Development of ADA Against Recombinant Human Interferon Beta in Immune Tolerant Mice Requires Rapid Recruitment of CD4+ T Cells, Induces Formation of.

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Development of ADA Against Recombinant Human Interferon Beta in Immune Tolerant Mice Requires Rapid Recruitment of CD4+ T Cells, Induces Formation of Germinal Centers but Lacks Susceptibility for (Most) Adjuvants Grzegorz Kijanka, Melody Sauerborn, Louis Boon, Huub Schellekens, Vera Brinks Journal of Pharmaceutical Sciences Volume 104, Issue 2, Pages 396-406 (February 2015) DOI: 10.1002/jps.24170 Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 1 Formation of total anti-rhIFNβ IgG in CD4+ T-cell depleted animals on day 8 (a) and 19 (b) of Betaferon® treatment. The x axis shows on which day of experiment the depletion of CD4+ T cells was initiated. White bars show average titer of tg ADA positive animals with corresponding SD. Black bars show average titer of non-tg ADA positive animals with corresponding SD. Numbers above bars indicate the number of ADA positive animals out of total amount of animals in group. The lines above the bars indicate significant differences between ADA titers between treatment group and nondepleted control group. *p<0.05, **p<0.01, ***p<0.001. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 2 (a) Effect of aluminum hydroxide on the production of total IgG anti rhIFNβ-1α Abs in tg and non-tg animals showed as the change of OD450 values. The Ab levels in tg animals, although in part of them exceeded the positivity threshold (see definition in Materials and Methods section), were too low to calculate titers according to described method. The bars show average OD450 of all animals in group with corresponding SD. The numbers above bars indicate the number of animals classified as positive out of total amount of mice per group. (b) Effect of aluminum hydroxide on the titer of total IgG anti rhIFNβ-1α Abs in tg and non-tg animals. The bars show the average titer of ADA positive animals with corresponding SD. Adjuvant significantly increased ADA titers of non-tg animals on day 19. (c) Production of anti Pneumovax23® total IgG. The treatment with Pneumovax 23® whether with or without adjuvant significantly increased total IgG titers when compared with control group. Bars show the average titer from all animals in group with corresponding SD. **p<0.01, ***p<0.001. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 3 (a) Formation of GCs in spleens of tg and non-tg animals 9 days after the beginning of rhIFNβ-1α or Pneumovax23® treatment. The red arrows indicate the GC specific, PNA positive B cells (dark blue) surrounded by naive, B220 positive cells (brown). (b) The relative number of GCs in the spleens 9 days after rhIFNβ-1α or Pneumovax23® treatment. (c) The relative number of GCs in the spleens 19 days after rhIFNβ-1α or Pneumovax23® treatment. The bars show relative number of GCs per section surface of the tg (white) and non-tg (black) animals’ spleen with corresponding SD. Adsorption of rhIFNβ-1α on aluminum hydroxide increased number of GCs in non-tg animals on day 10 of Betaferon® treatment. *p<0.05. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 4 Production of anti rhIFNβ-1α ADA on Day 22 in tg and non-tg mice in Experiment I (a) initial study, (b) follow-up study. Each symbol represents the ADA titer in a single mouse. *p<0.05, **p<0.01, ***p<0.001. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 5 Production of anti rhIFNβ-1α ADA in tg and non-tg mice on days 15 and 22 (primary treatment) of Experiment II. (a) Mice treated with rhIFNβ-1α, (b) mice treated with CTB-rhIFNβ-1α conjugates. Each symbol represents the ADA titer in a single mouse. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 6 Titers of anti rhIFNβ-1α ADA in tg and non-tg mice before (day 61) and after (days 68 and 73) rechallenge with rhIFNβ-1α in Experiment II. (a) Mice primarily treated with rhIFNβ-1α, (b) mice primarily treated with CTB-rhIFNβ-1α conjugates. Each symbol represents the ADA titer in a single mouse. **p<0.01, ***p<0.001. Journal of Pharmaceutical Sciences 2015 104, 396-406DOI: (10.1002/jps.24170) Copyright © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions