Design and Development of Cell-Based Potency Assays for Biologics Targeting T-Cell Co-Stimulation and Co-inhibition Pathways
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1 Design and Development of Cell-Based Potency Assays for Biologics Targeting T-Cell Co-Stimulation and Co-inhibition Pathways Shihua Lin, PhD. Senior Scientist Analytical Biotechnology Development, MedImmune One MedImmune Way, Gaithersburg, MD April 4-5, 2016 Silver Spring, MD
2 Outline of today s talk Introduction: T cell & Cancer immunotherapy Understanding T cell co-signaling molecules and pathways Cell-based potency assay for therapeutic biologics Design and Development of improved cell-based assays for biologics targeting: T cell co-stimulation pathways T cell co-inhibition pathways 2
3 Introduction T Cell Anti-Cancer Responses 4 T cells can recognize tumor antigens but its anti-cancer responses are suppressed via 1) T cell-intrinsic mechanisms such as expression of checkpoint proteins (PD-1, CTLA-4) lead to T cell exhaustion, 2) tumor-intrinsic mechanisms such as secretion of suppressive factors, and 3) suppressive cells such as Treg cells and tumor-associated macrophages. Adopted from Rambam Maimonides Med J Jan; 6(1): e0004
4 T cell and Cancer immunotherapy T cells play a central role in cell-mediated immunity in the body Therapy that targets T cell signaling pathways is now a major field of immunotherapy for a number of diseases The successful use of CTLA4 fusion proteins (abatacept, belatacept) for the treatment of RA represents an important milestone in this field Approval of CTLA4-Ab (ipilimumab) provides clear evidence for the efficacy of immunotherapy targeting T cell co-signaling Positive clinical results of PD1 (Keytruda ) and B7-H1 Abs provide significant impact on the trends of cancer drug development 4 New therapy strategies are being developed to target one or more T cell co-signaling molecules/pathways.
5 T cell function and co-signaling T cell function regulation Two-signal model (MHC/TCR, Co-signaling) Definition of T cell co-signaling -- Cell surface molecules that transduce signals into T cells to modulate TCR and other signaling T cell co-signaling receptors often colocalize with TCR at the immunological synapse T cell co-signaling regulation is determined by the type of ligands and counter receptors Co-signaling ligands and counter-receptors have now been identified on nearly all cell types 6
6 T cell co-signaling pathways T cell co-signaling Co-stimulation Co-inhibition Main co-signaling receptors for T cells: Immunoglobulin (Ig) superfamily: - CD28 and B7 families TNF receptor superfamily: - CD27, CD134, GITR 6 Co-signaling molecules have a crucial role: Regulation of T cell activation Subset differentiation Survival and proliferation Effector functions
7 Downstream pathways of T cell co-signaling Downstream of co-stimulation Downstream of co-inhibition T cell co-stimulation and co-inhibition share some downstream pathways 7 8 Nat Rev Immunol. 13(4): (2013)
8 Understanding of T cell co-signaling is evolving Co-stimulation receptors Co-inhibition receptors 9 Nat Rev Immunol. 13(4): (2013) 8
9 Cell-based potency assay for therapeutic biologics Conventional potency assays: Assessing Fab and Fc function using 2 or more assays Release assay Use a target-expressing cell line to evaluate drug potency --- focus on Fab portion only Characterization assay Use a binding assay and/or cellbased assay to evaluate Fc effector function --- focus on Fc portion only T Y Adapted from wikipedia 10 Conventional potency assays: Evaluate Fab and Fc function separately Do not mimic in vivo condition
10 Considering in vivo environment Expression of FcR is found on most blood cells FcRs CD Distribution FcγRI CD64 Monocyte, macrophage, DC, neutrophil, eosinophil FcγRII CD32 Monocyte, macrophage, DC, platelet, neutrophil, NK FcγRIII CD16 Monocyte, macrophage, DC, neutrophil, eosinophil, mast cell, NK D P M NK N T Y Eo B Mac Adapted from wikipedia 11 Adapted from wikipedia Target cells are surrounded by various blood cells. Therapeutic biologics interact with target cells (via Fab) and FcRs expressing cells (via Fc).
11 Assay design for T cell co-stimulating biologics (1) 1. One-cell method 2. One-cell plus stimulator AbX Target Receptor Y TCR p/gene Luc YYYY Y Y AbX TCRL Target Receptor TCR p/gene Luc Engineered target cell with reporter gene Target cell plus plate-bound cross-linking 3. Two-cell method Effecter cell Target cell FcRs Y AbX Target Receptor p/gene Luc TCR 12 FcR expressing effector cell and engineered target cell
12 Assay design for T cell co-stimulating biologics (2) 4. Two-cell plus (2-Cell + ) assay: 2-Cell + Assay = Effector cell + Target cell + Co-stimulator Effector Target Receptor Target FcRs AbX Y Y TCRL TCR p/gene Luciferase 13 Key features: Engage drug s Fc and Fab function in one assay. Add 2 nd stimulator to enhance co-signaling activation.
