TNF Superfamily Receptor Modulators Innovative Immuno-Oncology Therapeutics BioRN Lounge,

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1 TNF Superfamily Receptor Modulators Innovative Immuno-Oncology Therapeutics BioRN Lounge, Dr. Juergen Gamer, VP Business Development 1

2 Overview 1 Clinical stage immuno-oncology company focusing on best-in-class protein therapeutics 2 Apogenix was founded in Spin-out of the German Cancer Research Center - Located in Heidelberg, Germany - Financed by dievini (Dietmar Hopp), licensing deals and public grants 3 Apogenix has formed a network of partners - Academic collaborations with intl. institutions - Licensing partners Abbvie & CANbridge - Service & business partners 4 Apogenix has built an attractive IO pipeline with two assets in clinical development - Asunercept (CD95L checkpoint inhibitor), positive data from PII in GB and PI in MDS - HERA-TRAIL (TRAIL receptor agonist) in Phase I study - HERA-ligands in preclinical development June 2018 Apogenix AG TNF Superfamily Modulators 2

Cancer and Immune System The immune system is an efficient defense

suppressive molecules MDSC T reg cell However, under constant vigilance

evading the anti-tumor immune response Adapted from Yarchoan et al.

3 Cancer and Immune System The immune system is an efficient defense mechanism to eliminate tumor cells T eff cell NK cell Immune suppressive molecules MDSC T reg cell However, under constant vigilance of the immune system, tumor cells adapt and are able to form tumors by evading the anti-tumor immune response Adapted from Yarchoan et al. Nature Review Cancer : June 2018 Apogenix AG TNF Superfamily Modulators 3

Implications Development PD-1 Inhibitor Nivolumab From Bench to Bedside in 22 Years Discovery & Preclinical Phase I Phase II Phase III 1992 PD-1 gene discovered at Kyoto University 1994 Inhibitors of

4 Implications Development PD-1 Inhibitor Nivolumab From Bench to Bedside in 22 Years Discovery & Preclinical Phase I Phase II Phase III 1992 PD-1 gene discovered at Kyoto University 1994 Inhibitors of PD-1 patented by Ono 2002 PD-L1 expressed on tumor cells Anti PD-1 mabs have preclincial anti-tumor efficacy 2006 FiH 2009 Start PII 2013 Start PIII 2014 FDA / JP approval Publications 1,346 publications PD-1/PD-L1 5 approved drugs 126 in development Clinical trials 1,269 active trials June 2018 Apogenix AG TNF Superfamily Modulators 4

Immunosuppression in Tumor Microenvironment Heterogeneity regarding tumor microenvironment (TME) and immune cell infiltrates in tumors is observed The pre-existing immune landscape within the TME

5 Immunosuppression in Tumor Microenvironment Heterogeneity regarding tumor microenvironment (TME) and immune cell infiltrates in tumors is observed The pre-existing immune landscape within the TME seems to be of prognostic value in multiple malignancies CD3+ T cells (green), tumor marker (magenta) Lieke et al. Trends in Cancer, November 2017, Vol. 3, No. 11 June 2018 Apogenix AG TNF Superfamily Modulators 5

TNF Receptor Superfamily in Cancer Therapy Members of the TNF receptor/ligand family are key modulators of the immune response and attractive targets in immuno-oncology Apogenix TNF SF

presentation OX40 and immune cell GITR activation LIGHT CD27 CD40 CD40 Trafficking of tumor antigens to the lymph node T cells Lymph node Blood vessel Adoptive Cell Therapies Cancer Vaccines

6 TNF Receptor Superfamily in Cancer Therapy Members of the TNF receptor/ligand family are key modulators of the immune response and attractive targets in immuno-oncology Apogenix TNF SF modulators are ideal candidates for combination with other IO approaches such as cancer vaccines, cell therapies or checkpoint inhibitors Receptor Agonists HERA-Ligands 4-1BB Antigen presentation OX40 and immune cell GITR activation LIGHT CD27 CD40 CD40 Trafficking of tumor antigens to the lymph node T cells Lymph node Blood vessel Adoptive Cell Therapies Cancer Vaccines (e.g. mrna) TRAIL Direct killing of tumor cells Tumor PD-1 Ligand CD95 Ligand Kills activated immune cells (AICD) CD95L Inhibitor Asunercept PRIME Status June 2018 Apogenix AG TNF Superfamily Modulators 6

