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Immune checkpoints sot2016
In 3 sentences: Envigo is a global contract research organization dedicated to helping customers advance human and animal health. They provide contract research services and research models across 5 continents, employing over 3,800 people at 52 locations. The presentation discussed key considerations for the non-clinical safety evaluation of drugs targeting immune checkpoints, including challenges assessing immunotoxicity and predicting autoimmune risks in animal models.
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Immune checkpoints sot2016
- 1. © 2016 Envigoenvigo.com Chair: Greg Bannish Presenters: Lee A. Coney and Mandy Horn Key considerations in the safety evaluation of drugs targeting immune checkpoints
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- 3. We are aglobal contract research products and services company dedicated to helping our customers achieve the potential of their products which improve human life, advance animal welfare, and protect the environment and global food security. Who We Are
- 4. Our Brand Promise Together,we make the world a safer and healthier place to live. Our company places the customer at the center of everything we do. We focus on what matters to you, our customer, and work closely with you to secure the potential of your research and products. We are dedicated to research that makes a difference in the lives of people all over the world.
- 5. 52 locations Global availabilityof research models and CRO services 5 continents Extensive reach across the Americas, Europe, Asia, and the Middle East 3,800 employees Serving over 65 countries 150 years Combined industry experience $500 million Approximately $500m in annual revenues Capacity and Reach
- 6. Contract Research Services(CRS) locations United States of America + Princeton, New Jersey Envigo laboratories are located in The United States of America, Europe and the Middle East Europe Corporate HQ: Huntingdon, England + Huntingdon, England + Eye, England + Ely, England + Shardlow, England + Rossdorf, Germany + Barcelona, Spain + Valencia, Spain Middle East + Rehovot, Israel
- 7. Research Models andServices (RMS) locations Envigo production sites in North America, Europe, the Middle East and Asia North America + Dublin, VA + Frederick, MD + Haslett, MI + Houston, TX + Indianapolis, IN + Livermore, CA + Madison, WI + Mexico City, Mexico Europe + Blackthorn, UK + Bresso, Italy + Gannat, France + Horst, Netherlands + Loughborough, UK + Udine, Italy + Wyton, UK Middle East + Jerusalem, Israel + Rehovot, Israel + Yokneam, Israel India + Hyderabad, India Corporate HQ: Indianapolis, IN European Office: Venray, Netherlands
- 8. Key considerations inthe safety evaluation of drugs targeting immune checkpoints
- 9. + What iscancer immunotherapy? + What are the potential challenges in the safety assessment of antibodies targeting immune system checkpoints? + Things to consider when designing and running your non- clinical safety programmes for immune checkpoint targets? + Measuring immunotoxicity / immunopharmacology + Case study – what if your chosen therapeutic has no pharmacologically relevant non-clinical safety species? + Summary Presentation overview
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- 11. The utility ofthe immune system Heidi L. Nature 2014 508:24
- 12. A history ofcancer immunotherapy Kirkwood JM et al. CA Cancer J Clin 2012 62:309
- 13. + There aremultiple different platforms of cancer immunotherapy and many very different target pathways + Adoptive cell transfer + TILs, TCR–transfected T-cell, CAR therapy + Non-specific immunotherapies + Cytokines (IL-2, IFNa) CD40 agonist mAb, TLR agonist + Vaccination strategy + Sipuleucel-T, MAGE-3 ASCL, OncoVEX + Immune checkpoint blockade + CTLA-4 blocking mAb, PD-1 blocking mAb + The remainder of this talk with focus upon this latter approach so called immune checkpoint targeting antibodies Current state of cancer immunotherapy
- 14. + T-cell killingof tumour cells can be switched on and off + Regulated by signals from other cells of the immune system such as antigen presenting cells and tumours themselves + T-cells are effectively “switched off” by due to signalling via immunoinhibitory (checkpoint) receptors on activated T cells + T cells can be switched back on in lymph nodes or the tumour microenvironment by drugs that target checkpoint receptors + There are many such drugs in development and on the market today with some exciting biology behind them + PD1, CTLA-4, PDL, KIR, IDO1, 4-1BB, OX40, LAG3, B7-H3, CD27, CD70, CD28, CD30 etc. Checkpoint inhibitors: Background
- 15. Checkpoint inhibitors: Background ShinDS & Ribas A. Curr Opin Immunol 2015 33:23