13 Development of 2-cell + bioassay for T cell co-stimulating biologics Assay Procedures 1 2 Prepare assay buffer Serially dilute AbX RLU Add AbX dilutions Add target & APCs Incubate at 37 C Add Steady-Glo and read plates TCRL 100x TCRL 10x TCRL 1x TCRL TCRL [AbX] Cell Assay Cell + Assay Cell Assay AbX induced strong T cell activation signals in 2-cell + system. 2-Cell + Assay = Effector cell + Target cell + Co-stimulator 13
14 Assay performance of 2-cell + assay Linearity Stability sample testing RP% of stressed samples Observed RP% RLU [Ab] RLU Specificity testing O RS Control AbX Anti-CD16 Anti-CD64 O Formulation buffer 15 Expected RP% [Ab] The assay also has high accuracy and precision. 2-Cell + Assay = Effector cell + Target cell + Co-stimulator
15 Characterization of 2-cell + assay (1) AbX with different Fc formats (IgG1 vs. IgG4) Drugs Fab Fc IgG1 vs. IgG4 AbX (IgG1) Fab + Fc AbX (IgG4) Target cell Effector cell AbX-hIgG1 RLU AbX-hIgG4 [Ab] 16 2-Cell + assay is capable of distinguishing AbX molecules in different IgG formats. 2-Cell + Assay = Effector cell + Target cell + Co-stimulator
16 Characterization of 2-cell + assay (2) TCRL (intact) vs. Enzyme digested TCRL Enzyme TCRL (Ab) Fab + Fc Effector Target Receptor Target FcRs AbX Y YTCRL? TCR p/gene Luciferase RLU 2-Cell Assay 2-Cell + Assay (w/ TCRL) 2-Cell + Assay (w/ Enzyme digested TCRL) 17 [Ab] Binding of TCRL to TCR plays an important role on T cell activation. 2-Cell + Assay = Effector cell + Target cell + Co-stimulator
17 2-cell + vs. Other formats for T cell co-stimulating biologics 1-Cell Assay 1-Cell + Costimulator 2-Cell Assay 2-Cell + Assay Assay Design Target cell only Target cell Co-stimulator Target cell Effecter cell Target cell Effecter cell Co-stimulator Engage Fab & Fc? No No (no FcR involved) Yes Yes Signal? Easy to perform? MOA Reflective? Yes for target molecule No for T cell costimulation Yes for target molecule Yes for T cell costimulation Yes for target molecule No for T cell costimulation Yes for target molecule Yes for T cell co-stimulation 18 Compared to one-cell assays, the 2-cell + assay is one step closer to mimicking in vivo conditions.
18 Assay design for T cell co-inhibitory biologics MOA of AbY AbY Ligand Assay Procedures 1 Prepare assay buffer 2 Serially dilute AbY APC Assay Design B7 MHC B7 AbY Target TCR CD28 p/gene Luc Target cell Add AbY dilutions Add target & APCs Incubate at 37 C Add Steady-Glo and read plates 19 Stimulator
19 Assay development for T cell co-inhibitory biologics Time course 1 Time course 2 RLU RLU StdCu e Specificity Assay characterization RS Ctrl RLU RS AbY Other Ab1 Other Ab2 RLU No stimulator No AbY No APC No Target Other Ab3 [Ab] [Ab] 20 The assay has been validated with good Accuracy, Linearity, and Precision. The assay is also robust, stability indicative, and product specific.
20 Summary A potency assay should be product-specific and reflect the MOA. Since full activation of T cells often requires the interaction of two or more-signals, co-signaling pathway(s) should be considered during assay design and development. For T cell co-stimulating biologics, conventional one-cell potency assays tend to be oversimplified, the 2-cell + assay shown here is: Capable of monitoring Fab and Fc in one assay MOA-reflective for target molecule MOA-reflective for T cell co-stimulatory property Closer to in vivo conditions (compared to conventional assays) For T cell co-inhibitory biologics, the 2-cell + format also shows improved assay performance, and reflects T cell co-inhibitory property. 21
21 Acknowledgements Nick Santistevan Lian Tao Tianmeng Shao Weimin Chen Vicky Bushman Jing Zhao Jack Yang Yuan Chang Xu-Rong Jiang Mike Washabaugh Kripa Ram Bioassay group at MedImmune 22
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