutro Biopharma (2024) Research Forum: Advancing Science to Advance Patient Care, 10 October. Available at: https://d1io3yog0oux5.cloudfront. net/_fd47421889d7f11fe00287cbe8e6510b/sutrobio/ db/986/10061/presentation/Sutro+Research+Forum_ FINAL.pdf
5. Wang, P., Guo, K., Peng, J., Sun, J. and Xu, T. (2023). JSKN003, A Novel Biparatopic Anti-HER2 Antibody- Drug Conjugate, Exhibits Potent Antitumor Efficacy. Antibody Therapeutics, 6(Supplement_1). doi: https://doi. org/10.1093/abt/tbad014.009.
6. Meric-Bernstam, F., Beeram, M., Hamilton, E., Oh, D.-Y., Hanna, D.L., Kang, Y.-K., Elimova, E., Chaves, J., Goodwin, R., Lee, J., Nabell, L., Rha, S.Y., Mayordomo, J., El-Khoueiry, A., Pant, S., Raghav, K., Kim, J.W., Patnaik, A., Gray, T. and Davies, R. (2022). Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2- amplified cancers: a phase 1, dose-escalation and expansion study. The Lancet Oncology, [online] 0(0). doi: https://doi.org/10.1016/S1470-2045(22)00621-0