- 16. + CD28 + OX40 +GITR + CD137 + CD27 + HVEM Potential checkpoint targets (not exhaustive) Activating receptors + CTLA-4 + PD-1 + TIM-3 + BTLA + VISTA + LAG-3 Inhibitory receptors Inspired by Mellman I et al. Nature 2011 480:480 Agonistic antibodies Blocking antibodies
- 17. + Immunoinhibitory receptorsare expressed after normal MHC class I/II adaptive T cell activation + Ligation of CTLA-4 by B7-1/B7-2 or PD1 by PD-L1 or PD- L2 attenuates normal T cell activation + CTLA-4 and PD1 upregulation on chronically activated T cells makes them less responsive to antigenic stimulation + Inhibition of these targets can restore T cell function and enhance T-cell tumour killing + Checkpoint inhibitors play critical roles in maintenance of peripheral T cell tolerance + Drugs that target immune system checkpoints have the potential to promote inflammation/autoimmunity in humans Checkpoint inhibitors: Mechanism of action
- 18. Characteristic CTLA‐4 pathwayPD‐1 pathway Expression pattern Exclusively T cells (constitutively on Tregs) T, B, and NK cells (activated T cells) Natural ligands CD80 (B7-1) and CD86 (B7-2) PD‐L1 and PD‐L2 Expression profile of ligands Mainly on antigen presenting cells (APCs) APCs and tumour cells Phenotype of KO mice Early fatal autoimmune syndrome (lymphoproliferative disease) Strain‐specific autoimmunity presenting later in life in some strains Effect of target blockade Enhanced proliferation of CD4+ and CD8+ T cells with increase in ratio to Treg cells Enhanced proliferation of CD8+ T cells greater than CD4+ T cells and enhanced cytotoxicity of CD8+ T cells CTLA-4 v PD-1 pathways Greenwald RJ, et al. Ann Rev Immunol. 2005;23:515-548. Chambers CA, et al. Ann Rev Immunol. 2001;19:565-594. Dong H, et al. Nat Med. 2002;8:793-800. Curran MA, et al. Proc Natl Acad Sci U S A. 2010;107:4275-4280. Pilon-Thomas S, et al. J Immunol. 2010;184:3442-3449.
- 19. + CPIs controlcentral and peripheral immune tolerance to “self-antigens” + CPIs restrict positive selection in the thymus, inhibit the activation and function of self-reactive T cells in the peripheral circulation, effect Treg cell development and their function + Therefore inhibition of some CPI pathways may contribute to the development of immune-mediated disease + Findings consistent with autoimmunity observed in both CTLA-4 and PD-1 KO mice on certain backgrounds + Similar findings seen in humans with genetic anomalies in certain CPI genes + SLE, RA, MS, Type 1 diabetes + Immune-mediated events observed in clinical studies with CPIs and monitored in post-marketing PV Predicted risks based on mechanism of action
- 20. Checkpoint inhibitors: Mechanismof action Intlekofer AM et at. J Leukoc Biol 2013 94:25
- 21. + The intendedpharmacological action of each therapeutic is immune system activation – immediate alarm bells! + As with most biopharmaceuticals the balance between therapeutically desired pharmacology and clinical dose- limiting “exaggerated pharmacology” is a delicate balance + Acute effects such as systemic cytokine release may be manageable in some clinical situations + More chronic effects such as induction of autoimmune disease may be more difficult to model in healthy standard non-clinical models + SPF animals may also lack or have limited target expression of checkpoint molecules Challenges in safety assessment
- 22. + Binds humanCTLA-4 in vitro with high affinity + Inhibits in vitro binding of B7.1 (CD80) and B7.2 (CD86) to human CTLA-4 + CDC and ADCC activity investigated in vitro and in vivo + Colon carcinoma studies in human CTLA-4 transgenic mouse + Extensive TDAR investigation in cynomolgus monkey + Hepatitis B surface antigen (HBsAg) vaccine, a melanoma cell-based vaccine (Sk- mel), DNP (2,4-Dinitrophenyl)-Ficoll, keyhole limpet hemocyanin (KLH) and simian immunodeficiency virus (SIV), DNA vaccines (purified plasmid DNA) expressing the proteins for the gag (pSIVgag), env (pSIVenv), and pol (pSIVpol) portions of SIV. In one study, the SKmel tumour line was transfected to express GM-CSF. + Extensive immunophenotypic analysis of T cells and subsets in these studies + Extensive assessment of humoral immune responses to TDAR antigens Yervoy (Ipilimumab) anti-CTLA-4 antibody EMA Assessment Report For Yervoy (ipilimumab)
- 23. + Tissue crossreactivity studies + Safety pharmacology included as part of repeat dose toxicity programme + Combination studies with anti-CD137 and anti-PD-1 antibodies conducted in cynomolgus monkeys + Single species toxicology programme conduced in cynomolgus monkey as only pharmacologically relevant species + Studies up to 6 months in duration at a variety of dose levels conducted + No reproductive, developmental or juvenile toxicology studies were submitted for registration purposes Yervoy (Ipilimumab) anti-CTLA-4 antibody EMA Assessment Report For Yervoy (ipilimumab)
