Nektar Therapeutics · NASDAQ:NKTR
Nektar Therapeutics — Technical Presentation (November 2020)
22 slides from Nektar Therapeutics's technical presentation, Nov 19, 2020
Slide 1: Restoring NK Cell Activities in Multiple Myeloma with IL-15 Receptor Agonist NKTR-255
Restoring NK Cell Activities in Multiple Myeloma with IL-15 Receptor Agonist NKTR-255 Rafael Alonso Fernández, Laetitia Pierre-Louis, Yan Xu, Shidai Mu, Joaquín Martínez-López, Takahiro Miyazaki, Rao Prabhala, Kenneth C Anderson, Loui Madakamutil, Nikhil C Munshi and Mariateresa Fulciniti
Slide 2: Conflict of Interest
Conflict of Interest • Nothing to disclose
Slide 3: Background
Background Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development through the activation of cells with a suppressive effect, disruption of antigen presentation and dysregulation of proliferation and functionality of effector cells. Natural
Slide 4: The Challenge to Therapeutic Use of IL-15
The Challenge to Therapeutic Use of IL-15 IL-15 and IL-2 belong to the same cytokine family, yet important differences exist. IL-15 promotes proliferation and cytotoxicity of NK cells, NKT cells, γ/δ T cells or memory CD8+ T cells, enhancing innate and adaptive immunity against MM cells in pre-c
Slide 5: NKTR-255: an IL-15-based Therapeutic for Immuno-Oncology
NKTR-255: an IL-15-based Therapeutic for Immuno-Oncology NKTR-255 is a novel immunotherapeutic agent consisting of polymer-engineered (PEG) IL-15 designed to optimally engage all three IL-15 receptors (IL-15R) accessing the full spectrum of IL-15 biology. Design goals: Improve PK and PD to sustain
Slide 6: Major Aims of the Study
Major Aims of the Study Evaluate changes in the expression profile of inhibitory and activating markers on NK cells after treatment with NKTR- 255. Test the ex vivo enhancement of NK cell effector functions (degranulation, cytokine release, direct cytotoxicity or ADCC) to target MM cells followi
Slide 7: NKTR-255 Shifts the Balance of Stimulatory Receptors vs Inhibitory Receptors on NK Cells from MM Patients
NKTR-255 Shifts the Balance of Stimulatory Receptors vs Inhibitory Receptors on NK Cells from MM Patients Follow-up of receptor surface expression of NK cells from MM after administration of NKTR-255 Activating receptors Inhibitory receptors Fold change in MFI compared with baseline 20 20 NKp30 LAG3
Slide 8: NKTR-255 Increases Ex Vivo Expression of Stimulatory Receptors and Activation Markers on NK Cells
NKTR-255 Increases Ex Vivo Expression of Stimulatory Receptors and Activation Markers on NK Cells Follow-up of receptor surface expression of NK cells from MM after administration of NKTR-255 Other activation markers Fold change in MFI compared with baseline CD69 20000 CD57 10000 100 50 0 0 1 3 5 7
Slide 9: NKTR-255 Tilts the Balance Towards a More Activated Phenotype on NK Cells
NKTR-255 Tilts the Balance Towards a More Activated Phenotype on NK Cells and Promotes Expansion of Activated NK Cells Variation of NKG2D+ NK cell number over baseline after 5 days of incubation with NKTR-255 in PBMC from 9 MM patients Tracking of NKG2D expression (MFI) on NK cells along 14 days of
Slide 10: MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production
MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production in Response to Tumor Targets After Treatment with NKTR-255 Collection of PBMCs from MM patients Degranulation assay Incubation with NKTR-255 x 7 days 20 NK NK+U266 6 NK NK+H929 compared to isotype control compared to iso
Slide 11: MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production
MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production in Response to Tumor Targets After Treatment with NKTR-255 Collection of PBMCs from MM patients 2000 600 NK NK+U266 NK NK+KMS26 Interferon γ (pg/mL) Interferon γ (pg/mL) *** ** * 1500 *** 400 Incubation with NKTR-255 x 7
Slide 12: MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production
