Development of novel ultra-sensitive IL-11 target engagement assays to support mechanistic PK/PD modeling for an anti-IL-11 antibody therapeutic.
MAbs
; 14(1): 2104153, 2022.
Article
em En
| MEDLINE
| ID: mdl-35916739
ABSTRACT
An in-house antibody generation campaign identified a diverse, high affinity set of anti-interleukin-11 (IL-11) monoclonal antibodies (mAbs) to enable successful development of novel, custom ultra-sensitive target engagement assays for detection of "free" (unbound to the dosed anti-IL-11 therapeutic mAb) and "total" (free and mAb-IL-11 complexed form) IL-11 in preclinical species and human. Antibody hits from distinct epitope communities were screened on various platforms, including enzyme-linked immunosorbent assay, Meso Scale Discovery, Simoa HD-1 and Simoa Planar Array (SP-X), and used for assay development and sensitivity optimization. The ultra-sensitive SP-X format achieved a lower limit of quantitation of 0.006 pg/mL, enabling the first reported baseline levels of IL-11 in healthy control plasma determined by custom bioanalytical assays. These newly established baseline levels supported mechanistic pharmacokinetic/pharmacodynamic modeling in mouse, cynomolgus monkey, and human for a greater understanding of preclinical study design and in vivo dynamic interaction of soluble IL-11 with an anti-IL-11 antibody therapeutic candidate. Modeling and simulation also helped refine the utility of assays with respect to their potential use as target engagement biomarkers in the clinic.Abbreviations IL-11 Interleukin-11, TE Target engagement, PK/PD Pharmacokinetic/pharmacodynamic, mAb Monoclonal antibody, NHP Non-human primate, IgG Immunoglobulin G, Cyno Cynomolgulus monkey, GFR Glomerular filtration rate, BQL Below quantitation levels, DRM Disease relevant model, kDa kilodaltons, SPR Surface plasmon resonance, pSTAT3 phosphorylated STAT3, IL-11R Interleukin-11 receptor, TPP Target product protein, LLOQ Lower limit of quantitation, RLU Relative light units.
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Base de dados:
MEDLINE
Assunto principal:
Imunoglobulina G
/
Anticorpos Monoclonais
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article