Abstract
ND-L02-s0201/BMS-986263 is a lipid nanoparticle (LNP) drug product containing a heat shock protein 47 (HSP47)–specific small interfering ribonucleic acid (siRNA) and being developed for the treatment of liver and idiopathic pulmonary fibrosis. To address immunogenicity-related issues, we developed a robust, fit-for-purpose (FFP) three-tier electrochemiluminescent (ECL) anti-drug antibody (ADA) assay for the detection of antibodies (Abs) generated to surface-exposed components of BMS-986263. The drug was coated directly on plates, and several Abs specific for polyethylene glycol (PEG) and other surface components were tested for use as positive quality controls (QCs). Following selection of a rabbit monoclonal anti-PEG Ab, the assay was optimized, and various method development challenges specific to the modality and pseudo surrogate rabbit control were addressed. Screening, confirmatory, and titer cut points were validated following a statistical evaluation of 41 individual K2EDTA human plasma samples at a minimum required dilution (MRD) of 100. Assay precision, sensitivity, selectivity, drug tolerance, and hook effect were determined for the rabbit Ab prepared in human K2EDTA plasma matrix. The assay was used to interrogate anti-drug Ab (ADA) responses in normal human subjects who were administered 90 mg of the drug intravenously (IV) once every week for 3 weeks in phase I clinical trials. All pre- and post-dose samples were found to be negative for ADA. Based on these results, we concluded that BMS-986263 is not immunogenic. To the best of our knowledge, this work represents the first ADA method developed and reported for an LNP-based drug product.
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Acknowledgments
We are grateful to Dr. Murli Krishna for valuable discussion on anti-PEG antibody controls and Carol Gleason for statistical analysis and support. We would like to thank Dr. Giridhar Tirucherai for PK study design and Dr. Edgar Charles for clinical study design and manuscript review. We acknowledge the general contributions of the BMS Bioanalytical, Reagent Center of Excellence, and clinical development teams that have made the work reported here possible.
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Uma Kavita, Wendy Miller, Qin Ji, and Renuka Pillutla are current employees of Bristol-Myers Squibb Company (BMS). All financial support for the studies reported herein was provided by BMS. The authors have no further relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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The authors state that they have followed the principles outlined in Good Clinical Practice for all human experimental investigations reported here. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
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Kavita, U., Miller, W., Ji, Q.C. et al. A Fit-for-Purpose Method for the Detection of Human Antibodies to Surface-Exposed Components of BMS-986263, a Lipid Nanoparticle-Based Drug Product Containing a siRNA Drug Substance. AAPS J 21, 92 (2019). https://doi.org/10.1208/s12248-019-0360-8
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DOI: https://doi.org/10.1208/s12248-019-0360-8