Enhanced Cancer Vaccine Effectiveness with NKTR-214, a CD122-Biased Cytokine

Enhanced Cancer Vaccine Effectiveness with NKTR-214, a CD122-Biased Cytokine Jonathan Zalevsky SVP, Biology and Preclinical Development Nektar Therapeutics SMI Cancer Vaccines, September 2017

Nektar Therapeutics San Francisco, CA Huntsville, AL Hyderabad, India 100,000-sq.ft. State-of-the-Art R&D Center 114,000-sq.ft. Manufacturing Facility 88,000-sq.ft. R&D Support Facility Biopharmaceutical company leveraging polymer conjugation technologies to develop new therapies in multiple disease areas Strong heritage of partnership with top biopharma companies ~ 450 employees R&D Center and Headquarters in San Francisco, CA Pharmaceutical Development & Manufacturing in Huntsville, AL R&D support in Hyderabad, India 2

Evolution of Nektar s Polymer Conjugation Technology R&D 2001 2003 2007 2014 Small molecule NKTR-181 Hepatitis C 2002 Neutropenia Hepatitis C Large Molecule Half-life Extension Acromegaly Chronic kidney disease anemia 2004 2008 Wet macular degeneration Crohn s Concentration in Diseased Tissue Opioid induced constipation 2015 Hemophilia A Small Molecule Compartmental Distribution NKTR-262 Biologics NKTR-214 NKTR-255 NKTR-358 Bias Receptor Activity 3

Overview An introduction to IO research at Nektar NKTR-214 CD122 biased agonist based on PEG-conjugation of IL-2 Combination of NKTR-262 + pmel-1 Melanoma Vaccine pmel-1 cell expansion and functional activation in the tumor microenvironment 4

The Immunity Cycle and Multiple Points of Intervention for I-O Therapies 4. Trafficking of T cells to tumor 3. Priming and activation 5. Infiltration of T cells into tumors 2. Cancer antigen presentation 6. Recognition of cancer cells by T cells Source: Oncology Meets Immunology: The Cancer-Immunity Cycle Chen and Mellman Immunity, Volume 39, Issue 1, 1-10 1. Release of cancer cell antigens 7. Killing of cancer cells 5

Nektar s Immuno-Oncology Strategy to Create Therapies that Cover the Immunity Cycle 4. Trafficking of T cells to tumor (CTLs) Target as many steps as possible in the cycle with as few therapies as possible 3. Priming and activation (APCs & T cells) 2. Cancer antigen presentation (dendritic cells/apcs) 5. Infiltration of T cells into tumors (CTLs, endothelial cells) 6. Recognition of cancer cells by t cells (CTLs, cancer cells) Therapies need to be accessible as medicines 1. Release of cancer cell antigens (cancer cell death) 7. Killing of cancer cells (immune and cancer cells) 6

Nektar s Immuno-Oncology Strategy to Create Therapies that Cover the Immunity Cycle 4. Trafficking of T cells to tumor (CTLs) NKTR-214 (CD122 Agonist) Target as many steps as possible in the cycle with as few therapies as possible 3. Priming and activation (APCs & T cells) 2. Cancer antigen presentation (dendritic cells/apcs) Prime, Proliferate, Activate & Increase Tumor-Infiltrating Lymphocytes (TILs), Increase PD-1 expression 5. Infiltration of T cells into tumors (CTLs, endothelial cells) 6. Recognition of cancer cells by t cells (CTLs, cancer cells) Therapies need to be accessible as medicines 1. Release of cancer cell antigens (cancer cell death) 7. Killing of cancer cells (immune and cancer cells) 7

NKTR-214: Biasing Action to CD 122, or IL-2R Beta, to Stimulate T-Cell Production Biases signaling to favor the CD122 Receptor (IL- 2Rβγ complex) NKTR-214 Eliminates overactivation of IL-2 pathway that results in serious safety issues CTLs CD8+ T-Cells and NK Cells T regs CD4+ Regulatory T-Cells Achieves antibody-like dosing schedule in outpatient setting Stimulates Immune Response to Kill Tumor Cells Down-Regulates Proliferation of CD8+ T-cells and Suppresses Immune Response 8

