39 research outputs found
FcRn Affinity-Pharmacokinetic Relationship of Five Human IgG4 Antibodies Engineered for Improved In Vitro FcRn Binding Properties in Cynomolgus Monkeys
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Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys
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The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies
No full textPharmacokinetics, Metabolic Stability, and Subcutaneous Bioavailability of a Genetically Engineered Analog of DcR3, FLINT [DcR3(R218Q)], in Cynomolgus Monkeys and Mice
No full textTranslational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model
No full textLY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.status: publishe
Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics
No full textQuantitative characterization of the mechanism of action and impact of a ‘proteolysis-permitting’ anti-PCSK9 antibody
No full textFcRn affinity-pharmacokinetic relationship of five human IgG4 antibodies engineered for improved in vitro FcRn binding properties in cynomolgus monkeys. Drug Metab Dispos 2012; 40:1545-55; PMID:22584253; http://dx
No full textequilibrium dissociation constant; ELISA, enzyme linked immunosorbent assay; pH 50 , pH at which 50% of the FcRn-antibody complexes dissociate; HRP, horseradish peroxidase; IV, intravenous; LLOQ, lower limit of quantitation; pI, isoelectric point; cIEF, capillary isoelectric focusing; T m , thermal stability; DSC, differential scanning calorimetry; AUC 0-∞ , area under the plasma concentration curve from zero to infinity; CL, clearance; C max , maximal observed plasma concentration; t 1/2 , elimination half-life; k off , Our results suggest that there is likely not a single in vitro parameter that readily predicts in vivo pharmacokinetics, but that the relative contribution and interplay of several factors along with the FcRn binding affinity are important determinants of mAb pharmacokinetic properties
