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Open Access 01-10-2019 | Evolocumab | Original Research Article

Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies

Authors: Ellen Q. Wang, Jack F. Bukowski, Carla Yunis, Charles L. Shear, Paul M. Ridker, Pamela F. Schwartz, Daniel Baltrukonis

Published in: BioDrugs | Issue 5/2019

Abstract

Background

Anti-drug antibodies (ADAs) to bococizumab were detected in > 40% of subjects in the SPIRE lipid-lowering trials. The risk of cross-reactivity between anti-bococizumab antibodies and other approved anti-proprotein convertase subtilisin/kexin type-9 (PCSK9) monoclonal antibodies (mAbs) was investigated using a single-assay approach.

Methods

Bococizumab immunogenicity was assessed in SPIRE-HR, a 52-week study. The highest ADA titer sample from each ADA-positive subject (n = 155) was tested in vitro for cross-reactivity to alirocumab and evolocumab using a novel ADA assay approach. Additional specificity tiers within the bococizumab ADA assay against each drug were validated using recombinant PCSK9 as a surrogate cross-reactive positive control. If the highest ADA titer sample showed cross-reactivity, additional samples from that subject were analyzed. Cross-reactivity was determined by the ability of alirocumab or evolocumab to inhibit the sample signal greater than or equal to the cross-reactivity cut-points.

Results

ADAs were detected in 44.0% (155/352) of bococizumab-treated subjects, and 27.0% also developed neutralizing antibodies (NAbs). Median ADA and NAb titers ranged from 276 to 526 and 8 to 12 over the course of the study, respectively. From 155 ADA-positive subjects tested for cross-reactivity, one (0.6%) subject showed weak cross-reactivity to both alirocumab and evolocumab. This cross-reactivity signal was transient (from Days 337 to 373) and undetectable at the last ADA-positive timepoint (Day 407).

Conclusion

A novel, single-assay approach was validated to assess the potential cross-reactivity of anti-bococizumab antibodies to alirocumab and evolocumab. In subjects who developed ADAs to bococizumab, the likelihood of clinically relevant cross-reactivity to marketed anti-PCSK9 mAbs is remote, based on the low frequency of cross-reactivity observed, which was weak in signal inhibition and transient in nature.

Clinical Trial Registration

The SPIRE-HR study is registered on ClinicalTrials.gov under the identifier NCT01968954.

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Title: Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies
Authors: Ellen Q. Wang
Jack F. Bukowski
Carla Yunis
Charles L. Shear
Paul M. Ridker
Pamela F. Schwartz
Daniel Baltrukonis
Publication date: 01-10-2019
Publisher: Springer International Publishing
Keywords: Evolocumab
Alirocumab
Published in: BioDrugs / Issue 5/2019
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI: https://doi.org/10.1007/s40259-019-00375-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies

Abstract

Background

Methods

Results

Conclusion

Clinical Trial Registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Clinical Trial Registration

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