Sutro Biopharma Overview Best-‐in-‐Class Biotherapeu6cs Through ProteinSAR™ Bill Newell, CEO Trevor Hallam, CSO Jeremy Bender, CBO Ed Albini, CFO 310 Utah Avenue Suite 150 South San Francisco, CA 94080 +1 650 392 8412 www.sutrobio.com Sutro’s Xpress CF™ Platform: Cell-Free Synthetic Biology input (DNA) Assembled IgG + Energy + Accessories* (AA, proteins, RNAP, metabolites) Ribosome (Catalyst) output Engineered cell-free extract (multi-domain (E. coli) eukaryotic proteins) *To be incorporated into strain for commercial production Highlights • Sutro’s ProteinSAR™ platform: the first practical technology for defining protein structure-activity relationships • The first homogeneous antibody-drug conjugates (ADCs) • Combinatorial optimization of bispecific antibodies • Rapid, high-throughput protein production reduces time from concept to clinical candidate from >24 months to <12 months • Strategic partnerships • Celgene: ADC, bispecific and monoclonal antibody collaboration plus expansion into multispecific antibodies targeting immuno-oncology pathways • Merck-Serono: multi-target ADC collaboration • J&J Innovation Center: spin-out of vaccine company SutroVax • Initial product focus ADCs • Broad, fundamental IP • Experienced management team 3 Pipeline Program /Ini6al Therapeu6c Target Research Preclinical Phase I/II Oncology An6body-‐drug conjugates Mul6ple an6body-‐drug conjugates An6body-‐drug conjugate Bispecific an6body Therapeu6c an6body Mul6specific an6bodies targe6ng immuno-‐oncology 4 Fundamental Breakthroughs in Therapeutic Antibodies Human and humanized antibodies Abgenix, Medarex, PDL and others 40 FDA-‐approved therapeu9c an9bodies 35 30 Human or humanized mAbs $37.9B (2012 U.S. sales) Sutro’s ProteinSAR™ platform New state-ofthe-art for ADCs: homogeneity, site-specific conjugation 25 20 15 10 Murine or chimeric mAbs 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 5 ProteinSAR™ bispecifics: optimal structures for superior drug-like properties 5 Current ADCs Are Suboptimal Mixture Products # drugs / Ab 0 1 2 3 4 5 6 7 8 9 Random Lysine Conjugation # drugs / Ab 0 1 2 3 4 5 6 7 8 9 Cysteine Conjugation: S-S bonds # drugs / Ab 0 1 2 3 4 5 6 7 8 9 Specific conjugation at any site ADC Design is Complex; Homogeneity is Key Efficacy Resistance Antigen Choice of Epitope Density Internalization rate Antibody / Scaffold Tumor Distribution/Disposition Safety Tumor Heterogeneity (inter and intra Antigen mutation or shedding Therapy-induced changes Alterations in apoptotic pathways Healthy tissue expression Stability Fc functionality and PK Non-specific Fc binding ADCC and CDC activity Conjugation Specificity Linkers Cleavable or non-cleavable Stability Immunogenicity Stability Physicochemical props Warheads Potency Payload Mechanism becomes redundant MDR/Pgp status Altered metabolism Immunogenicity Bystander effect Systemic release 7 ADC SAR: Production of Every Possible Site-Specific ADC Variant in Hours o Mutate Sites in IgG o Produce nnAA IgGs o Conjugate o Purify o Test 8 Selecting the Best Positional Variants 2500 MFI 2000 1500 1000 Mean Fluorescence Rela%ve'MFIIntensity Binding of Site variant ADCs to tumor cells; selecting the best 500 3000 R61 S63 2000 S65 R66 Herceptin T69 D70 Sutroceptin T72 T74 S76 E293 S77 WT K334 1000 0 0.1 150 1 150 Transform of Transform of Data 101 Data 1001 nM 1000 nM warheads (Cellular ATP content, % of control) Relative Cell Relative Cell Viability Viability Relative Cell Viability (Cellular ATP content, % of control) But do they all kill tumors cells efficiently?; 0 T359 T359 differences….. 