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Abstract
Aim: This paper describes a case study of an antibody therapeutic targeting a membrane-bound receptor, also present in systemic circulation, as a soluble receptor. During phase I studies of astegolimab, nonlinear pharmacokinetics (PKs) were observed. We investigated the potential contribution of antidrug antibodies, target-mediated drug disposition and assay format. Materials & methods: A more target-tolerant assay was developed, and a subset of phase I samples were evaluated in both free and total PK assay formats. Results & conclusion: Our results demonstrate that there were two main contributors to PK nonlinearity: soluble target interference in the free PK assay, in addition to target-mediated drug disposition. Antidrug antibody status did not significantly impact PK.
Author contributions
G Sperinde, M Dolton, W Zhang and J Mathews made substantial contributions to the data acquisition, analysis, and interpretation of this work and drafting of the manuscript. SK Fischer and W Putnam made significant contributions to the conception and design of the work as well as drafting and critical revision for important intellectual content.
Ethical conduct of research
All trials were conducted in accordance with good clinical practice guidelines, applicable laws and regulations, and in accordance with the Declaration of Helsinki. Appropriate Institutional Review Board (IRB) approvals and signed consents were obtained from all study participants before enrollment in the study. The trial was registered with clinicaltrials.gov (NCT02170337).
Acknowledgments
Manuscript editing was provided by Anshin Biosolutions, Inc.
Financial disclosure
All work described in this paper was funded by Genentech, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors are employees of Genentech and stockholders of Roche. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.