Overcoming Challenges in the Development of Antibody Drug Conjugates

Andreas Dreps, Senior VP and Global Head Drug Development Unit, ICON plc

Over the years, extensive research and clinical trials have led to the development of highly potent and specific antibody–drug conjugates (ADCs), which have shown remarkable efficacy against a wide range of hematologic and solid tumors. ADCs are targeted therapies that use antibodies to direct highly cytotoxic drugs specifically to cancer cells. While simple in concept, developing an ADC that can balance the potency required for cancer cell apoptosis with stability and tolerability has proven challenging, in part because it has required the optimization of three distinct components:

1. The antibody—designed to specifically target an antigen expressed on cancer cells, but not on healthy cells
2. The payload—generally a cytotoxic drug potent enough to induce apoptosis of cancer cells at low doses
3. The linker—which must bind the antibody to the payload stably while in the bloodstream, and readily release the payload once inside the cancer cell

Innovations address limitations of first-generation ADCs

Since the first ADC approval of gemtuzumab ozogamicin in 2000, optimized ADC components have helped to overcome initial limitations of ADCs—particularly off-target toxicity, which limited the dosage levels of ADCs below those needed for anti-cancer effects.¹ Some of these key innovations include the type of linkers used, and increased control over how many payloads are linked to an antibody.

Cleavable Linkers

The very first generation of ADCs used non-cleavable linkers, which relied on digestion by the cancer cell’s lysosomes to release cytotoxic drugs from the antibody. ADCs using these linkers faced challenges with uncontrolled payload release—which also contributed to challenges with achieving sufficient potency in cells—and with limited efficacy in tumors with heterogenous antigen expression, or antigen down-regulation. Subsequently, the design of cleavable linkers has helped to overcome many of these aforementioned challenges, by offering greater control over when, where and how a payload is released from the antibody.

For example, some cleavable linkers have been designed to be cleaved only under specific conditions, such as low pH, or in the presence of a chemical trigger present specifically inside cancer cells to decrease their off-target toxicity from nonspecific uptake.² Additionally, cleavable linkers have been designed to give payloads a polarity that allows them to be effluxed from cancer cells, so that nearby cells are also exposed to the payload, and killed. This feature, called the bystander killing effect, has helped to overcome challenges with resistance of a tumor to ADCs due to heterogeneous antigen expression on cancer cells, or antigen down-regulation. However, enabling a bystander killing can introduce trade-offs of potential off-target toxicity.³

Site-specific conjugation

Another challenge faced by first-generation ADCs was a synthesis process with insufficient control over the number of payloads that linked to any one antibody. This resulted in heterogeneous ADCs with inconsistent drug-to-antibody ratios. Subsequently, researchers determined that the ratio of drugs per antibody was critical to the safety and efficacy of ADCs. On the one hand, too many payloads per antibody can limit safety through uncontrolled and premature release of drugs, and limit efficacy through increased clearance by the immune system. Conversely, too few payloads per antibody can make ADCs insufficiently potent.

Conjugation technology, allowing for more control over where on the antibody the drug is linked and how many drugs are linked, has enabled the development of ADCs with more homogenous and optimized antibody-to-drug ratios, and has led to considerable improvements in ADC design.⁴ In particular, site-specific conjugation has proven to be an especially promising method of controlling antibody-to-drug ratios during ADC synthesis—although it has not been successful in the clinic so far.⁵

Room for improvement

The efforts to address the limitations of first-generation ADCs has culminated in nearly double the number of ADC approvals since 2019 as there were between 2000—when the first ADC was approved by the FDA—and 2018. Now, the 15 FDA approved therapies and more than 150 ongoing clinical trials underscore ADCs significant therapeutic potential, and ADCs have reemerged as one of the fastest-growing segments of pharmaceutical development in 2024, with future applications even extending beyond cancer.⁵

