Sensitivity and Specificity of the Nude Mouse Bioassay to the - PowerPoint PPT Presentation

Sensitivity and Specificity of the Nude Mouse Bioassay to the Clinical Islet Allotransplantation Outcome. Klearchos Papas, PhD University of Minnesota Medical School

Outline • Islet product testing objectives • Correlation of nude mouse bioassay data with human transplantation outcome 21 CFR 600.3 (s)

Islet Product Testing Objectives • Determine whether product release testing results are within a pre-defined specification range • Determine whether manufacturing process controlled and consistent • Prevent, detect, and correct deficiencies in the manufacturing process that may compromise product integrity or function, or may lead to the transmission of infectious agents 21 CFR 211.22

Assessing the Final Product Product safety Product Quality • Identity • Sterility • Purity • Endotoxin • Potency • Mycoplasma 21 CFR 610

Correlation of Nude Mouse Bioassay Data with Human Transplant Outcome • The diabetic nude mouse bioassay is considered the gold standard BUT • Do islet product testing results obtained in the diabetic nude mouse bioassay correlate with post-transplant islet function in type 1 diabetic recipients?

Concordance of primate and mouse recipients of primate islet grafts from the same donor with insulin independence/euglycemia as readout 16 Consecutive islet transplants 15 14 13 12 11 Insulin independence/euglycemia 10 9 Insulin dependence/hyperglycemia 8 Outcome concordant. 7 6 Outcome discordant. 5 4 3 Concordance in 93% 2 1 (P=0.03, N=15) 0 Primate Mice

19 Single-Donor Islet Allografts • 16 restored insulin independence • 2 resulted in partial function • 1 showed primary non-function

Concordance of human and mouse recipients of human islet grafts from the same donor with insulin independence/euglycemia as readout 20 19 Consecutive islet transplants Insulin independence/euglycemia 18 17 16 Insulin dependence/hyperglycemia 15 14 Outcome concordant. 13 12 Outcome discordant. 11 10 9 Concordant in 74% 8 7 (N=19) 6 5 19 single- -donor islet allografts donor islet allografts 19 single 4 3 - 16 restored insulin independence 16 restored insulin independence - 2 Human Mice 1 - 2 resulted in partial function 2 resulted in partial function - 0 - - 1 showed primary non 1 showed primary non- -function function

Statistical Analysis of Bioassay Sensitivity Based on the statistical analysis provided by the City of Hope ABCC, the mouse outcome is 100% sensitive but only 68.8% specific to the human outcome.

Conclusion The nude mouse bioassay outcome is highly sensitive and relatively specific to the human transplantation outcome