NKTR-214 Is A CD122-biased Cytokine, Designed To Improve Efficacy And Mitigate Toxicity of the IL-2 Pathway IL-2 Structural model of IL-2 docked with IL-2Rαβγ IL-2Rα (CD25) NKTR-214 High molecular weight hydrolyzable polymers located at strategic sites IL-2Rβ (CD122) IL-2: purple IL-2Rβ: cyan IL-2Rα: blue IL-2Rγ: green IL-2Rγ (CD132) IL-2 cytokine core rhil-2, same amino acid sequence as clinically validated molecule (aldesleukin) 9

NKTR-214: Biased Signaling And Prodrug Design To Improve Risk/Benefit Profile NKTR-214 (essentially inactive) % Phospho-STAT5 Charych, D., et al. AACR 2013, Abstract #482 10

NKTR-214: Biased Signaling And Prodrug Design To Improve Risk/Benefit Profile NKTR-214 (essentially inactive) Active Species (Biased signaling, increased potency with fewer PEGs) % Phospho-STAT5 Charych, D., et al. AACR 2013, Abstract #482 11

NKTR-214: Biased Signaling And Prodrug Design To Improve Risk/Benefit Profile NKTR-214 (essentially inactive) Active Species (Biased signaling, increased potency with fewer PEGs) % Phospho-STAT5 Charych, D., et al. AACR 2013, Abstract #482 12

NKTR-214: Biased Signaling And Prodrug Design To Improve Risk/Benefit Profile NKTR-214 (essentially inactive) Active Species (Biased signaling, increased potency with fewer PEGs) % Phospho-STAT5 Charych, D., et al. AACR 2013, Abstract #482 13

NKTR-214 Mechanism of Action Delivers a Controlled and Biased Signal to the IL-2 Pathway In mice, a single dose of NKTR-214 gradually builds and sustains pstat5 levels through seven days postdose. In contrast, IL-2 produces a rapid burst of pstat that declines four hours post-dose. pstat5 is a biomarker of IL-2 receptor target engagement. pstat5= signal transducer and activator of transcription 5 p=phosphorylated (activated) Charych, D., et al. AACR 2013, Abstract #482 C57BL/6 mice were treated with either one dose of NKTR-214 (blue) or aldesleukin (red); blood samples were collected at various time points postdose. pstat5 in peripheral blood CD3+ T cells was assessed using flow cytometry. Top graph is an inset showing the 0-4 hour time period. Bottom graph shows the full 10 day time course of the experiment. Histograms on right depict pstat5 MFI for IL-2 (red) and NKTR-214 (blue) 14

NKTR-214 Increases The Quality And Quantity Of The T-cell Response in Mice Mouse melanoma model CD8/Treg ratio 1600 1400 1200 1000 800 600 400 200 0 * * treatment duration Total CD8 / Treg ratio 0 2 4 6 8 10 12 14 16 Days > 400-fold increased ratio of CD8 to Treg cells B16F10 melanoma, C57Bl/6 mice; N=9-12/group NKTR-214, 2mg/kg i.v. q9dx3; Aldesleukin, 3mg/kg i.p. bidx5, 2 cycles *, p<0.05, ANOVA with Tukey s post-test (left) or Log-Rank (right) w.r.t. vehicle, p<0.05, Student s T-test (left) or Log-Rank (right) w.r.t. Aldesleukin 15

NKTR-214 Selectively Grows T Cells, NK Cells in Tumor Microenvironment in Cancer Patients Analysis of T cell Populations in Tumor 40 29.8 30 20 10 1.6 0 CD8 Tregs NKTR-214 drives immune activation in the tumor Increase in total T cells, NK and CD8 T cells No increase in Tregs Increase in PD-1 positive CD8 T cells Increase in newly proliferating CD8 T cells Activation and expression of anti-tumor genes Change in T cell clonality in the tumor Fold change expressed as Week 3 / predose Shown are results from N=10 patients 16

Nektar s Immuno-Oncology Strategy to Create Therapies that Cover the Immunity Cycle 4. Trafficking of T cells to tumor (CTLs) NKTR-214 (CD122 Agonist) 3. Priming and activation (APCs & T cells) Prime, Proliferate, Activate & Increase Tumor-Infiltrating Lymphocytes (TILs), Increase PD-1 expression 5. Infiltration of T cells into tumors (CTLs, endothelial cells) 2. Cancer antigen presentation (dendritic cells/apcs) Checkpoint Inhibitors 6. Recognition of cancer cells by t cells (CTLs, cancer cells) 1. Release of cancer cell antigens (cancer cell death) 7. Killing of cancer cells (immune and cancer cells) 17