0.01 0.1 1 huge 10 100 1000 K360 K360 CF-Herceptin N361 N361 nM 100 50 0 0.0001 100 50 Q362 Q362 K370 Y373 S375 W381 K370 Y373 S375 W381 S383 S383 N384 N384 S136, GY S136, GY DAR=1.6 WT HIC WT HIC 0 0.0001 0.001 S136 ERB2 E S136 ERB2 ELISA 0.001 0.01 ug/ml 0.010.1 ug/ml ug/mL 0.1 1 1 9 Homogeneous ADCs Kill Tumor Cells More Efficiently Than Heterogeneous mixtures It takes 4 to 5-fold higher cytotoxic drug loads to kill tumor cells using SGEN’s linker technology than Sutro’s Sutrocep)n+Variants 150 Published Data – Genentech patent MMAF+AB3626+(No+Peg)+Only H-MC-MMAF [cys] (120 hours) MMAF+AB3627+(++Peg)+Only From: US Patent 7,994,135 B2 Aug 9, 2011; Fig 7 Hercep)nTM 100 ADC - 3.8 drugs/Ab ADC - 4.1 drugs/Ab MMAF+AB3617+Only ADC – 4.8 drugs/Ab Sutrocep)n++ 1 Drug/Ab 4-5 Drugs/Ab Cell Viability (relative Luminescence) Rela)ve+Cell+Viability (Cellular+ATP+content,+%+of+Control) Cell Viability Assay with Single ADC Variants A118FAB3626+(No+Peg) 50 A118FAB3627+(++Peg) S375FAB3626+(No+Peg) S375FAB3627+(++Peg) T135FAB3626+(No+Peg) 0 0.0001 0.001 0.01 ug/ml µg/ml 0.1 1 10 ug/ml 10 Position Matters for Effective Killing of Human Tumors in Animal Models—Proof Established 1600 Free Drug, 0.54mg/kg Dose equivalence at DAR of 4.0 Vehicle Tumor Volume, mm3 1200 IgG HC site 1 15mg/kg Trastuzumab-CF IgG HC site 6, DAR 1.959 IgG HC site 5, DAR 1.970 800 IgG HC site 1, DAR 1.840 15mg/kg Trastuzumab-CF MMAF Conjugates IgG HC site 4, DAR 1.973 400 Trastuzumab, 1x 30mg/kg (t =0), 3x15mg/kg (weekly) 0 0 10 20 30 40 50 60 70 Days • • • • n =10 each treatment group All treatments (except Trastuzumab) are single intra-venous dose @ t=0 Trastuzumab multiple dose group dosed i.p No significant weight loss observed in any treatment group 11 scFv-‐Fc DBCO MMAF Conjugate Scaffolds are Very Effec9ve at Equivalent Molar ADC Doses 2000 1500 Vehicle 1000 IgG ADC** scFv-‐Fc ADC** 500 0 Tumor Volume, mm3 HIGH 20 40 MID 1500 1000 500 0 0 60 0 20 40 60 Days Days 2000 LOW Vehicle Vehicle IgG1 (ScFv-Fc)2 IgG Site 5 AB4285 scFv-‐Fc Site 5 AB4285 DOSE Trastuzumab-CF IgG1 HC SITE 5 pAzMF DBCO MMAF AB4285, 15mg/kg, DAR 1.7 DAR 1.7 DAR 1.8* Tumor Volume, mm3 Tumor Volume, mm3 2000 1500 Trastuzumab-CF IgG1 HC SITE 5 pAzMF DBCO MMAF AB4285, 10mg Trastuzumab-CF scFv-Fc SITE 5 pAzMF DBCO MMAF AB4285, 7.18m Trastuzumab-CF scFv-Fc SITE 5 pAzMF DBCO MMAF AB4285, 10.77mg/kg, DAR 1.8 HIGH 15 mg/kg (542ug MMAF/m2) 10.77 mg/kg (570ug MMAF/m2) MID 10 mg/kg (361ug MMAF/m2) 7.18 mg/kg (380ug MMAF/m2) LOW 5 mg/kg (180ug MMAF/m2) 3.59 mg/kg (190ug MMAF/m2) * Matched Drug Dosing ** HC Site 5 ADCs Used 1000 500 0 0 20 40 Days 60 An Industry First: Two Different Payloads Enabling two different specifically posi9oned payloads per an9body Mul9ple payload (2, 4, 6, 8+) op9ons Benefits payloads • Synergistic mechanisms of action enable more effective tumor killing with reduced toxicity potential • Overcome resistance due to toxin transport or metabolism • Eliminate effects of tumor heterogeneity 13 Dual Payload Proof Drug1 on HC Drug1 DAR Drug2 on LC Drug2 DAR Total DAR MMAF 1.8 SN-38 1.4 3.2 MMAF 1.8 PBD dimer 1.5 3.4 MMAF 1.9 Gemcitabine 1.6 3.6 PBD dimer 1.9 MMAF 1.7 3.7 Gemcitabine 2.0 MMAF 1.6 3.5 PBD Dimer/ MMAF Dual Warhead ADC DAR=3.7 14 The Ideal ADC Profile Desired Characteris6cs