- 24. + Most findingsconsidered adverse seen in combination toxicity or exploratory (TDAR) pharmacology studies not anti-CTLA-4 alone GLP studies + Low incidence of immune-meditated toxicities + Colitis, dermatitis, or infusion reactions + Responses consistent with proposed MOA of CTLA-4 in maintaining self-tolerance + Findings in cynomolgus monkeys correlated with findings in humans, although with less frequently – under predict? + CTLA-4 blocking did result in an over stimulation of the T- cell compatment + Few meaningful changes in immunophenotype or autoimmune organ pathology (with exception of colitis and dermatitis) + Increased TDAR was observed demonstrating expected pharmacodynamics Yervoy (Ipilimumab) anti-CTLA-4 antibody EMA Assessment Report For Yervoy (ipilimumab)
- 25. + Agonist antibodies +Systemic cytokine release + Hepatotoxicity + Antagonist (blocking) antibodies + Immune system activation and autoimmunity + Dermatitis, colitis, hepatitis, thyroiditis, hypophysitis, uveitis, pneumonitis + Adverse events observed in clinic include: pneumonitis, colitis, skin effects (rash, pruritis, vitiligo), conjunctivitis, uveitis, hepatotoxicity, thyroid toxicity, nephritis + Normal cynomolgus monkeys not predictive of all clinical findings – how do we increase the potential to translate understanding from non-clinical to clinical? Clinical experience
- 26. + Can studiesin normal animals (were lower expression of checkpoint receptors since lower numbers of activated T cells) predict adverse events in cancer patients? + Do the immune changes in normal animals adequately reflect the risk of immune-mediated pathology in humans? + Should greater focus be on safety studies in models of autoimmunity, cancer, vaccination, where more activated T cells & checkpoint expression / activity is higher? + Could these models then become over predictive? + Is it useful to understand relative risk of combos of checkpoint inhibitors to monotherapy; benchmark new therapies to anti-CTLA-4 & anti-PD-1 marketed products? Checkpoint inhibitors: Key considerations for safety
- 27. + “Classical” NOAELapproach less relevant for molecules targeting check point inhibitors + First in human dosing likely to be based on extensive non- clinical investigations + In vitro potency assessment including relative potency between human and non- clinical species + Receptor occupancy + FIH dose likely to be based on PAD and / or MABEL. Generally clinical dose setting will be conservative with slow dose escalation in the clinic + Extensive PK/PD modelling to inform clinical dosing and dose escalation. Challenging given huge diversity in clinical subjects T-cell populations Increasing the translation of non-clinical to clinical
- 28. + Non-standard approachesto safety assessment will continue to be evolved to increase the predictiveness of non-clinical models + Vaccination / antigen challenge in non-clinical studies + Host defense approach adapted for safety evaluation + Comprehensive analysis of T-cell subsets by flow cytometry (Treg, Tem, Teff, Tcm, Th1, Th2 in addition to normal panels) + Receptor occupancy in blood and other lymphoid tissue + In vitro and in vivo cytokine analysis (large multiplex panels) + RO, PAD/MABEL, in vitro / in vivo (EC50s), integrate exposure/PD/efficacy/safety; close patient monitoring + The sample burden on animals is likely to be extensive, increases the requirement for microsampling / microanalysis even in non-rodent species Increasing the translation of non-clinical to clinical
- 29. Measuring immunotoxicity /immunopharmacology
- 30. Immunotoxicology synopsis Normal animals Immunosuppression Immunostimulation Infection/ cancer risk Hypersensitivity & Autoimmunity Morbidity potential Morbidity potential
- 31. Immunotoxicology focus forimmune checkpoints Normal animals Immunosuppression Immunostimulation Infection / cancer risk Hypersensitivity & Autoimmunity Morbidity potential Morbidity potential
- 32. + There isno single assay or suitable biomarker to measure all aspects of immunotoxicology + A weight of evidence approach is undertaken + Existing understanding of drug pathway engagement / pharmacological properties + Immune system effects observed in animal toxicity and clinical safety studies + Drugs with a high predicted risk will require immune function testing to characterise that risk and understand dosing limitations Measuring immunotoxicology