7 HERA-Ligands June 2018 Apogenix AG TNF Superfamily Modulators 7

First Generation TNF SF Receptor Agonists: TNFR SF Receptor Antibodies Have a Complex MoA Binding of a

Anti-tumor efficacy of agonistic antibodies is based on a complex mixture of FcR-mediated activities

activity Agonistic mabs induce multiple activities Clustering Backsignaling Stimulation Stimulation

$aggregates 2 Cell viability assay of cancer cells with fractionated anti-trailreceptor antibodies$

8 First Generation TNF SF Receptor Agonists: TNFR SF Receptor Antibodies Have a Complex MoA Binding of a trimeric ligand induces TNF SF receptors multimerisation, thereby triggering receptor activation Anti-tumor efficacy of agonistic antibodies is based on a complex mixture of FcR-mediated activities inducing opposite effects and potential safety issues Nature Monomeric mabs have low agonistic activity Agonistic mabs induce multiple activities Clustering Backsignaling Stimulation Stimulation CD40 TNF SF Ligands TNF SF Receptors Immune Cell a-dr5 mab monomer a-dr5 mab aggregates 1 a-dr5 mab aggregates 2 Cell viability assay of cancer cells with fractionated anti-trailreceptor antibodies Stimulation ADCC CDC Gieffers et al. Mol Cancer Ther; 12(12) December 2013 June 2018 Apogenix AG TNF Superfamily Modulators 8

VL VL NH 2 HERA-Ligands Best-In-Class TNF Receptor SF Agonists Goal: Design a receptor agonist with defined, stabilized trimerization capabilities This versatile

HERA-ligands HERA-ligands Design HERA-ligands have potent agonistic activity Next generation HERA-ligands HERA-TRAIL / ABBV621 COOH COOH C H3 C H3 C H2 C H2 NH 2

NH 2 C H2 C H2 NH 2 NH2 C L COOH NH C H2 C 2 H2 NH 2 V H C H1 V H C H1 C L COOH NH2 Cell viability assay of cancer cells with monomeric HERA-ligands Stimulation

9 VL VL NH 2 HERA-Ligands Best-In-Class TNF Receptor SF Agonists Goal: Design a receptor agonist with defined, stabilized trimerization capabilities This versatile platform allows realization of various agonistic protein formats Apogenix HERA-ligands mechanism of action purely relies on their potent agonistic activity HERA-ligands HERA-ligands Design HERA-ligands have potent agonistic activity Next generation HERA-ligands HERA-TRAIL / ABBV621 COOH COOH C H3 C H3 C H2 C H2 NH 2 Singlechain TNF SF Ligand HERA- TRAIL + xlink HERA-TRAIL (monomer) NH2 V L V H NH 2 COOH COOH COOH COOH C H3 C H3 C H3 C H3 COOH C L C H1 COOH COOH NH 2 NH 2 COOH NH 2 C H2 C H2 NH 2 NH2 C L COOH NH C H2 C 2 H2 NH 2 V H C H1 V H C H1 C L COOH NH2 Cell viability assay of cancer cells with monomeric HERA-ligands Stimulation Trivalent, Targeting Hexavalent, non-fc Hexavalent Fc Hexavalent Fc Targeting Gieffers et al. Mol Cancer Ther; 12(12) December 2013 June 2018 Apogenix AG TNF Superfamily Modulators 9

HERA-Ligands Production HERA-ligands are produced as homogenous, non-aggregating proteins in physiological buffers 4-1BBL Features: Hexavalent TNF receptor agonists, 140-180 kd Production process:

10 HERA-Ligands Production HERA-ligands are produced as homogenous, non-aggregating proteins in physiological buffers 4-1BBL Features: Hexavalent TNF receptor agonists, kd Production process: CHO based fed batch suspension culture Receptor interaction: Verified by various methods (ELISA*, QCM*, FACS*) Analytics prior to biological characterization: Endotoxin, residual DNA-content, host cell protein *QCM: Quartz Crystal Microbalance; FACS: fluorescence-activated cell scanning; ELISA: Enzyme-linked Immunosorbent Assay June 2018 Apogenix AG TNF Superfamily Modulators 10

confirmed by cellular receptor binding assays (FACS*) *FACS: fluorescence-activated cell

11 HERA-Ligands Receptor Binding All HERA-ligands bind specifically to the immobilized receptor ELISA* assays rely on functional binding to coated recombinant receptors ELISA data were confirmed by cellular receptor binding assays (FACS*) *FACS: fluorescence-activated cell scanning; ELISA: Enzyme-linked Immunosorbent Assay June 2018 Apogenix AG TNF Superfamily Modulators 11

CD206 (log scale) Cell number Ikbα positive cells [%] Ikbα positive cells [%] HERA-CD40L Stimulation of B cell Activation & Survival B cells + HERA-CD40L Activation Survival HERA-CD40L induces NF-kB

monocytes to anti-tumorigenic M1-like macrophages CD40-expressing Ramos B cells were treated with 100 ng/ml HERA-CD40L or 5 μg/ml anti-cd40 mab (HB14 or G28.

12 CD206 (log scale) Cell number Ikbα positive cells [%] Ikbα positive cells [%] HERA-CD40L Stimulation of B cell Activation & Survival B cells + HERA-CD40L Activation Survival HERA-CD40L induces NF-kB signaling in B cells independent of crosslinking HERA-CD40L time [min] crosslink + crosslink 0 αcd40 mab HB time [min] HERA-CD40L shifts monocytes to anti-tumorigenic M1-like macrophages CD40-expressing Ramos B cells were treated with 100 ng/ml HERA-CD40L or 5 μg/ml anti-cd40 mab (HB14 or G28.5) either alone or in the presence of a crosslinking agent. Medium HERA-CD40L αcd40mab 5C3 αcd40mab HB14 Monocytes + HERA-CD40L Compound Medium M2-like Macrophages Antitumorigenic Protumorigenic M1-like Macrophages CD54: ICAM 1 (log scale) M2: 76% M1: 18% M2: 22% M1: 61% M2: 66% M1: 27% M2: 68% M1: 26% Apogenix compounds (100ng/ml) or antibodies (1µg/ml, mouse IgG1,k) added on 0d. Analysis 3d. CD163 (log scale) June 2018 Apogenix AG TNF Superfamily Modulators 12

HERA-CD40L promotes infiltration of T cells in a syngeneic CT26wt model Tumour size (day 24) Infiltration of T cells (day

13 HERA-CD40L Treatment Increases T Cell Infiltration HERA-CD40L impairs tumor growth in syngeneic MC38-CEA model Therapy was started on day 5 after tumors reached 100mm 3. HERA-CD40L (1mg/kg 2qW). HERA-CD40L promotes infiltration of T cells in a syngeneic CT26wt model Tumour size (day 24) Infiltration of T cells (day 24) Therapy was started on day 14 after tumors reached 100mm 3. HERA-CD40L (2qW) PBS HERA-CD40L 1 mg/kg HERA-CD40L 10 mg/kg June 2018 Apogenix AG TNF Superfamily Modulators 13

HERA-Ligands Best-In-Class TNFR Agonists HERA-ligands act via well characterized MoA with superior efficacy over antibodies HERA-ligands consistently boost antigen-specific immune cell activity

14 HERA-Ligands Best-In-Class TNFR Agonists HERA-ligands act via well characterized MoA with superior efficacy over antibodies HERA-ligands consistently boost antigen-specific immune cell activity across cell types and antigens without affecting the non-specific immune cells HERA-ligands show strong anti-tumor efficacy in vitro and in vivo HERA-CD27L, -CD40L, -GITRL: Safe and well tolerated in a pilot monkey tox study Lead candidates selected in cell line development show high productivity June 2018 Apogenix AG TNF Superfamily Modulators 14

