2021 FDA Science Forum
Clavulanic Acid Binds with a Second Target of Nonclassical Peptidoglycan Synthase (33 linkage) L, D -Transpeptidase of Mycobacterium Tuberculosis
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Contributing OfficeNational Center for Toxicological Research
Abstract
There is potential for impurities in chemically synthesized generic peptide products to elicit unwanted immune responses. To address these regulatory challenges, we utilized bone marrow-liver-thymus (BLT) immune humanized mice that develop a fully engrafted human immune system. Our goal was to determine the predictive value of the animal model compared to in silico and in vitro immunogenicity testing methods. Initially, we evaluated salmon calcitonin, known to induce anti-drug antibodies in patients, and two of its isolated impurities which were predicted highly immunogenic in silico and in vitro. Teriparatide, which is not associated with immunogenicity in patients, was tested as a negative control to validate our animal model. Mice were dosed daily with salmon calcitonin, impurities or teriparatide for 28 or 56 days at different doses and routes of application. Dose response data from intranasal or subcutaneous drug administration will be presented. Histology showed intranasal salmon calcitonin caused more severe inflammation in the nasal cavity compared to saline control or impurities alone. Flow cytometric analysis showed salmon calcitonin increased immune responses in a dose-dependent manner and enhanced the number of cells producing class-switched antibody. Lower B-cell responses in teriparatide-treated mice support clinical observations of low immunogenicity to teriparatide. This model allowed us to investigate doses of peptide drugs and routes of exposure that have the potential to trigger immune responses from drug products expected to produce immunogenicity. This model will be used to further investigate humoral immune responses to generic peptide drugs and impurities from these generic products and originator products.