NKTR-214: Combination With Anti-PD-1 Consistently Produces Durable Responses in Mice Long-term survival Colon Cancer Model Long-term survival Breast Cancer Model 100 * NKTR-214 + Anti PD-1 100 75 75 50 25 Vehicle Anti-CTLA-4 Anti PD-1 Anti CTLA-4 + Anti PD-1 * 50 25 * NKTR-214 + anti-pd-1 NKTR-214 0 0 20 40 60 80 100 Days anti-ctla-4 + anti-pd-1 0 0 20 40 60 80 Days NKTR-214 + anti-pd-1 is superior to anti-ctla-4 + anti-pd-1 CT26 colon carcinoma, Balb/c mice, N=10/group Anti-CTLA-4, 100µg i.p., twice-weekly; Anti-PD-1, 200µg i.p., twice weekly NKTR-214, 0.8mg/kg i.v. q9dx3 *, p<0.05, ANOVA with Tukey s post-test (left) or Log-Rank (right) w.r.t. vehicle EMT6 breast carcinoma, Balb/c mice, N=10/group Anti-CTLA-4, 100µg i.p., twice-weekly; Anti-PD-1, 200µg i.p., twice weekly NKTR-214, 0.8mg/kg i.v. q9dx3 *, p<0.05, ANOVA with Tukey s post-test (left) or Log-Rank (right) w.r.t. vehicle 18

NKTR-214 Drives Greater T-cell Expansion And T-Cell Clonality in Mice 1600 1400 1200 1000 800 600 400 200 0 NKTR-214 + apd-1 ImmunoSeq Data (in collaboration with Adaptive Biotechnologies) NKTR-214 + apd-1 0 5 10 15 20 25 30 35 1800 Days Mean Tumor Volume (mm 3 ) 1600 1400 1200 1000 800 600 400 200 NKTR-214 + actla4 actla4 + apd-1 NKTR-214 + actla4 NKTR-214 0 0 5 10 15 20 25 30 35 Days actla4 + apd-1 Vehicle actla-4 apd-1 19

Harnessing the IL-2 Pathway the Right Way to Increase TILs Prodrug (inactive) Prodrug design to enable safe, outpatient dosing Q2w or Q3w Active cytokine species bias signaling through the heterodimeric IL-2 receptor pathway (IL- 2Rβγ) Biased and sustained signaling to preferentially activate and expand effector CD8+ T and NK cells over Tregs in the tumor microenvironment Currently in multiple clinical trials NKTR-214 + checkpoint Combo with nivolumab: 14 tumor types Combo with pembrolizumab in 2 tumors Combo with atezolizumab in 2 tumors Other NKTR-214 combination trials to begin 2018 20

Nektar s Immuno-Oncology Strategy to Create Therapies that Cover the Immunity Cycle 4. Trafficking of T cells to tumor (CTLs) NKTR-214 (CD122 Agonist) Target as many steps as possible in the cycle with as few therapies as possible 3. Priming and activation (APCs & T cells) 2. Cancer antigen presentation (dendritic cells/apcs) Prime, Proliferate, Activate & Increase Tumor-Infiltrating Lymphocytes (TILs), Increase PD-1 expression Vaccine Model Provide Antigens Activate Dendritic Cell Response 1. Release of cancer cell antigens (cancer cell death) 7. Killing of cancer cells (immune and cancer cells) 5. Infiltration of T cells into tumors (CTLs, endothelial cells) 6. Recognition of cancer cells by t cells (CTLs, cancer cells) Checkpoint Inhibitors Therapies need to be accessible as medicines 21

Melanoma Vaccine Mouse Model to Study NKTR-214 Pmel-1 cancer vaccine developed by Overwijk and Rosenberg Pmel-1 cells adoptive transfer + peptide vaccination for killing B16F10 tumors IL-2 is essential for driving anti-tumor pmel-1 response Vaccine Vaccine + IL-2 Pmel-1 are genetically marked killer T cells Easy to track in tumor and blood Responsive to anti-melanoma vaccine Kill melanoma cells Use model to study effect of NKTR-214 o o o o o Overwijk et al. JEM 2003 Adoptive transfer of gp100-specific Pmel-1 cells Gp100 peptide (50 ug/mouse)-l-tyr (adjuvant) anti CD40 (50 ug/mouse) TLR-7 agonist (Imiquimod- 5 mice/pack) Recombinant IL-2 (100,000 IU X 5 doses_ Day 0, D1 and D2) or NKTR-214 (0.2mg/kg) 22