MM Patient Derived NK Cells Show Improved Degranulation and Cytokine Production in Response to Tumor Targets After Treatment with NKTR-255 Collection of PBMCs from MM patients 2000 600 NK NK+U266 NK NK+KMS26 Interferon γ (pg/mL) Interferon γ (pg/mL) *** ** * 1500 *** Incubation with NKTR-255 x 7 day
Slide 13: Dose and T:E Ratio-Dependent Increase in NK Cytotoxicity After Administration of NKTR-255
Dose and T:E Ratio-Dependent Increase in NK Cytotoxicity After Administration of NKTR-255 Collection of PBMCs from MM patients 100 Target cell lysis (%) Incubation with NKTR-255 x 7 days T: KMS12BM over background E: HD NK 0.01 80 Isolation of NK cells 0.1 NKTR-255 60 1 (µg/mL) Stimulated NK cells +
Slide 14: NKTR-255 Enhances Anti-Tumor Responses of Human NK Cells Against MM Cell Targets
NKTR-255 Enhances Anti-Tumor Responses of Human NK Cells Against MM Cell Targets Assessment of NK cytotoxicity against MM cells after 4-hour co-incubation of NK and MM cells U266 (T:E ratio 1:8) H929 (T:E ratio 1:5) KMS12BM (T:E ratio 1:2) * 50 *** ns ** ns 25 20 * * Target cell lysis (%) *** over b
Slide 15: NKTR-255 Enhances Anti-Tumor Responses of Human NK Cells Against MM Cell Targets
NKTR-255 Enhances Anti-Tumor Responses of Human NK Cells Against MM Cell Targets Assessment of NK cytotoxicity against MM cells after 4-hour co-incubation of NK and MM cells U266 (T:E ratio 1:8) H929 (T:E ratio 1:5) KMS12BM (T:E ratio 1:2) *** * 50 25 ns 20 ** ns * * Target cell lysis (%) *** over b
Slide 16: NKTR-255 Increases Daratumumab or Elotuzumab-Mediated ADCC
NKTR-255 Increases Daratumumab or Elotuzumab-Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) Assessment of NK ADCC after 4-hour co- incubation of NK and Elo/Dara pre-treated MM cells
Slide 17: No Direct Effect of NKTR-255 or Recombinant Human IL-15 on Growth and Viability of MM Cells
No Direct Effect of NKTR-255 or Recombinant Human IL-15 on Growth and Viability of MM Cells Viability assessment of 5 MM cell lines after 10 days of incubation with maximal doses of NKTR-255/IL-15 2.0 2.0 Control Control compared to control compared to control NKTR-255 IL-15 1.5 1000 ng/mL 1.5 100 n
Slide 18: A Humanized Mouse MM Model Was Employed for the In Vivo Studies
A Humanized Mouse MM Model Was Employed for the In Vivo Studies Subcutaneous engraftment with 5x106 NCI-H929 cells Human CD34+ hematopoietic stem cells DAY 0 Tumor volume >50 mm3 End-point: tumor volume >1500 mm3 Collection of blood, spleen and tumor tissue Recombinant human -Daily monitoring of une
Slide 19: NKTR-255 Enhances the Anti-MM Activity of Daratumumab in the Humanized Mouse Model of MM
NKTR-255 Enhances the Anti-MM Activity of Daratumumab in the Humanized Mouse Model of MM 1200 Vehicle Daratumumab When tumors reached an average volume of 50 mm3, Tumor volume (mm3) NKTR 255 800 mice were randomized (n=5 per cohort) to receive: Daratumumab + NKTR 255 -Vehicle -Daratumumab 5 mg/kg
Slide 20: NKTR-255 Improves Immune Status Following Anti-CD38 Treatment
CD4+ T Cells(103 cells/ul) %CD38+ CD4 T cells 0 10 20 30 40 50 0 1000000 2000000 3000000 4000000 V V D eh D eh ar ic ar at at ic um le um le um um N ab N ab K * D * D KT ar TR ar R a -2 at -2 + um 55 +N tum 55 N K um TR K um a * TR a -2 b b 55 25 5 * CD8+ T Cells(103 cells/ul) %CD38+ CD8 T cells 0 2
Slide 21: Conclusions
Conclusions 1) The induction of an activated profile in NK cells by NKTR-255 results in an effective enhancement of their anti-myeloma effector functions (direct cytotoxicity, degranulation, cytokine release, aDCC) in ex vivo assays. 2) In vivo studies confirmed superiority of the combination of dar
Slide 22: Acknowledgements
Acknowledgements Dr. Nikhil C Munshi Dr. Joaquín Martínez-López Mariateresa Fulciniti Antonio Valeri Laetitia Pierre-Louis Almudena García-Ortiz Shidai Mu Jessica Encinas Yan Xu Elena Maroto Martín Sanika Derebail José María Sánchez-Pina Clara Cuéllar All lab members Takahiro Miyazaki All lab and cl
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