flexible by design ProTIA Bispecific T cell engagers designed for local activation in the tumor environment

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1 flexible by design ProTIA Bispecific T cell engagers designed for local activation in the tumor environment Volker Schellenberger, PhD Keynote lecture at 4 th Biologics Congress, Berlin

2 Cancer Therapeutics With Best-in-Class Therapeutic Index XTEN Protein Polymers The Problem with T Cell Engagers ProTIA Provides a Solution Lead Program AMX-268 2

3 XTEN Brings the Precision of Recombinant Production to Polymer Chemistry Chemical Polymer XTEN Protein Polymer Typical Protein Chemical Reactor Live Cells Live Cells Monomers Random Polymerization Ribosomal Biosynthesis Ribosomal Biosynthesis RANDOM LENGTH RANDOM SEQUENCE UNDEFINED STRUCTURE 1-3 MONOMERS DEFINED LENGTH DEFINED SEQUENCE UNDEFINED STRUCTURE 6-7 MONOMERS DEFINED LENGTH DEFINED SEQUENCE DEFINED STRUCTURE 20 MONOMERS 3

4 Absorbance Log MW SEC Analysis of XTEN MW, kda XTEN XTEN Globular proteins 5.0 Globular proteins MW, kda Time, min Time, min Hydrodynamic radius of XTEN >> Radius of weight-matched globular protein 4

5 XTEN Offers Superior CMC Properties Versus Chemical Polymers such as PEG Peptide-XTEN G-CSF-PEG (Neulasta) Intensity Mass Mass (Da) (Da) Mass Mass (Da) (Da) XTEN PEG, Chemical Polymers Homogeneity 1 Species >100 Species Chromatography Sharp peaks Broad peaks Polymer purification Ion exchange, scalable Size exclusion, not scalable Recombinant Fusion Yes No Cleavage Site Insertion Yes No 5

6 Highly Flexible Platform Offers Many Product Formats Growth Hormone Recombinant Fusion Chemical Conjugation Exendin-4 Undisclosed Factor VIII Factor IX Undisclosed XTEN Protein Polymer Highly soluble, stable Fully biodegradable Defined chemical composition Long in vivo half-life Low immunogenicity Well tolerated (>300 patients) Undisclosed Partner Undisclosed AMX-268 ProTIA #2 XTEN-Drug Conjugates Immune Activators (ProTIA) 6

7 Cancer Therapeutics With Best-in-Class Therapeutic Index XTEN Protein Polymers The Problem with T Cell Engagers ProTIA Provides a Solution Lead Program AMX-268 7

8 Efforts to Increase Antibody Potency Have Resulted in Concomitant Increases in Toxicity T Cell Engagers (BiTE, DART, bsigg) CAR-T Class Drug Dose Range (mg per patient) Low High Toxicity ADCs IgG Herceptin 140, ,000 Erbitux 450, ,000 Rituxan 450, ,000 Naked Antibodies ADC Kadcyla 252, ,000 Adcetris 126, ,000 T Cell Engager Revomab Blincyto 9 28 Potency T cell engagers require very low dosing to mitigate systemic toxicity 8

9 Example of On-Target but Off-Tumor Toxicity Before treatment After treatment Eyes (MART1+) Tumor (MART1+++) Skin (MART1+) Patient treated with adoptive T-cell therapy Target MART1 is expressed at low level in eyes and skin Severe on target toxicity was observed Source: Nat. Biotechnol. (2013) 31, Most tumor antigens show low-level expression in healthy tissues Additional mechanisms are required to limit toxicity in healthy tissues 9

10 Cancer Therapeutics With Best-in-Class Therapeutic Index XTEN Protein Polymers The Problem with T Cell Engagers ProTIA Provides a Solution Lead Program AMX