15 Asunercept June 2018 Apogenix AG TNF Superfamily Modulators 15

16 Tumor Escape from the Immune System Tumors establish an immune-cell barrier to escape from the immune attack CD95L is one of the key defense mechanisms T cells Courtesy of Prof. Dr. Jäger, NCT Heidelberg June 2018 Apogenix AG TNF Superfamily Modulators 16

CD95 Ligand An Immune Checkpoint Physiological Role of CD95L Homeostasis of Immune Response CD95L induces apoptotic T

important mechanism to establish immune homeostasis and has been described in more than 600 publications since 1993 Role

Head & neck cancer 30% Gastric cancer 41% Renal cancer Colon cancer 47% 20% CD8 + T cells in human ovarian cancer tissue

2014 Jun;20(6):607-15 CD95L is expressed by various cell types in the tumor microenvironment thereby protecting tumor

17 CD95 Ligand An Immune Checkpoint Physiological Role of CD95L Homeostasis of Immune Response CD95L induces apoptotic T cell death CD95L induces apoptotic T cell death by activation-induced cell death (AICD) CD95L-mediated AICD is an important mechanism to establish immune homeostasis and has been described in more than 600 publications since 1993 Role of CD95L in Solid Tumors Lung cancer (NSCLC) 52% Pancreatic cancer 51% Melanoma 24% Ovarian cancer 50% Glioblastoma 66% Head & neck cancer 30% Gastric cancer 41% Renal cancer Colon cancer 47% 20% CD8 + T cells in human ovarian cancer tissue CD95L positive patient CD95L negative patient Motz et al, Nat Med Jun;20(6): CD95L is expressed by various cell types in the tumor microenvironment thereby protecting tumor cells from immune attack Motz et al. showed that CD95L expressed in the tumor correlates with reduced amounts of CD8 positive T cells June 2018 Apogenix AG TNF Superfamily Modulators 17

18 CD95 Signaling in Tumor Physiology Recent publications point towards a major role of CD95L/FasL in the tumors immune escape June 2018 Apogenix AG TNF Superfamily Modulators 18

CD95 Signaling in Tumor Microenvironment Upregulation of CD95L in the tumor mircroenvironment forms a deadly barrier for activated T cells CD95L (endothelial cells)

19 CD95 Signaling in Tumor Microenvironment Upregulation of CD95L in the tumor mircroenvironment forms a deadly barrier for activated T cells CD95L (endothelial cells) CD95L (MDSCs) CD95L (tumor associated fibroblasts) Van der Woude et al. Trends in Cancer, November 2017, Vol. 3, No. 11 June 2018 Apogenix AG TNF Superfamily Modulators 19

Apoptosis Sensitivity (RFU) Asunercept Inhibition of CD95L-Mediated Cell Death

killing CD95L induces death of activated T cells derived from human PBMCs

PBMC donor #2 CD95 acd3/ acd28 PBMC donor #3 Fc IgG1 Activated T cell CD95L

Asunercept 500 ng/ml CD95L 5 mg/ml APG122 T cell death CD95L dose-dependently

blocks apoptosis of activated immune cells Non functional APG122 (CD95-Fc

20 Apoptosis Sensitivity (RFU) Asunercept Inhibition of CD95L-Mediated Cell Death Asunercept inhibits sensitivity of primary human immune cells to CD95L-induced killing CD95L induces death of activated T cells derived from human PBMCs Asunercept inhibits CD95L-mediated immune cell death Human PBMCs PBMC donor #1 PBMC donor #2 CD95 acd3/ acd28 PBMC donor #3 Fc IgG1 Activated T cell CD95L Medium 20 ng/ml 100 ng/ml 500 ng/ml CD95 ligand 500 ng/ml CD95L 5 mg/ml Asunercept 500 ng/ml CD95L 5 mg/ml APG122 T cell death CD95L dose-dependently induced apoptotic cell death of activated immune cells Asunercept (CD95-Fc) blocks apoptosis of activated immune cells Non functional APG122 (CD95-Fc derivative R87S point mutation) has no effect on immune cell apoptosis June 2018 Apogenix AG TNF Superfamily Modulators 20

