Abstract
Manufacturing highly potent antibody–drug conjugates (ADCs) is a demanding task—combining conventional organic synthesis with biotechnological manufacturing. Hence a series of new and unique engineering and chemistry challenges have to be addressed to support clinical trials and commercial manufacturing. These include the development of reliable processes leading to uniform product properties, as well as establishment of ADC-specific analytical methods and safe strategies for handling cytotoxic compounds. This review focuses on process development and scale-up for the production of ADCs and highlights the most important features in such a process.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Polson AG, Ho WY, Ramakrishnan Y (2011) Investigational antibody-drug conjugates for hematological malignancies. Expert Opin Investig Drugs 20:75–85
Pasquetto MV, Vecchia L, Covini D, Digillio R, Scotti C (2011) Targeted drug delivery using immunoconjugates: principles and applications. J Immunother 34:611–628
Fitzgerald DJ, Wayne AJ, Kreitman RJ, Pastan I (2011) Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Cancer Res 71:6300–6309
Hughes B (2010) Antibody–drug conjugates for cancer: poised to deliver? Nat Rev Drug Discov 9:665–667
Vermeer AWP, Norde W (2000) The thermal stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J 78:394–404
Shire SJ, Gombotz W, Bechtold-Peters K, Andya J (2010) Current trends in monoclonal antibody development and manufacturing. Springer, New York
Hamblett KJ, Senter PD, Chace DF, Sun MMC, Lenox J, Cerveny CG, Kissler KM, Bernhardt SX, Kopcha AK, Zabinski RF, Meyer DL, Francisco JA (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063–7070
Guidance for industry—process validation: general principles and practices, U.S. Department of Health and Human Services Food and Drug Administration, Jan 2011
McDonagh CF, Kim KM, Turcott E, Brown LL, Westendorf L, Feist T, Sussman D, Stone I, Anderson M, Miyamoto J, Lyon R, Alley SC, Gerber H-P, Carter PJ (2008) Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index. Mol Cancer Ther 7:2913–2923
Chari RVJ (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41:98–107
Eriksson L, Johansson E, Kettaneh-Wold N, Wikström C, Wohl S (2008) Design of experiments—principles and applications. Umetrics Academy, Umea
Design Expert, Stat-Ease, Inc. 2021 E. Hennepin Avenue, Suite 480 Minneapolis, MN 55413-2726
MODDE, Umetrics Inc./MKS Inst., 70 W. Rio Robles Drive, San Jose, CA 95134, USA
Statistica, StatSoft Inc., 2300 East 14th Street, Tulsa, OK 74104, USA
Gagnon P (2012) Technology trends in antibody purification. J Chromatogr 1221:57–70
Van Reis R, Gadam S, Frautschy LN, Orlando S, Goodrich EM, Saksena S, Kuriyel R, Simpson CM, Pearl S, Zydney AL (1997) High performance tangential flow filtration. Biotechnol Bioeng 56:71–82
Van Reis R, Zydney A (2001) Membrane separations in biotechnology. Curr Opin Biotechnol 12:208–212
Van Reis R, Zydney A (1997) Bioprocess membrane technology. J Membr Sci 297:16–50
(2008) A hands-on guide to ultrafiltration/diafiltration optimizing using Pellicon® Cassettes. Application note, Millipore http://www.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4eee/08773250551d1562852574e0007d4570/$FILE/an2700en00.pdf
(1990) Mixing band agitation. In: Walas SM (ed) Chemical process equipment—selection and design. Elsevier See http://www.sciencedirect.com/science/book/9780123725066. Chemical Process Equipment (Third Edition), Author(s):James R. Couper, W. Roy Penney, James R. Fair and Stanley M. Walas, therein “Chapter 10 - MIXING AND AGITATION, 273–324”
Acknowledgements
We thank Dr. Nikolaus Bieler for helpful discussions regarding the application of the DoE approach to bioconjugation reactions.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Stump, B., Steinmann, J. (2013). Conjugation Process Development and Scale-Up. In: Ducry, L. (eds) Antibody-Drug Conjugates. Methods in Molecular Biology, vol 1045. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-541-5_14
Download citation
DOI: https://doi.org/10.1007/978-1-62703-541-5_14
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-540-8
Online ISBN: 978-1-62703-541-5
eBook Packages: Springer Protocols