- 33. + Inclusion ofimmunotoxicology / pharmacology endpoints in toxicity studies aids us in… + …demonstrating the relevance of the tox species + …preclinical toxicity study dose selection + …TK / PD demonstrates durable pharmacology and exposure in studies + …understanding applicability of immunogenicity + …identifies translatable biomarkers for clinic + …interpretation of dose-response relationship with toxicity and identification of clinical doses Immunotoxicology v pharmacology
- 34. + Can biomarkersof immune activation improve our nonclinical models? + Understand relevance of the non-clinical model + Demonstrate PD and maintenance of PD in presence of immunogenicity + Potentially increase target expression when it requires immune activation for expression + Establish pharmacodynamic range + Help set doses for toxicity studies + Help define FIH starting dose + Immunotoxicity – extension of the pharmacology + Help identify and/or understand adverse findings + Cytokines, complement activation, immune complexes, auto-antibodies Immune activation biomarkers?
- 35. + Immune systemover stimulation can cause pathological changes + Immune complex deposition + Hypersensitivity + Activation of pre-existing disorders + Autoimmune cross-reactivity + Inflammatory responses + How do we predict autoimmunity in animal models? + Molecular mimicry + Pathogen (or vaccine antigen) contains a similar linear T cell epitope or conformational B cell epitope to host leading to a cross reactive immune response to healthy tissue Autoimmune cross-reactivity
- 36. Disease Implicated agentMechanism? Rheumatic heart disease Group A Streptococcus T cell mimicry (GAS Prt-M with vascular heart protein) Guillain-Barre Syndrome Campylobacter jejuni B cell mimicry (LPS oligosaccharides cross react with gangliosides) Chronic Lyme arthritis Borrelia burgdorferi T cell mimicry (OspA cross reactivity with human LFA-1 Idiopathic thrombocytopenia VZV, EBV, Rubella B cell mimicry (viral epitopes cross reactivity with platelet glycoprotein IIb/IIIa Reactive arthritis Chlamydia trachomatis T cell mimicry (epitope cross reactivity with HLA-B27) Type I Diabetes Rotavirus/ Enterovirus Epidemiological evidence (trigger effect?) Infection and autoimmune disease
- 37. + Haematology: total& absolute differential leukocyte counts (incl. macrophages) + Clinical chemistry - globulin levels and A/G ratios + Gross pathology of lymphoid organs and tissues + Organ weights - thymus, spleen, lymph nodes etc. + Histopathology of lymphoid organs (bone marrow, spleen, lymph node, thymus etc.) + Flow cytometry of T, B & NK cells + All included within most general toxicology studies study General immune status
- 38. + General immunophenotypingof cellular component of immune system by flow cytometric methods + T-cell-dependent antibody response (TDAR) to model antigens e.g. KLH, SRBC, TT, OVA, flu' immunised during dosing & after recovery + Measure primary (IgM/IgG) & secondary (IgG) antibody response + Measure cellular response to vaccination with viral / DNA / tumour vaccines + T cell responses + DTH responses, LLNA + NK activity + Macrophage function Measuring immunomodulation
- 39. + Increases inin vitro cytotoxicity, receptor expression, T cell proliferative / cytokine responses to mitogens, NK activity + Histopathology of target tissues for autoimmunity + Serum cytokine levels + Show immune system returns to / towards normal on cessation of dosing / removal of drug + Activation quantified by increase in in vitro cytotoxicity, cytokine secretion, receptor expression (flow cytometry) + General immune status- flow cytometry of T and B cells, monocytes, histopathology of lymphoid organs, haematology Immune system activation
- 40. TDAR principle 1st Vaccination2nd Vaccination IgM IgG
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- 42. Unstimulated PHAUnstained (Isotype controls) CD25 FoxP3 TregTreg +Intracellular staining: Increased CD4+CD25+foxP3+ Tregs following stimulation of whole blood from cynomolgus macaque Treg cell staining by flow cytometry
- 43. CD8 T CD4 T CD3 CD4 SSC FSC +A gating strategy for IL4, IFNg, IL17, IL13 Intracellular T cell activation I
- 44. + Expression ofIFNg in CD4T and CD8 T cells Intracellular T cell activation II CD4 T CD8 T Unstim Stim. IL4 IFNg
- 45. + Expression ofIL17 in CD4 T cells Intracellular T cell activation III Unstim Stim. IL17 IL13 CD4 T CD8 T
- 46. Control Dosed IL-4 IFN-g Draining LN Non- Draining LN PBMC Intracellularexpression of IL-4 and IFNg in total CD3 T lymphocytes
- 47. Intracellular expression ofIL-4 and IFNg in CD4 T lymphocytes Control Dosed IL-4 IFN-g Draining LN Non- Draining LN PBMC
- 48. Intracellular expression ofIL-4 and IFNg in CD8 T lymphocytes Control Dosed IL-4 IFN-g Draining LN Non- Draining LN PBMC
- 49. TEM TCM TNaive TEM TCM TNaive Cyno DTH -increased TEM in CD8+
- 50. Case study –What if your chosen therapeutic has no pharmacologically relevant non-clinical safety species?
