Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys
<p>Abstract</p> <p>Background</p> <p>Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD) activity, pharmacokinetics, and anti-product antibody responses of human a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-04-01
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| Series: | Journal of Translational Medicine |
| Online Access: | http://www.translational-medicine.com/content/8/1/41 |
| _version_ | 1818358871195910144 |
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| author | Spaulding Vikki Ma Margery Ryan Mark Bree Andrea Szklut Pamela Allen Scott Vugmeyster Yulia Young Deborah Guay Heath Bloom Laird Leach Michael W O'Toole Margot Adkins Karissa |
| author_facet | Spaulding Vikki Ma Margery Ryan Mark Bree Andrea Szklut Pamela Allen Scott Vugmeyster Yulia Young Deborah Guay Heath Bloom Laird Leach Michael W O'Toole Margot Adkins Karissa |
| author_sort | Spaulding Vikki |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD) activity, pharmacokinetics, and anti-product antibody responses of human anti-IL-21R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys.</p> <p>Methods</p> <p>The PD assay was based on the ability of recombinant human IL-21 (rhuIL-21) to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples <it>ex vivo</it>. Monkeys screened for responsiveness to rhuIL-21 stimulation using the PD assay, were given a single 10 mg/kg IV dosage of Ab-01, Ab-02, or a control antibody (3/group), and blood samples were evaluated for PD activity (inhibition of IL-2RA expression) for up to 148 days. Anti-IL-21R antibody concentrations and anti-product antibody responses were measured in serum using immunoassays and flow cytometry.</p> <p>Results</p> <p>Following IV administration of Ab-01 and Ab-02 to cynomolgus monkeys, PD activity was observed as early as 5 minutes (first time point sampled). This PD activity had good correlation with the serum concentrations and anti-product antibody responses throughout the study. The mean terminal half-life (t<sub>1/2</sub>) was ~10.6 and 2.3 days for Ab-01 and Ab-02, respectively. PD activity was lost at ~5-13 weeks for Ab-01 and at ~2 weeks for Ab-02, when serum concentrations were relatively low. The estimated minimum concentrations needed to maintain PD activity were ~4-6 nM for Ab-01 and ~2.5 nM for Ab-02, and were consistent with the respective K<sub>D </sub>values for binding to human IL-21R. For Ab-01, there was noticeable inter-animal variability in t<sub>1/2 </sub>values (~6-14 days) and the resulting PD profiles, which correlated with the onset of anti-product antibody formation. While all three Ab-01-dosed animals were positive for anti-Ab-01 antibodies, only one monkey (with the shortest t<sub>1/2 </sub>and the earliest loss of PD activity) had evidence of neutralizing anti-Ab-01 antibodies. All three Ab-02-dosed monkeys developed neutralizing anti-Ab-02 antibodies.</p> <p>Conclusions</p> <p>For anti-IL-21R antibodies Ab-01 and Ab-02, there was good correlation between PD activity and PK profiles following IV administration to cynomolgus monkeys. Compared with Ab-01, Ab-02 was eliminated markedly faster from the circulation, which correlated with a shorter duration of PD activity.</p> |
| first_indexed | 2024-12-13T20:35:53Z |
| format | Article |
| id | doaj.art-35d31fdcc02545418bf857e6cc8413e7 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-13T20:35:53Z |
| publishDate | 2010-04-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj.art-35d31fdcc02545418bf857e6cc8413e72022-12-21T23:32:17ZengBMCJournal of Translational Medicine1479-58762010-04-01814110.1186/1479-5876-8-41Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeysSpaulding VikkiMa MargeryRyan MarkBree AndreaSzklut PamelaAllen ScottVugmeyster YuliaYoung DeborahGuay HeathBloom LairdLeach Michael WO'Toole MargotAdkins Karissa<p>Abstract</p> <p>Background</p> <p>Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD) activity, pharmacokinetics, and anti-product antibody responses of human anti-IL-21R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys.</p> <p>Methods</p> <p>The PD assay was based on the ability of recombinant human IL-21 (rhuIL-21) to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples <it>ex vivo</it>. Monkeys screened for responsiveness to rhuIL-21 stimulation using the PD assay, were given a single 10 mg/kg IV dosage of Ab-01, Ab-02, or a control antibody (3/group), and blood samples were evaluated for PD activity (inhibition of IL-2RA expression) for up to 148 days. Anti-IL-21R antibody concentrations and anti-product antibody responses were measured in serum using immunoassays and flow cytometry.</p> <p>Results</p> <p>Following IV administration of Ab-01 and Ab-02 to cynomolgus monkeys, PD activity was observed as early as 5 minutes (first time point sampled). This PD activity had good correlation with the serum concentrations and anti-product antibody responses throughout the study. The mean terminal half-life (t<sub>1/2</sub>) was ~10.6 and 2.3 days for Ab-01 and Ab-02, respectively. PD activity was lost at ~5-13 weeks for Ab-01 and at ~2 weeks for Ab-02, when serum concentrations were relatively low. The estimated minimum concentrations needed to maintain PD activity were ~4-6 nM for Ab-01 and ~2.5 nM for Ab-02, and were consistent with the respective K<sub>D </sub>values for binding to human IL-21R. For Ab-01, there was noticeable inter-animal variability in t<sub>1/2 </sub>values (~6-14 days) and the resulting PD profiles, which correlated with the onset of anti-product antibody formation. While all three Ab-01-dosed animals were positive for anti-Ab-01 antibodies, only one monkey (with the shortest t<sub>1/2 </sub>and the earliest loss of PD activity) had evidence of neutralizing anti-Ab-01 antibodies. All three Ab-02-dosed monkeys developed neutralizing anti-Ab-02 antibodies.</p> <p>Conclusions</p> <p>For anti-IL-21R antibodies Ab-01 and Ab-02, there was good correlation between PD activity and PK profiles following IV administration to cynomolgus monkeys. Compared with Ab-01, Ab-02 was eliminated markedly faster from the circulation, which correlated with a shorter duration of PD activity.</p>http://www.translational-medicine.com/content/8/1/41 |
| spellingShingle | Spaulding Vikki Ma Margery Ryan Mark Bree Andrea Szklut Pamela Allen Scott Vugmeyster Yulia Young Deborah Guay Heath Bloom Laird Leach Michael W O'Toole Margot Adkins Karissa Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys Journal of Translational Medicine |
| title | Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys |
| title_full | Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys |
| title_fullStr | Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys |
| title_full_unstemmed | Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys |
| title_short | Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys |
| title_sort | correlation of pharmacodynamic activity pharmacokinetics and anti product antibody responses to anti il 21r antibody therapeutics following iv administration to cynomolgus monkeys |
| url | http://www.translational-medicine.com/content/8/1/41 |
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