Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

Boris Gorovits,Heather Myler,Crystal Sung,Marta Starcevic Manning,Meina Liang,Lakshmi Amaravadi,Adrienne Clements-Egan,Shobha Purushothama,Li Xue,Mary Birchler

doi:10.1208/s12248-017-0153-x

Abstract

Anti-drug antibodies (ADA) pose a potential risk to patient safety and efficacy and are routinely monitored during clinical trials. Pre-existing drug-reactive antibodies are present in patients without prior drug exposure and are defined by their ability to bind to a component of the drug. These pre-existing drug-reactive antibodies are frequently observed and could represent an adaptive immune response of an individual who has been previously exposed to antigens with structural similarities to the biotherapeutic. Clinical consequences of these antibodies can vary from no impact to adverse effects on patient safety, exposure, and efficacy, and are highly dependent on biotherapeutic modality, disease indications, and patient demographics. This paper describes how the immunogenicity risk assessment of a biotherapeutic integrates the existence of pre-existing drug-reactive antibodies, and provides recommendations for risk-based strategies to evaluate treatment-emergent ADA responses.

Highlights

Several reports describe pre-existing reactivity from antidrug antibody (ADA) assays in baseline samples collected from treatment-naïve subjects [1,2,3,4,5,6,7]
The FDA mentions pre-existing antibodies in five sections of the Guidance for Industry on Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products, with special emphasis on the impact to assay cut point, considerations for assay development, titer determination, obtaining patient baseline samples, understanding the degree of pre-existing reactivity, and the potential implications pre-existing antibodies might have on patient safety and efficacy [57,58]
This paper provides specific recommendations on how to address these concerns in the context of immunogenicity risk assessments

Summary

INTRODUCTION

Several reports describe pre-existing reactivity from antidrug antibody (ADA) assays in baseline samples collected from treatment-naïve subjects [1,2,3,4,5,6,7]. The scope of the risk assessment includes the following: [1] the likelihood of pre-existing antibody presence at baseline (in pre-dose samples); [2] the potential for analytical methodology to detect clinically meaningful preexisting antibodies versus low positive assay signal; and [3] the potential impact of pre-existing antibodies on treatmentemergent immunogenicity, PK, PD, efficacy, and patient safety. The strategy used to identify pre-existing antibodies and treatmentboosted ADA responses must be informed by the totality of evidence provided by the pre-study validation experiment results, the assessment of clinical study baseline samples, the assay technology, and the known pre-existing antibody risk factors of the biotherapeutic. In cases where pre-existing antibodies demonstrate a clinical consequence, the prevalence of pre-existing antibodies along with clinical impact should be included in the label

SUMMARY

COMPLIANCE WITH ETHICAL STANDARDS