11 Toxicity Three Targeting Mechanisms for Class-Leading Therapeutic Index ProTIA Combines 3 Targeting Mechanisms Administration as Prodrug ADCs T Cell Engagers CAR-T 1 Tumor antigen binding 2 Localized activation 3 EPR effect Low activity Long half-life Limited uptake by health tissues 3 EPR effect Naked Antibodies ProTIA 2 Localized Activation Potency High activity Short half-life Rapid tissue uptake 1 Tumor antigen binding 11

12 ProTIA: Rapidly Assembled from Standard Domains Building Blocks acd3 IgG atumor IgG Trigger Site XTEN ProTIA-X (Administered Form) ProTIA activation by tumorassociated proteases XTEN is a Key Component of ProTIA Blocks T-cell activation of prodrug form Provides long circulation half-life Reduces uptake by healthy tissues Minimizes aggregation risk Facilitates manufacturing ProTIA-A (Activated Form) 12

13 ~20nm ProTIA versus IgG Tumor Binding Site T Cell Binding Site Tumor Binding Site T Cell Binding Site Trigger Site Cleaved by tumorassociated proteases XTEN Polymer Model curtesy of Dr. Ruben Abagyan, Dr. Larissa Podust, Skaggs School of Pharmacy, UC San Diego School of Medicine 13

14 ProTIA Combines 3 Mechanisms to Achieve Best-In-Class Therapeutic Index Tumor Tissue Normal Tissue Blood Vessel Blood Vessel EPR effect Vascular Endothelium Vascular Endothelium Localized activation Protease-rich tumor environment Tumor antigen binding Low tumor antigen T Cell Tumor Cell T Cell Normal Cell 14

15 buffer Robust and Scalable Manufacturing Platform Rapid E. coli Manufacturing Defined Chemical Structure aepcam ORI acd3 XTEN Expression Plasmid Selection ESI-MS MW calc 138,649 MW exp 138,660 E. Coli XTEN Prevents Aggregation Single protein chain Soluble production No refolding No cell line development One week fermentation time Size Exclusion Chromatography Time, min 15

16 ESI-MS Analysis of Herceptin and ProTIA Herceptin ProTIA MW calc 138,649 Da MW exp 138,660 Da Antibodies are produced in cell culture Glycosylation results in heterogeneity ProTIA is produced in E. coli No post-translational modifications Defined chemical structure 16

17 Summary of Cellular Binding Affinities Pharmaceutical Form X Blocked Form B Activated Form A Target ProTIA-X ProTIA-B ProTIA-A X/A Ratio EpCAM CD XTEN masks CD3 binding by 17x and EpCAM binding by 7x The protease trigger site has no impact on masking AS7563/AS7569 DT 17

18 % Specific Lysis Impact of XTEN on T Cell Activity ProTIA-A ProTIA-X ProTIA-B x Target: SKOV-3 Effector: PBMC E:T ratio: 5:1 Incubation: 24 to 48 h Log Concentration (nm) ProTIA-A is highly active (similar to BiTE) XTEN blocks T cell activation ProTIA-X is partially activated during assay 18

19 Marker (kda) Before cleavage Protease A Protease B Protease C Protease D ProTIA Therapeutics are Designed for Activation by Multiple Tumor-Associated Proteases Tumor protease digests analyzed by electrophoresis ProTIA-X (Injected form) Experiment AMX-168 was incubated with tumorassociated proteases Reactions were analyzed by electrophoresis ProTIA-A (Activated form) Released XTEN Proteases A, B, and C cleave at ProTIA-X at the trigger site releasing active ProTIA-A Protease D degrades XTEN polymer releasing ProTIA-A but no intact XTEN 19

20 ProTIA Provides 10x Improved Therapeutic Index vs BiTEs Target+ expression in multiple organs Tumor (Target+++) ProTIA is 10x Less Toxic vs BiTE ProTIA Matches Efficacy of BiTE 800 Percent survival x dose 1x dose ProTIA-X 3x dose 1x dose 3x dose 10x dose ProTIA-A ~ BiTE ProTIA-A ~ BiTE ProTIA-X Prodrug CA125 (U/mL) CA125 (U/mL) Day Day Mouse specific surrogate Day Human xenograft model 20

