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Human Disease Modeling Using the NSG Mouse Cutting Edge Human Disease Modeling Using The NSG Mouse Dominique Kagele, Ph.D. Technical Information Services Cutting Edge Human Disease Modeling The NSG Mouse NSG Basics Enhanced disease modeling o Solid and hematological cancers o Human immunity and inflammation Advanced and future disease modeling Additional information and resources JAX® Mice | 2 Cutting Edge Human Disease Modeling The NSG Mouse NSG Basics Enhanced disease modeling o Solid and hematological cancers o Human immunity and inflammation Advanced and future disease modeling Additional information and resources JAX® Mice | 3 The Immune System in Mice JAX® Mice | 4 NOD scid gamma (NSG) Strain nomenclature: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ Stock Number: 005557 Additional resources: NSG Web Resources www.jax.org/jaxmice/research/immunology/005557.html JAX® Mice | 5 NSG A Highly Immunodeficient Mouse NOD background Absence of hemolytic complement Reduced dendritic and NK cell function Defective macrophages Optimal human hematopoietic stem cell engraftment (Sirpa allele) scid mutation prevents development of mature T and B cells gamma chain (Il2rg knockout) Eliminates signaling from 6 distinct interleukins and blocks NK cell development JAX® Mice | 6 NSG A Highly Immunodeficient Mouse JAX® Mice | 7 Gamma Chain Knockout (Il2rgtm1Wjl) Complete deficiency of the interleukin 2 receptor, gamma chain Common subunit found in multiple cytokine cell signaling receptors IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 are key signaling molecules in function and maturation of T, B, NK, neutrophils and dendritic cells Rochman Y et al. 2009. Nat Rev Immunol 9(7):480-90. PMID:19543225 JAX® Mice | 8 NSG A Highly Immunodeficient Mouse Longer lifespan (> 16 months) than NOD-scid (~ 9 months) scid side effects: Radiation sensitivity; genotoxic drugs can have higher toxicity A platform for developing refined models (transgenic and knockout) JAX® Mice | 9 The Most Useful and Versatile Immunodeficient Mouse Research applications: Primary tumor engraftment Cancer stem cells Human hematopoiesis Humanized mice Infectious disease Transplantation research JAX® Mice | 10 Cutting Edge Human Disease Modeling The NSG Mouse NSG Basics Enhanced disease modeling o Solid and hematological cancers o Human immunity and inflammation Advanced and future disease modeling Additional information and resources JAX® Mice | 11 Classical Cancer Xenograft Modeling Nude Mice Before treatment After treatment Gulliya et al. 1994. Cancer 74:1725-1732. PMID:8082074 ® JAX Mice | 12 Patient Tumor Characteristics NSG vs scid Cancer Patient’s Lung Tumor Fragment NSG H&E C.B-17 scid H&E Human cells Mouse blood cells (anti-HLA) (anti-mCD45) Simpson-Abelson MR et al. 2008.J Immunol 180(10):7009-18. PMID:18453623 JAX® Mice | 13 JAX® Patient-Derived Xenograft (PDX) Program Patient-derived tumor bank in NSG mice Clinical information o Tumor type, grade and markers (if known) o Treatment history Histology Gene expression and CNV analysis In Vivo Pharmacology Services | 14 JAX® Patient-Derived Xenograft (PDX) Program In Vivo Pharmacology Services | 15 JAX® PDX Tumor Model Bank (>350) Tumor type Number of models Appendiceal 1 Bladder 15 Brain 33 Breast 16 Colorectal 32 Endometrial 4 Gastric/GIST 2 Hematology 4 Hepatocellular 1 Kidney 9 Lung 49 Ovary 10 Pancreas 18 Prostate 2 Sarcoma 14 Skin 8 To see all of our PDX models, visit www.tumor.informatics.jax.org In Vivo Pharmacology Services | 16 PDX modeling in NSG Estrogen Receptor-Positive Breast Carcinoma TM00386 (ER+/PR+/Her2-) TM00386-PT TM00386-P0 TM00386-P1 PT= Patient Tumor; P0 = first patient derived xenograft (PDX) generation in mouse; P1 = 2nd generation • NSG supports growth of ER+ breast tumors • Tumors retain “organoid” growth pattern In Vivo Pharmacology Services | 17 Orthotopic PDX Modeling in NSG Bladder Cancer Fidelity during tumor passaging Orthotopic model (subcutaneous) Lin TY et al. 2012. Nanomedicine (Lond).[Epub ahead of print] PMID:23199207 In Vivo Pharmacology Services | 18 PDX Modeling in NSG mice Bladder Cancer Tumor-Targeting Micelles Prevent …and Improve Survival Tumor Growth… Lin TY et al. 2012. Nanomedicine (Lond).