21 Results Study Design Positive Results from Controlled Phase II Study in Glioblastoma Recurrent GB Patients (n=84) (n=58) Randomization (2:1) (n=26) Radiotherapy (18x 2 Gray) + Asunercept weekly i.v.; 400mg Radiotherapy (18x 2 Gray) No further treatment Safety: Excellent safety profile and very good tolerability Efficacy: All clinical endpoints were reached Endpoint Asunercept / RT RT only P value PFS6 21% 4% p=0.048 Median PFS 4.5 months 2.5 months p=0.016 mos (per protocol) 13.2 months 11.5 months p=n.s. mos (CD95L biomarker) 16.2 months 7.7 months p= year OS N=4 (6.9%) N=0 Based on the PII data, asunercept received PRIME Status (July 2017) EMA opened pathway to accelerated approval June 2018 Apogenix AG TNF Superfamily Modulators 21

$mediating hematopoietic commitment and homeostasis Standard Therapy MDS Patients (Low-int1 risk) EPO 70% 30% EPO Non-Responder EPO Refractory EPO Responder No therapeutic option, only red blood cell$

22 Myelodysplastic Syndromes (MDS) Myelodysplastic syndromes (MDS) are clonal hematologic malignancies that are characterized by ineffective hematopoiesis, resulting in anemia CD95 has a key role in mediating hematopoietic commitment and homeostasis Standard Therapy MDS Patients (Low-int1 risk) EPO 70% 30% EPO Non-Responder EPO Refractory EPO Responder No therapeutic option, only red blood cell transfusions June 2018 Apogenix AG TNF Superfamily Modulators 22

MDS Patient Hematopoiesis Asunercept in PI Study MDS Patients Summary Asunercept Asunercept Hematopoietic stem cell BFU-E* Reticulocyte Erythrocyte Asunercept Transfusions CD95L involvement

23 MDS Patient Hematopoiesis Asunercept in PI Study MDS Patients Summary Asunercept Asunercept Hematopoietic stem cell BFU-E* Reticulocyte Erythrocyte Asunercept Transfusions CD95L involvement Asunercept treatment was well tolerated. Mechanism of action proposed by preclinical studies could be confirmed. Short-term treatment with asunercept improved erythropoiesis (BFU-Es, reticulocytes). In highly transfusion-dependent MDS patients (7-16 transfusions/12weeks) asunercept decreased the number of required RBC transfusions in 47% of the patients. Treatment effect of asunercept was dose-dependent. A better response rate was observed in the 400mg dose group (66%) compared to the 100mg dose group (36%). June 2018 Apogenix AG TNF Superfamily Modulators 23

24 Summary Attractive and diversified IO pipeline with two assets in clinical development PRIME Status granted from EMA paves the way for accelerated approval in EU PROGRAM INDICATION Preclinical Phase I Phase II Phase III Partner Asunercept (CD95L inhibitor) 2nd line Glioblastoma 1st line Glioblastoma Myelodysplastic Syndromes PRIME STATUS PRIME STATUS (China) Solid Tumors HERA-TRAIL HERA-CD40L HERA-CD27L HERA-GITRL HERA-HVEML Hematologic & Solid Tumors HERA-OX40L HERA-4-1BBL June 2018 Apogenix AG TNF Superfamily Modulators 24

Heidelberg, Germany Apogenix AG Im Neuenheimer Feld 584 D-69120 Heidelberg Germany Telephone +49

25 Heidelberg, Germany Apogenix AG Im Neuenheimer Feld 584 D Heidelberg Germany Telephone +49 (0) Fax +49 (0) June 2018 Apogenix AG TNF Superfamily Modulators 25

Immune Checkpoints. PD Dr med. Alessandra Curioni-Fontecedro Department of Hematology and Oncology Cancer Center Zurich University Hospital Zurich

Immune Checkpoints. PD Dr med. Alessandra Curioni-Fontecedro Department of Hematology and Oncology Cancer Center Zurich University Hospital Zurich Immune Checkpoints PD Dr med. Alessandra Curioni-Fontecedro Department of Hematology and Oncology Cancer Center Zurich University Hospital Zurich Activation of T cells requires co-stimulation Science 3