However, despite the acceleration in approvals and clinical development of new ADCs, a striking number of ADC clinical trials have been discontinued. According to a 2023 literature review of the ADC clinical landscape, 35% of trials (92/260) of ADCs have been discontinued with the prevailing reason for the discontinuation being insufficient efficacy at the tolerated doses. In other words, candidates have not been safe enough to be dosed at the levels required for efficacy.⁶

Challenges with balancing efficacy and off-site toxicity of ADCs remain even for therapies that have gained FDA approval. Many patients have required dose reduction, treatment delays or even treatment discontinuation due to the severity of ADC-associated toxicities. So, while the development of novel ADC technologies—including site-specific conjugation and linker design—have expanded the potential applications of ADCs, much remains to be done to improve ADC safety and efficacy.¹

Improving ADC translational data

Novel ADC candidates may rely on new, innovative approaches to ADC design to overcome these challenges. Some promising approaches in development include (1) designing ADCs with dual payloads to increase potency; (2) designing ADCs with dual antigen targeting to counter tumor antigen heterogeneity; (3) using antibody fragments to increase solid tumor penetration of ADCs; and (4) combination therapies.^6,7

There is also a need for concurrent advancement in the preclinical testing that informs candidate selection. Many of the toxicity and efficacy hurdles faced in ADC clinical trials today might be mitigated by preclinical testing in models that more accurately represent the human target cell or tissue type in the relevant human disease context.⁸ In particular, differences between the human immune system and that of animal models has led to inaccurate preclinical predictions about how an experimental ADC will interact with a human body.

Encouragingly, several recent advances in preclinical research approaches could help to improve ADC candidate selection, including advancements in preclinical tumor models that better represent the natural conditions of a tumor, and preclinical imaging techniques, such as bioluminescence imaging, that allow for ADCs to be visualized post-administration in a model organism. However, further innovations, including in pharmacokinetics/pharmacodynamics modeling and in-silico modeling, are critically needed. More stringent and robust preclinical evaluation of ADCs would help to focus time, research effort and money on ADC candidates with the best chance of translating to the clinic.⁸

ADCs are coming of age

After decades of piecemeal innovation, ADCs may finally be reaching their potential. Still, challenges balancing efficacy and tolerability remain, as do opportunities to de-risk development. To further accelerate the translation of the next wave of ADCs from the lab to the clinic, developers of ADCs should interrogate their selection of preclinical models in combination with optimizing their ADC design.

Andreas Dreps, Senior VP and Global Head Drug Development Unit, ICON plc

References

1. Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability. Cancers. 2023;15(3):713. doi:10.3390/cancers15030713

2. Su Z, Xiao D, Xie F, et al. Antibody–drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B. 2021;11(12):3889-3907. doi:10.1016/j.apsb.2021.03.042

3. Metrangolo V, Engelholm LH. Antibody–Drug Conjugates: The Dynamic Evolution from Conventional to Next-Generation Constructs. Cancers. 2024;16(2):447. doi:10.3390/cancers16020447

4. Matsuda Y, Malinao MC, Robles V, Song J, Yamada K, Mendelsohn BA. Proof of site-specificity of antibody-drug conjugates produced by chemical conjugation technology: AJICAP first generation. J Chromatogr B. 2020;1140:121981. doi:10.1016/j.jchromb.2020.121981

5. Dumontet C, Reichert JM, Senter PD, Lambert JM, Beck A. Antibody–drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023;22(8):641-661. doi:10.1038/s41573-023-00709-2

6. Maecker H, Jonnalagadda V, Bhakta S, Jammalamadaka V, Junutula JR. Exploration of the antibody–drug conjugate clinical landscape. mAbs. 2023;15(1):2229101. doi:10.1080/19420862.2023.2229101

7. Ma X, Wang M, Ying T, Wu Y. Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate. Antib Ther. 2024;7(2):114-122. doi:10.1093/abt/tbae005

8. Lyons S, Dennis Plenker, Lloyd Trotman. Advances in preclinical evaluation of experimental antibody-drug conjugates. Cancer Drug Resist. 2021;4(4):745-754. doi:10.20517/cdr.2021.37