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Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study

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Abstract

Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses. Current bridging electrochemiluminescence (ECL) ADA assays using Meso Scale Discovery (MSD) platform are also significantly more sensitive and drug tolerant with wider assay ranges compared to historic ELISA platforms; therefore, ADA response based on S/N may help differentiate and identify those ADA samples that are more likely to be clinically relevant. Bococizumab is a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), which reduces plasma levels of low-density lipoprotein (LDL) cholesterol. Bococizumab was discontinued during Phase 3 clinical development based in part on the high rate of ADA and wide variation in LDL cholesterol responses among patients. The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA.

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© 2017 Massachusetts Medical Society. Reprinted with permission (6)

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Acknowledgements

The authors would like to thank Naren Surampalli for supporting all the LDL cholesterol, bococizumab, and PCSK9 data programming using S/N. The authors would also like to thank Meghana Deshpande and Katrina Olson for their detailed quality data review.

Funding

This work was exclusively supported by Pfizer, Inc. SPIRE ClinicalTrials.gov numbers: SPIRE-HR (NCT01968954), SPIRE-LDL (NCT01968967), SPIRE-FH (NCT01968980), and SPIRE-LL (NCT02100514).

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Authors and Affiliations

  1. Clinical Pharmacology and Bioanalytics, Pfizer Research and Development, 445 Eastern Point Road, Groton, Connecticut, 06340, USA

    Fred McCush & Daniel Baltrukonis

  2. Clinical Pharmacology and Bioanalytics, Pfizer Research and Development, New York, New York, USA

    Ellen Wang

  3. Clinical Development and Operations, Pfizer Research and Development, Lake Mary, Florida, USA

    Carla Yunis

  4. Statistics, Pfizer Research and Development, Groton, Connecticut, USA

    Pamela Schwartz

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  1. Fred McCush
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All authors were involved in contributing and interpreting data, reviewed the final version of the manuscript, and have met the criteria for authorship as established by the ICMJE.

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Correspondence to Fred McCush.

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This study was funded by Pfizer, Inc. All the authors listed are employees of the Pfizer, Inc.

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McCush, F., Wang, E., Yunis, C. et al. Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study. AAPS J 25, 85 (2023). https://doi.org/10.1208/s12248-023-00846-x

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