Abstract
Application of an integrated approach for inclusion of pharmacology principles in drug development is a foundational step for effective modality design and selection of antibody-based therapeutics. Clarity on patient-related variables, manufacturing considerations, underlying biology and pathophysiology, as well as integration of key translational variables can accelerate drug development processes, ultimately benefiting patients in need of such therapies. Establishing design goals with respect to antibody affinity is a necessary step for achieving this goal and should be incorporated into the development strategies from the earliest stages of the discovery process for biologic modalities. Evaluation of affinity design goals is a complex process contingent on many critical variables. Knowledge of the target antigen biology and its role in the pathogenesis of disease is of high importance in establishing affinity design goals. Selection of the adequate affinity for a functional biologic construct should allow achievement of the maximum therapeutic benefit at a dose associated with a manageable cost of goods. This chapter will further expand on the topics discussed previously (Development of antibody-based therapeutics: translational considerations, Springer, New York, 2012).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Change history
20 October 2018
Owing to an oversight on the part of the Springer Fig. 3.3 of this chapter was initially published with errors.
References
Bodmer J-L, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci. 2002;27(1):19–26.
Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 2013;2013:1–25. https://doi.org/10.1155/2013/371854. Article ID 371854: Hindawi Publishing Corporation.
Deanne M, Compaan DM, Hymowitz SG. The crystal structure of the costimulatory OX40-OX40L complex. Structure. 2006;14:1321–30.
Haidar A, Legault L, Dallaire M, Alkhateeb A, Coriati A, Messier V, Cheng P, Millette M, Boulet B, Rabasa-Lhoret R. Glucose-responsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial. CMAJ. 2013;185(4):297–305.
Huskens J. Multivalent interactions at interfaces. Curr Opin Chem Biol. 2006;10:537–43.
Kenakin T. Stimulus-response mechanisms. In: Weissman G, editor. Pharmacologic analysis of drug–receptor interaction. New York: Raven Press; 1993. p. 39–68.
Klotz IM. Ligand-receptor energetics: a guide for the perplexed. New York: Wiley; 1997. 192p.
Klotz IM, Hunston DL. Protein affinities for small molecules: conceptions and misconceptions. Arch Biochem Biophys. 1979;193:314–28.
Krishnamurthy VM, Estroff LA, Whitesides GM. Multivalency in ligand design (Chapter 2). In: Jahnke W, Erlanson DA, editors. Fragment based approaches in drug discovery. Weinheim, Germany: Wiley-VCH; 2006.
Lahiri J, Isaacs L, Grybowski B, Carbeck JD, Whitesides GM. Bispecific binding of carbonic anhydrase to mixed SAMs presenting benzenesulfonamide ligands: a model system for studying lateral steric effects. Langmuir. 1999;15:7186–98.
Lam J, Nelson CA, Ross FP, Teitelbaum SL, Fremont DH. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest. 2001;108:971–9.
Lee L, Gupta M, Sahasranaman S. Immune checkpoint inhibitors: an introduction to the next generation cancer immunotherapy. J Clin Pharmacol. 2016;56(2):157–69.
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.
Lundquist JJ, Toone EJ. The cluster glycoside effect. Chem Rev. 2002;102:555–78.
Mack ET, Snyder PW, Perez-Castillejos R, Whitesides GM. Using covalent dimers of human carbonic anhydrase II to model bivalency in immunoglobulins. J Am Chem Soc. 2011a;133:11701–15.
Mack ET, Cummings L, Perez-Castillejos R. Mathematical model for determining the binding constants between immunoglobulins, bivalent ligands, and monovalent ligands. Anal Bioanal Chem. 2011b;399:1641–52.
Mack ET, Snyder PW, Perez-Castillejos R, Bilgicer B, Moustakas DT, Butte MJ, Whitesides GM. Dependence of avidity on linker length for a bivalent ligand-bivalent receptor model system. J Am Chem Soc. 2012a;134:333–45.
Mack ET, Bracher PJ, Perez-Castillejos R. Thermodynamic analysis to assist in the design of recombinant antibodies. Crit Rev Immunol. 2012b;32:503–27.
Tabrizi M, Bornstein GG, Klakamp SL, Drake A, Knight R, Roskos L. Translational strategies for development of monoclonal antibodies from discovery to the clinic. Drug Discov Today. 2009a;14(5–6):298–305.
Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J. 2009b;12:33–43.
Tabrizi M, Funelas C, Suria H. Application of quantitative pharmacology in development of therapeutic monoclonal antibodies. AAPS J. 2010;12(4):592–601.
Tabrizi M, Bornstein GG, Klakamp SL. Development of antibody-based therapeutics: translational considerations. New York: Springer; 2012.
Wajant H. Principles of antibody-mediated TNF receptor activation. Cell Death Differ. 2015;22:1727–41.
Wyzgol A, Muller N, Fick A, Munkel S, Grigoleit GU, Pfizenmaier K, Wajant H. Trimer stabilization, oligomerization, and antibody-mediated cell surface immobilization improve the activity of soluble trimers of CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand. J Immunol. 2009;183:1851–61.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Tabrizi, M.A., Klakamp, S.L. (2018). Considerations for Construct and Affinity Design Goals. In: Tabrizi, M., Bornstein, G., Klakamp, S. (eds) Development of Antibody-Based Therapeutics. Adis, Singapore. https://doi.org/10.1007/978-981-13-0496-5_3
Download citation
DOI: https://doi.org/10.1007/978-981-13-0496-5_3
Published:
Publisher Name: Adis, Singapore
Print ISBN: 978-981-13-0495-8
Online ISBN: 978-981-13-0496-5
eBook Packages: MedicineMedicine (R0)