- 51. + The novelantibody needs a safety package but does not bind to the checkpoint inhibitor (CPI) in any standard toxicity species + An academic group has a transgenic mouse model expressing the CPI (KO/KI) that may be suitable for safety assessment of the therapeutic + The transgenic model is a good well characterised one, the transgene expression and distribution of the CPI is consistent with the human expression profile + Initiated a project to breed the transgenic mouse for use in toxicity studies Challenges with a checkpoint blocking antibody
- 52. + The transgenicmouse model is on a C57BL/6N background + One mutation is x-linked + One mutation is somatic + Currently maintained in academic institution with unacceptable health status and poor availability due to small colony size Transgenic mouse model background
- 53. + Rederive modelto acceptable health status + Develop breeding colony + Genetic testing required to confirm genotype in offspring and future breeders + Model maintained mating heterozygous / hemizygous males x heterozygous / homozygous females + Expand colony for provision of acceptable numbers of animals at requested frequency Next steps
- 54. Breeder genotype FEMALE BREEDER n/+ XmXm MALEBREEDER n/+ XmY
- 55. n Xm n Xm + Xm + Xm n Y n/n XmY n/n XmY n/+ XmY n/+ XmY n Xm n/n XmXm n/n XmXm n/+ XmXm n/+ XmXm + Y n/+ XmY n/+ XmY +/+ XmY +/+ XmY + Xm n/+ XmXm n/+ XmXm +/+ XmXm +/+ XmXm Preferred mating scheme Female(n/+ XmXm) Male(n/+XmY) + 50% to be selected as future breeders + 25% proper genotype for research studies + 25% discarded due to incorrect genotype
- 56. + Colony micepositive for pinworms and Helicobacter spp + 5 x 10 breeding pairs provided for rederivation via embryo transfer + Females superovulated; embryos collected, pooled, washed, then surgically transferred into recipient pseudopregnant females of an approved health status + Pups born and genotyped; health monitoring performed to confirm approved health status + 4 females and 6 males provided Rederivation
- 57. + Breeding pairsreceived into flexible film isolator to maintain approved health status + Based on feedback from original institution, mice maintained on 18% protein, 6% fat diet and wood pulp bedding + Mice maintained for six weeks with only three females pregnant and one cannibalized litter Develop breeding colony
- 58. + Housing andhusbandry reviewed; mice switched to higher fat diet (19% protein, 9% fat) and crinkle paper enrichment added to cages + The addition of enrichment and diet change improved breeding; however, two females died unexpectedly, leaving 6 breeding males and 2 breeding females in the Foundation Colony Root cause analysis #1
- 59. + Concept ofbackcrossing discussed with geneticist + C57BL/6N females at an approved health status were available + Females were introduced into male breeding cages (1x2) + Breeding efficiency improved, but now more extensive record keeping and genetic testing needed to confirm which mice are acceptable for future breeder selection Root cause analysis #2
- 60. + X+ n Xm n/+ XmX+ n Y n/+ X+Y + Xm +/+ XmX+ + Y +/+ X+Y Backcross generation 1 Female(+ X+) Male(n/+XmY) + 50% to be selected as future breeders + 50% discarded due to incorrect genotype
