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| Content Provider | Springer Nature Link |
|---|---|
| Author | Nellis, David F. Michiel, Dennis F. Jiang, Man Shiow Esposito, Dominic Davis, Richard Jiang, Hengguang Korrell, Angela Knapp, George C. Lucerni, Lauren E. Nelson, Roy E. Pritt, Emily M. Procter, Lauren V. Rogers, Mark Sumpter, Terry L. Vyas, Vinay V. Waybright, Timothy J. Yang, Xiaoyi Zheng, Amy M. Yovandich, Jason L. Gilly, John A. Mitra, George Zhu, Jianwei |
| Copyright Year | 2011 |
| Abstract | The use of recombinant human interleukin (rhIL)-15 as a potential therapeutic immune modulator and anticancer agent requires pure, stable preparations. However, purified rhIL-15 preparations readily accumulated heterogeneities. We sought to improve rhIL-15 stability through process, formulation, and targeted amino acid changes.The solution state of rhIL-15 versus buffer composition and temperature was studied using SEC and IEX methods. rhIL-15 deamidation was confirmed using RP-HPLC/ESI-MS, enzymatic labeling, and peptide mapping. Deamidation kinetics were measured versus buffer composition and pH using RP-HPLC. Deamidation-resistant rhIL-15 variants (N77A, N77S, N77Q, G78A, and [N71S/N72A/N77A]) were produced in E. coli, then assayed for T-cell culture expansion potency and deamidation resistance.Adding 20% ethanol to buffers or heating at ≥32°C dispersed rhIL-15 transient pairs, improving purification efficiencies. Asparagine 77 deamidated rapidly at pH 7.4 with activation energy of 22.9 kcal per mol. Deamidation in citrate buffer was 17-fold slower at pH 5.9 than at pH 7.4. Amino acid substitutions at N77 or G78 slowed deamidation ≥23-fold. rhIL-15 variants N77A and (N71S/N72A/N77A) were active in a CTLL-2 proliferation assay equivalent to unsubstituted rhIL-15.The N77A and (N71S/N72A/N77A) rhIL-15 variants are resistant to deamidation and remain potent, thus providing enhanced drug substances for clinical evaluation. |
| Starting Page | 722 |
| Ending Page | 738 |
| Page Count | 17 |
| File Format | |
| ISSN | 07248741 |
| Journal | Pharmaceutical Research |
| Volume Number | 29 |
| Issue Number | 3 |
| e-ISSN | 1573904X |
| Language | English |
| Publisher | Springer US |
| Publisher Date | 2011-10-19 |
| Publisher Place | Boston |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Medical Law Pharmacology/Toxicology Pharmacy Biochemistry Biomedical Engineering |
| Content Type | Text |
| Resource Type | Article |
| Subject | Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science |
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