[Epub ahead of print] PMID:23199207 In Vivo Pharmacology Services | 19 NSG Improved Melanoma Metastasis Modeling Cell line: A375 (RhoC, Luciferase) injected I.V. *NSG also better platform for cell line engraftment (data not shown) Carreno et al. 2008. Clin Cancer Res 15(10):3277-86. PMID:19447870 In Vivo Pharmacology Services | 20 NEW PDX Live™ NSG MiceM Readily Available from Inventory and Pre-Engrafted with Patient-Derived Tumors Fast-track PDX Studies of 12 Human Tumor Types Triple negative breast carcinoma (2), acute myeloid leukemia (4), non-small cell lung cancer, B-cell lymphomas, metastatic colon adenocarcinoma, metastatic rectal carcinoma, serous adenocarcinoma, squamous cell carcinoma Save 6-12 Weeks of Valuable Research Time Eliminate the need to cryo-recover & passage tumors between donor and study mice Make Decisions Earlier during Drug Development JAX® PDX Mice are available at lower passages than any other patient-derived xenograft model provider. Low passage tumors… o Preserve the heterogeneity of the original human cancers and the closest possible response to primary human tumors o Improve accuracy in assessing clinical efficacy of novel therapeutics PDX Live™ 21 Cutting Edge Human Disease Modeling The NSG Mouse NSG Basics Enhanced disease modeling o Solid and hematological cancers o Human immunity and inflammation Advanced and future disease modeling Additional information and resources JAX® Mice | 22 Effective Modeling of Patient-Derived ALL (T & B Cell) Cells: Unsorted patient-derived T or B cell ALL Route: Tail vein Age of mice: 6-8 weeks *Patient samples engrafted at lower doses and with faster kinetics in NSG Diamanti P et al. 2011. Leukemia Feb;26(2):376-80. PMID:21860430 JAX® Mice | 23 NSG Efficiently Models Patient AML Samples from different patients showed improved engraftment versus other models (NSB) Sanchez PV et al. 2009. Leukemia 23(11):2109-2117. PMID:19626050 JAX® Mice | 24 Cutting Edge Human Disease Modeling The NSG Mouse NSG Basics Enhanced disease modeling o Solid and hematological cancers o Human immunity and inflammation Advanced and future disease modeling Additional information and resources JAX® Mice | 25 NSG Supports a Human Immune System Most efficient engraftment of human HSCs to date Permits differentiation of all major cell types: o Myeloid lineage Erythrocytes, megakaryocytes, platelets Monocytes, macrophages, dendritic cells, granulocytes o Lymphoid lineage B cells T cells (CD4+ and CD8+) NK cells Some mucosal and adaptive immune function JAX® Mice | 26 NSG Supports a Human Immune System NSG is a superior host for human immune cells when compared to other strains: 1. Any strain expressing the scid mutation alone (NOD-scid, B6-scid, C.B17-scid) 2. “scid beige” 3. The same mutations—scid (or a Rag1 or Rag2 knockout) and “gamma”—on other backgrounds (for example, BALB/c) Shultz LD et al. 2005. J Immunol 174(10):6477-89. PMID:15879151 Lepus CM et al. 2009. Hum Immunol Oct;70(10):790-802. PMID:19524633 Brehm MA et al. 2010. Clin Immunol 135(1):84-98. PMID:20096637 JAX® Mice | 27 Improved Engraftment of CD34+ HSCs and PBMCs *NSG also steadily engrafts human immune cell populations over time (data not shown) King M et al. 2008. Clin Immunol 126(3):303-14. PMID:18096436 Brehm MA et al. 2010. Clin Immunol 135(1):84-98 PMID:20096637 In Vivo Pharmacology Services | 28 NSG The Most Efficient Humanized Model Engraftment Efficiency of Bone Marrow Strain Exp 1 Exp 2 Combined Percentage NOD/Lt-scid 9/11 5/7 14/18 77.8 NOD/Shi-scid 12/12 3/11 15/23 65.2 NSG 12/12 11/11 23/23 100 NOG 10/12 9/10 19/22 86.4 *NSG also had the greatest efficiency in spleen & thymus Adapted from McDermott SP et al. 2010. Blood. Jul 15;116(2):193-200. PMID:20404133 JAX® Mice | 29 Experimental Timeline for JAX® Hu-NSG Whole body irradiation Human Human Tail vein injection B cells T cells appear appear Mouse Age 3 weeks 12 weeks 15 weeks CD34+ cells engrafted in 3 week old female mice In Vivo Pharmacology Services | 30 Successful Engraftment in Peripheral Blood Human Mouse Engrafted NSG Mostly neutrophils, monocytes Human CD45 Mouse CD45 Human white blood cells abundant in circulation Mature human T (CD3+) and B (CD20+) cells differentiated in the NSG mouse Human CD3 Human CD20 In Vivo Pharmacology Services | 31 Multi-lineage Differentiation in Bone Marrow Human vs Mouse Human HSC 86.1% 88.6% 0.13% 11.2% SSC hCD34 hCD45 FSC mCD45 hCD38 Human Erythroid Human B cells Human APCs DTH Response in Humanized NSG is Evidence for Intact T Cell Functions Sensitization Sensitization Challenge +/- treatment Day -1 Day 1 Day 2 Day 7 Day 8 Day 9 Day 14 Ear thickness Ear thickness Ear thickness Ear thickness Ear thickness Ear thickness Naive Sensitized with DNFB Sensitized with Olive Oil DNFB + Hydrocortisone In Vivo Pharmacology Services | 33 Transplant Rejection Studies: Diabetes Diabetic mice: NSG treated with STZ Transplanted with human islets, +/- PBMCs H&E hCD45 Insulin 32 days post-engraft. + PBMC No PBMC King M et al. 2008. Clin Immunol 126(3):303-14. PMID:18096436 JAX® Mice | 34 NSG is Superior to NOD scid for Humanized HIV Models Infectivity correlates with infiltration of human T cells into vaginal mucosa Stoddart CA et al. 2011. Virology Aug 15;417(1):154-60. PMID:21684569 35 Research Ready Humanized NSG Routinely engraft NSG mice with human CD34+ hematopoietic stem cells BLT & PBMC engrafted mice available Mice are delivered 12 weeks after
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