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20 BioPharm International ® Emerging Therapies eBook September 2024 www.biopharminternational.com Antibody-Drug Conjugates specialized capabilities. However, building a strong foundation of expertise and infrastructure in linker design and production in-house requires a signifi- cant investment of time and capital and may not be realistic for all organizations. Working with a partner can be a more time- and resource-efficient pathway for less established organizations to access a broader range of design and synthesis capabilities, as well as robust analytical methods that ensure the quality of the linkers (10). Whether an ADC developer pursues linker design and production internally or with specialized exter- nal partners, several key considerations can help guide design strategy and support development success. As discussed previously, many parameters of linker structure and bioconjugation can be modified to fine- tune the performance of an ADC product. These dis- tinct variables, as well as the highly specific nature of an ADC's target within a physiological context, make it challenging to accurately predict a candidate's be- havior until it is tested in vivo. Using a highly tunable linker scaffold to generate and test a range of different linkers with distinct physicochemical properties can help researchers explore the impact of linker struc- ture on pharmacokinetic or biodistribution early in discovery and choose the most promising candidates for development. Many manufacturers supply a range of off-the-shelf linker options, with more specialized providers offering deeper customization capabilities. Effectively adapting complex synthetic processes from laboratory to clinical and commercial scale while maintaining product consistency and quality can be a daunting challenge. Robust quality control meth- ods throughout every step of manufacturing are also crucial to ensure the purity and homogeneity of in- creasingly complex linkers and ADCs. Because of the demanding and multifaceted nature of linker man- ufacturing scale-up, leveraging partnerships with experienced and well-equipped experts in the field can enable drug developers to confidently navigate these processes. Ideally, an established manufactur- ing partner can offer efficient and reliable synthetic processes, specialized manufacturing infrastructure, and sophisticated, multi-method purity analyses to fully characterize products and meet stringent qual- ity requirements. For organizations building internal linker design and manufacturing capabilities, seeking guidance from experts familiar with the key quality attributes and best practices for linker production can ensure a strong foundation for product quality. Taken together, these resources can maximize efficiency and reduce the development time of potentially ground- breaking ADC therapeutics. In the two decades since the first ADC therapeutic was approved by FDA, a growing foundation of basic research in chemical biology and lessons learned from preclinical and clinical studies have underscored the crucial role of linkers in ADC performance. Novel linker technology and bioconjugation methods have redefined researchers' capacity to fine-tune specific parameters of an ADC candidate. As drug developers develop a deeper understanding of linkers, expand- ing design capabilities and leveraging more efficient, scalable, and reliable methods for synthesizing these complex molecules will help bring the field closer to realizing the full potential of ADC therapeutics for cancer and beyond. 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 Conju- gates. 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 Conju- gation and Linker Chemistry. Protein Cell. 2018, 9 (1), 33–46. DOI: 10.1007/s13238-016-0323-0 5. Su, Z., Xiao, D.; Xie, F.; et al., Antibody-Drug Con- jugates: Recent Advances in Linker Chemistr y. Acta. Pharm. Sin. B. 2021, 11 (12), 3889–3907. DOI: 10.1016/j.apsb.2021.03.042 6. Lucas, A. T.; Moody, A.; Schorzman, A. N.; Zam- boni, W. C. Importance and Considerations of An- tibody Engineering in Antibody-Drug Conjugates Development f rom a Clinical Pharmacologist's Perspective. Antibodies (Basel) 2021,10 (3), 30. DOI: 10.3390/antib10030030 7. Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sa- bourin, C . Antibody-Drug Conjugates: The Last Decade. Pharmaceuticals (Basel) 2020, 13 (9), 1–30. DOI: 10.3390/ph13090245 8. Geise, M. W.; Woodman, R. H. Chapter 9: The Use of Uniform PEG Compounds in the Design of ADCs. In Chemical Linkers in Antibody-Drug Conjugates (ADCs); van Delf, F.; Lambert, J. M., Eds.; The Royal Society of Chemistry, 2021; pp. 286–376. 9. Jackson, D.Y. Processes for Constructing Homog- enous Antibody-Dr ug Conjugates. Org. P rocess. Res. Dev. 2016, 20 (5), 852–866. DOI: 10.1021/acs. oprd.6b00067 10. Sc a n l a n , C.; Z h ao, J.; Roger s, M.; e t a l. A nt i- body-D r ug Conjugates: M a nu f ac t u r i ng C h a l- l e n g e s a n d Tr e n d s . A D C R e v i e w J . A nt i b o d y Dr ug Conj. on line, Mar. 21, 2017. DOI:10.14229/ jadc.2017.21.03.001 Q