- 61. Intercross generation 2 Female(n/+ XmX+) Male(n/+X+Y) + 25% to be selected as future breeders + 75% discarded due to incorrect genotype n Xm n X+ + Xm + X+ n Y n/n XmY n/n X+Y n/+ XmY n/+ X+Y n X+ n/n XmX+ n/n X+X+ n/+ XmX+ n/+ X+X+ + Y n/+ XmY n/+ X+Y +/+ XmY +/+ X+Y + X+ n/+ XmX+ n/+ X+X+ +/+ XmX+ +/+ X+X+
- 62. Intercross generation 3 Female(n/+ XmX+) Male(n/+XmY) + 25% to be selected as future breeders + 12.5% proper genotype for research studies + 62.5% discarded due to incorrect genotype n X+ n Xm + X+ + Xm n Y n/n X+Y n/n XmY n/+ X+Y n/+ XmY n Xm n/n XmX+ n/n XmXm n/+ XmX+ n/+ XmXm + Y n/+ X+Y n/+ XmY +/+ X+Y +/+ XmY + Xm n/+ XmX+ n/+ XmXm +/+ XmX+ +/+ XmXm
- 63. + Backcross complete! +Adequate number of future breeders available to expand colony rapidly + Genetic testing still necessary to confirm pups carrying transgenes + Health monitoring performed quarterly to ensure appropriate health status Colony expansion
- 64. + CPI expressedon activated T lymphocytes + Harvest spleens from naïve and transgenic mice + Stimulate with PMA + Ionomycin for 24 hours + Flow cytometry analysis of activated T lymphocytes to evaluate endogenous and human CPI Verification of CPI expression in T cells of Tg mouse
- 65. FSC-A SSC-A 0 65536 196608 -2523 63644 129810 195977 262144 LM FSC-W FSC-A 065536131072 262144 0 65536 131072 196608 262144 Single_Cells CD3AF488 FITC-A Count 10 0 10 1 10 2 10 3 10 4 10 5 0 298 596 893 1191 T Cells Single Cells Lymphocytes T Lymphocytes Verification of CPI expression in T cells of Tg mouse: Gating Strategy
- 66. PD-1 PerCP-Cy5-5-A Count 10 0 10 1 10 2 10 3 10 4 10 5 0 9 19 28 37 CPI, 30.26 PD-1 PerCP-Cy5-5-A Count10 0 10 1 10 2 10 3 10 4 10 5 0 60 119 179 238 CPI, 1.75 PD-1 PerCP-Cy5-5-A Count 10 0 10 1 10 2 10 3 10 4 10 5 0 8 16 24 32 CPI, 44.59 Isotype PerCP-Cy5-5-A Count 10 0 10 1 10 2 10 3 10 4 10 5 0 10 19 29 38 CPI, 0.09 Naïve Mouse Transgenic Mouse Mouse CPI Human CPI no endogenous expression Transgene expressed Verification of CPI expression in T cells of Tg mouse CPICPI CPI
- 67. CD4 PE-A CD8V500-A -10 3 -10 2 10 3 10 4 10 5 -10 2 10 2 10 3 10 4 10 5 CD4 T CD8T CD28 PE-Cy7-A CD95V450-A -10 2 10 2 10 3 10 4 10 5 -10 2 10 2 10 3 10 4 10 5 46.72%0.38% 42.80%10.10% FoxP3 PE-A CD25PacificBlue-A -10 2 10 2 10 3 10 4 10 5 -10 2 10 2 10 3 10 4 10 5 CD4TregFoxP3 CD3+CD4+ T helper CD3+CD4+ T helper (total T) CD25 CD62L CD8 CD4 FoxP3CD44 T naive Tcm TemCD8 T CD4 T T reg Other T cell subsets evaluated for CPI expression
- 68. Rederivation •~ 3 months BreedingColony Development •~ 3 months Backcrossing Project •~ 6 months Colony Expansion •~ 5 months Receipt of Animals Conclusions 0 3 6 9 15 18 + Process is time consuming and labor intensive + Genetic testing and proper record keeping paramount to success of colony development and expansion + Provision of high quality mice approximately 17 months after initiation of project
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- 70. + Immunomodulatory biologicsare increasing in complexity + A translational approach to safety assessment with focus upon the biologics mechanism of action is essential in designing fit for purpose safety packages + Although standard species offer enormous value in determining the safety profiles of drugs that target CPIs, new approaches are being considered all the time to produce clinically translatable data + Biology…biology…biology… Summary
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