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Therapeutics


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11 Adler, Adam S, Bedinger, Daniel, Adams, Matthew S, Asensio, Michael A, Edgar, Robert C, Leong, Renee, Leong, Jackson, Mizrahi, Rena A, Spindler, Matthew J, Rao Bandi, Srinivasa, Huang, Haichun, Tawde, Pallavi, Brams, Peter and Johnson, David S (2018). A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library, MAbs. 2018 Jan 29:1-13. 12 Ching, KH, Collarini, EJ, Abdiche, YN, Bedinger, D, Pedersen, D, Izquierdo, S, Harriman, R, Zhu, L, Etches, RJ, van de Lavoir, MC, Harriman, WD, Leighton, PA. Chickens with humanized immunoglobulin genes generate antibodies with high affinity and broad epitope coverage to conserved targets. MAbs. 2018 Jan;10(1):71-80. 13 Kaplon, Hélène and Reichert, Janice M. Antibodies to watch in 2018. (2018), mAbs, 10:2, 183-203. 14 Pellesi, L, Guerzoni, S, Pini, LA. Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date. Clin Pharmacol Drug Dev. 2017 Nov;6(6):534-547. 15Van Blarcom, T, Rossi, A, Foletti, D, Sundar, P, Pitts, S, Bee, C, Melton, Witt J, Melton, Z, Hasa-Moreno, A, Shaughnessy, L, Telman, D, Zhao, L, Cheung, WL, Berka, J, Zhai, W, Strop, P, Chaparro-Riggers, J, Shelton, DL, Pons, J, Rajpal, A. Precise and efficient antibody epitope determination through library design, yeast display and next- generation sequencing. J Mol Biol. 2015 Mar 27;427(6 Pt B):1513-34. 16 Rojas, Gertrudis, Tundidor, Yaima and Cabrera Infante, Yanelys (2014). High throughput functional epitope mapping: Revisiting phage display platform to scan target antigen surface, mAbs, 6:6, 1368-1376.


Figure 3: Epitope binning a panel of 106 mAbs via Array SPR into several distinct clusters12. Network plots are coloured by orthogonal data to provide an even more comprehensive analysis; (a) epitope mapping to the target’s subdomains (labelled alphabetically), (b) mAb library, and (c) cross-reaction to the mouse ortholog


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when sufficient time was allowed for the interact- ing samples to reach equilibrium. In contrast, the correlation with BLI was rather poor, as it consis- tently underestimated the affinity of low-picomo- lar antibodies, reaching an apparent affinity limit at 100pM, likely due to a combination of loading level limitations and rebinding artefacts. While binding affinities determined via both MSD and Gyrolab platforms10 have shown excellent correla- tion with KinExA measurements, these equilibri- um-based assays rely on secondary detection, so are not considered label-free, even though the


interaction being measured is performed in solu- tion phase. Affinity-ranking can help triage clones, but oftentimes, dissecting affinities into their kinet- ic components, as provided by real-time biosensor analyses is important in evaluating clones for a given MOA. To accelerate the kinetic screening of a large


panel of antibodies, Array SPR has been gaining popularity as evidenced by several publications reporting kinetic and affinity measurements col- lected on single arrays comprising 96 or more clones11,12. These highly parallel analyses employ


Drug Discovery World Summer 2018


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