21 Plasma Concentration (%ID/g) Trigger Site is Stable in Tumor-Bearing Mice Implant tumor cells Intraperitoneal Inject mixture ProTIA-A ProTIA-X ProTIA-B Day 0 Collect Plasma 0 4h 8h 24h 2d 3d 5d 7d ProTIA-A ProTIA-X ProTIA-B ProTIA-X ProTIA-B 0.1 ProTIA-A Time (h) ProTIA-X = ProTIA-B Trigger site is stable in tumor-bearing mice ProTIA-A is rapidly eliminated Minimal risk of systemic exposure 21

22 CA125 (U/mL) CA125 (U/mL) CA125 (U/mL) CA125 (U/mL) CA125 (U/mL) CA125 (U/mL) ProTIA-B ProTIA-X ProTIA-A AMX-N68 in Platinum-Resistant Ovarian Ascites Model Implant OVCAR-3 (IP) Inject PBMC Inject test article (2x per week, IP) Day CA ProTIA-A ProTIA-X ProTIA-B Day Low Dose Day Day Day Day x Dose Day Low dose intraperitoneal ProTIA-X and ProTIA-A eliminates most/all CA-125 secretion ProTIA-B has minor(no) impact on CA-125 secretion even at 5x increased dose level Study: AX

23 Cancer Therapeutics With Best-in-Class Therapeutic Index XTEN Protein Polymers The Problem with T Cell Engagers ProTIA Provides a Solution Lead Program AMX

24 EpCAM+ Expression/Cancer Incidence/Market Potential Global assessment of potential patient populations for AMX-268 EpCAM Overexpression (TIS >4) Cancer ESTIMATED CANCER INCIDENCE, WORLD New Cases per Year 75% (including SCLC) Lung 1,824,701 46% (~75% TNBC) Breast 1,671,149 94% Colorectum 1,360,602 89% Prostate 1,094,916 74% Stomach 951,594 65% Oesophagus 455,784 63% Pancreas 337,872 Very large therapeutic potential No competitive therapies in this space Multibillion dollar market potential $50,000/treatment x 100,000 patients = $5 BB 55% Kidney 337,860 87% Thyroid 298,102 73% Ovary 238,719 66% Gallbladder 178,101 Sources: GLOBOCAN 2012 IARC Spizzo et al., J Clin Pathol 2011;64:415 24

25 Significant Improvement vs Competing T Cell Engagers Property ProTIA Probodies, Bispecific Bispecifc Fragments IgG-Like Companies Amunix (ProTIA) Cytomx (Probodies) Akriveia (Akluded) Amgen (BiTE) MacroGenics (DART) Affimed (TandAbs) Immunocore (ImmTAC) Xencor (XmAb) Regeneron (BiAb) Roche (TCB) Janssen (FynomAb) Emergent (ADAPTIR) Binding to tumor antigen Localized activation EPR Effect ProTIA vs Bispecific Probodies: Activated Probodies have long circulation half-life Accumulation in circulation? Activated ProTIA has very short half-life No accumulation in circulation 25

26 Highlights Innovative ProTIA Format Combines Three Targeting Modes Strong Validation Administered as inactive prodrugs (ProTIA-X) with long circulation half-life Converted at the tumor site into highly active T cell engager (ProTIA-A) Activated form has short half-life to minimize risk of systemic exposure Binding to tumor antigen Localized protease activation EPR effect (Limited permeation of healthy tissues) 10X widened therapeutic window demonstrated Sub nanomolar activity against multiple targets XTEN component of ProTIA validated in multiple clinical trials Proven Partnering >$80 million in non dilutive revenue to date Genentech, Celgene, Bioverativ, Roche, Janssen, Versartis, Naia Please contact us with questions about ProTIA or our XTEN for half-life extension Partnering/licensing requests: matt@gellerbp.com 26

27 Thank You Please contact us if you want to use XTEN: 27