Evaluation of NKTR-214 in Pmel-1 Vaccine Model 1. No treatment 2. Aldesleukin 3. NKTR-214 4. Vaccine 5. Vaccine + Aldesleukin (IL-2) 6. Vaccine + NKTR-214 Pmel-1 Cell Transfer Vaccine = gp100 peptide + anti-cd40 + TLR-7 agonist Aldesleukin (IL-2) 100,00 IU b.i.d_d0,d1,d2_q8d NKTR-214-0.2 mg/kg_q8d Collaboration with Meenu Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 23

NKTR-214 More Effective that Aldesleukin to Delay Tumor Growth in Mouse Melanoma Vaccine Model M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 24

NKTR-214 Promotes Massive Pmel-1 Cell Expansion After Vaccination p= <0.001 NKTR-214-vaccine significantly enhanced Pmel-1 T cell response as compared to Aldesleukin-vaccine M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 25

NKTR-214 Vaccine Combination Superior to Aldesleukin for Pmel-1 CD8 T Cell Expansion in Tumor and Spleen Number of Thy1.1+ CD8 T cells / gram of tumor 600000 400000 200000 Untreated Vaccine Vaccine + Aldesleukin Vaccine + NKTR-214 Tumor *** 0 D3 D5 D7 D10 Days after vaccination M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center Untreated Vaccine Vaccine + Aldesleukin Vaccine + NKTR-214 Number of Thy1.1+ CD8 T cells /Spleen No Tx Vaccine 2000000 Vaccine + Aldesleukin Untreated Vaccine + NKTR-214 Vaccine Vaccine + Aldesleukin 1500000 Vaccine + NKTR-214 *** 1000000 500000 *** Spleen *** 0 D3 D5 D7 D10 Days after vaccination 26

NKTR-214 Promotes Higher Pmel-1/Treg Ratio than Aldesleukin in Tumor and Spleen ure 5 Day 3 No Treatment Vaccine Vaccine + Aldesleukin Vaccine +NKTR-214 B Day 3 Day 5 Day 5 Day 7 Day 7 Day 10 Day 10 0 1000 2000 3000 4000 Pmel-1/Tregs (Tumor) 0 50 100 150 Pmel-1/Tregs (Spleen) M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 27

NKTR-214 Preferentially Drives Pmel-1 Proliferation Day 7 As compared to Vaccine alone and aldesleukin-vaccine combination, NKTR-vaccine treatment significantly maintained higher proliferation of Pmel-1 T cells and lower proliferation of Tregs in tumor as well as in spleen M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 28

NKTR-214 Preferentially Promotes Pmel-1 Survival Day 7 In tumor, addition of NKTR-214 to vaccine reduced annexin V expression on Pmel-1 and enhanced it on Tregs though no significant change was exhibited in Aldesleukin-Vaccine treatment group In contrast to tumor, Annexin V expression in spleen was reduced on both Pmel-1 T cells and Tregs, in NKTR-vaccine group as compared to vaccine alone M. Sharma, Willem Overwijk Laboratory, MD Anderson Cancer Center 29

Summary and Conclusions NKTR-214 is a CD122-biased agonist that effectively activates the IL-2 receptor pathway in preclinical and clinical settings Addition of NKTR-214 to peptide vaccine drives enhanced Pmel-1 T cells in tumor as well as in spleen NKTR-214 is better than Aldesleukin in stably maintaining high CD8+ (Pmel-1 cells) and low Treg numbers in tumor At the peak of Pmel-1 response on day 7, number of Tregs dramatically reduced in tumor of NKTR-vaccine treated group Relative expression of Ki67 and Annexin V indicated that NKTR-vaccine treatment supports proliferation and survival of Pmel-1 T cells in tumor as well as in spleen Reduced proliferation and moderately enhanced apoptosis in intratumoral Tregs, seem to contribute to observed low number of Tregs in tumor of NKTR-vaccine treated mice 30