Impact of Precipitation of Antibody Therapeutics After Subcutaneous Injection on Pharmacokinetics and Immunogenicity
| Autor: | John Ferbas, Francis Kinderman, Johnathan Herskovitz, Nathan H. Joh, Vibha Jawa, Marisa K. Joubert, Jennifer Malella, Brittany Yerby, Helen J. McBride, Jiansong Xie |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Injections Subcutaneous Dose-Response Relationship Immunologic Pharmaceutical Science 02 engineering and technology Pharmacology 030226 pharmacology & pharmacy Mice Protein Aggregates 03 medical and health sciences Subcutaneous injection Subcutaneous Tissue 0302 clinical medicine Immune system Pharmacokinetics Animals Humans Distribution (pharmacology) Tissue Distribution biology Chemistry Immunogenicity Antibodies Monoclonal Germinal center Germinal Center 021001 nanoscience & nanotechnology Injection Site Reaction Disease Models Animal Solubility biology.protein Female Lymph Antibody 0210 nano-technology |
| Zdroj: | Journal of Pharmaceutical Sciences. 108:1953-1963 |
| ISSN: | 0022-3549 |
| Popis: | Antibody therapeutics with poor solubility in the subcutaneous matrix may carry unintended risks when administered to patients. The objective of this work was to estimate the risk of antibodies that precipitate in vitro at neutral pH by determining the impact of poor solubility on distribution of the drug from the injection site as well as immunogenicity in vivo. Using fluorescence imaging in a mouse model, we show that one such precipitation-prone antibody is retained at the injection site in the subcutaneous space longer than a control antibody. In addition, we demonstrate that retention at the injection site through aggregation is concentration-dependent and leads to macrophage association and germinal center localization. Although there was delayed disposition of the aggregated antibody to draining lymph nodes, no overall impact on the immune response in lymph nodes, systemic exposure of the antibody, or enhancement of the anti-drug antibody response was evident. Unexpectedly, retention of the precipitated antibody in the subcutaneous space delayed the onset of the immune response and led to an immune suppressive response. Thus, we conclude that precipitation due to poor solubility of high doses of antibody formulations delivered subcutaneously may not be of special concern in terms of exposure or immunogenicity. |
| Databáze: | OpenAIRE |
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