Valuing Specialized Experience in ADC Development

Over the past several decades, bioconjugate therapeutics, which unite synthetic chemistry with biological mechanisms, have gained immense interest in research and drug development. Antibody-drug conjugates (ADCs) represent the most prominent class within this modality. Fifteen ADC therapeutics have been approved by FDA since 2000, and more than 150 clinical trials are currently active, roughly 12% of which are late-phase (1). Comprised of a monoclonal antibody (mAb) and a cytotoxic drug compound joined by a linker molecule, ADCs are promising as a novel cancer treatment strategy that enables targeted delivery of potent chemotherapeutic agents while sparing healthy cells and reducing systemic toxicity. However, challenges with off-target toxicities of early ADC candidates slowed the expansion of the field and underscored the importance of linker design in drug safety and efficacy. It is now well-established that linker chemistry and bioconjugation strategies play fundamental roles in the controlled delivery of cytotoxic drugs, presenting new complexities as researchers and drug developers work to optimize ADC performance and deploy linker technology at clinical and commercial scale.

Unraveling the intricate role of linker design in ADC performance

The function of a linker extends far beyond simply attaching a drug and antibody. It is well-known that the stability of an ADC and the mechanism of payload release can impact ADC performance, and most drug developers recognize that the choice of cleavable or non-cleavable triggers is one of the first decisions to consider. Cleavable linkers employ a chemical or enzymatic trigger within their structure that enables efficient cleavage for controlled drug release within the tumor target. Conversely, non-cleavable linkers do not incorporate a trigger but instead rely on internalization by endocytosis and lysosomal processing to release the payload (2). This choice has a direct impact on the efficacy and toxicity of an ADC, but many other decisions are vital to shaping the final product’s characteristics. The choice of conjugation chemistry, linker backbone, number of payloads per linker, and linker architecture also impact ADC properties such as drug-to-antibody ratio (DAR), ADC aggregation, yield, blood clearance, and the ability of the antibody to bind to its target (3). All of these linker elements can be modified to fine-tune the characteristics of the ultimate ADC product, improving safety, efficacy, stability, manufacturability, and more.

Additionally, linker design can be leveraged to overcome chemical and pharmacological limitations posed by some drug payloads. For example, many payloads are hydrophobic, potentially resulting in poor conjugation yield, aggregation, and increased clearance. Because altering the payload itself to improve hydrophilicity can compromise its activity, linker design can instead be leveraged to modulate ADC solubility and reduce these effects (4). Including a linker with a hydrophilic backbone such as polyethylene glycol (PEG) or modifying the linker architecture to include one or more hydrophilic arms without changing the proximity of the payload to the antibody are options that can effectively shield the hydrophobic payload from the environment, improving conjugation yield and preventing aggregation. Importantly, the variable parameters of ADC components are not independent of one another and must be carefully modified and assessed to maximize desirable features without compromising other functional traits.

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References

1. Sasso, J.M.; Tenchov, R.; Bird, R.; et al. The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress. Bioconjugate Chem. 2023, 34 (11), 1951-2000. DOI: 10.1021/acs.bioconjchem.3c00374
2. Bargh, J. D.; Isidro-Llobet, A.; Parker, J. S.; Spring, D. R. Cleavable Linkers in Antibody-Drug Conjugates. Chem. Soc. Rev. 2019, 48 (16), 4361-4374. DOI: 10.1039/c8cs00676h
3. Kostova, V.; Désos, P.; Starck, J. B.; Kotschy, A. The Chemistry Behind ADCs. Pharmaceuticals (Basel) 2021, 14 (5), 442. DOI: 10.3390/ph14050442
4. Tsuchikama, K.; An, Z. Recent Advances in Conjugation and Linker Chemistry. Protein Cell. 2018, 9 (1), 33–46. DOI: 10.1007/s13238-016-0323-0

About the author

Pamela James, PhD, is vice-president, Product, at Vector Laboratories.

Article details

BioPharm International®
eBook: Emerging Therapies
September 2024
Pages: 16–20

Citation

When referring to this article, please cite it as James, P. Valuing Specialized Experience in ADC Development. BioPharm International Emerging Therapies eBook, September 2024.