Homogeneous, not heterogeneous, ADC Site-‐specific conjuga9on – anywhere in the mAb; all sites are evaluable Ability to site-‐specifically conjugate mul9ple numbers of warhead (DAR =2, 4, 6, 8 or more) Ability to site-‐specifically conjugate two different warhead killing mechanisms Op9mized an9body scaffolds Scalable manufacturability Sutro PlaXorm þ þ þ þ þ þ 15 Rapid Execution of Bispecific Antibody Discovery Programs Discover novel an9body fragments using ribosome display and screening Express an9bodies and fragments with Sutro protein synthesis system Reformat fragments in host of different bispecific and an9body frameworks Select the best lead candidate based on in vitro and in vivo ac9vity 16 Source of Antibodies and Integration into the Sutro System • • • • • Mouse Rabbit Chicken Humanized Mice Human B-cells B-‐Cell Based Technologies Phage Display Bacteriophage Display Cell-‐Based Display Ribosome Display Bispecifics Many Scaffolds • Bacteria Display • Yeast Display • Mammalian Display Sutro Cell Free Antibody Discovery Antibody Engineering Sutro System nnAA Linkerwarhead ADCs 17 Sutro Platform Enables Multiple Bispecific Antibody Formats scFv scFv1scFv2 scFv1-scFv2- Fc scFv1-Fc-scFv2 scFv-scFc scFv-Fc scFv1-scFc-scFv2 Rapid expression of multiple scaffolds to define product format with optimal activity and half-life 18 BiTE Scaffolds for Testing T cell Engagement and Half-Life Extension In Vivo Y short serum half-life (several hours) traditional BiTE Y scFv x Z scFv Z human serum albumin (HSA)-associated BiTEs Y Y Z Z HSA-binding peptide HSA HSA fusion increased serum half-life (several days desired) Knobs-into-Holes BiTEs Y Y Z Z Y Y-knob + Z-hole Z Knob-Y + hole-Z BiTE-knob + hole Important criteria to be met • Yield • Purity of assembled product • Binding affinity of scFvs • T cell killing activity • Serum half-life and stability Example of Sutro-Produced Bispecific Antibody: MT103 BiTE (= Bispecific T Cell Engager) Teach Antibodies to Engage T Cells α-CD19 -Tumor Antibody BiTE VH -CD3 Single-chain Antibody VL Linker Single-chain Antibody Source: Micromet AG/ AMGEN 20 MT-103CF: Pre-Optimized Expression Standard Expression Conditions 1-7 C14 Incorporation 97 69 55.4 46 30 12 MT103CF Initial Expression Level 0.4 gram / Liter Soluble 0.5 gram / Liter Total (6 hours Expression) (30% Extract) Minimal: • Proteolysis • Mixed Multimers • Truncation Products Large Scale Production of MT103CF SDS-‐PAGE of MT103CF: 250 kD-‐ 150 kD-‐ 100 kD-‐ 75 kD-‐ 50 kD-‐ 37 kD-‐ 25 kD-‐ 20 kD-‐ 15 kD-‐ 10 kD-‐ • Single Column Purification using Protein L support • Large Monomeric Peak on Analytical SEC Column MT103CF binding to Nalm-6 cells Nalm-6 cells CF MT-103 HEK MT-103 CHO MT-103 400 MFI 300 200 100 0 10-310-210-1 100 101 102 103 104 Kd Kd CF-‐MT103 1.5 CF MT-103 1.467 HEKMMT-103 2.033 HEK T-‐103 2.0 CHO MT-103 3.880 CHO MT-‐103 3.9 nM MT103CF: comparable affinity to HEK and CHO MT103 specific cytotoxicity (%) T-cell donor 1 Donor 1 70 60 50 40 30 20 10 0 10-510-410-310-210-1100 101 specific cytotoxicity (%) specific cytotoxicity (%) Comparison of MT103 Produced in Sutro Platform and Cell-Based Systems T-cell donor 3 T-cell donor 3 Donor 2 70 7060 CF MT-103 6050 MT-103 CFHEK MT-103 5040 CHO MT-103 HEK MT-103 4030 CHO MT-103 3020 2010 10 0 0 10-510-410-310-210-1100 101 -310-210-1 100 101 10-510-410SB-1 (ng/ml) SB-1 (ng/ml) SB-1 (ng/ml) CF MT103 HEK MT103 CHO MT103 CD8+ T-‐cell EC50 (pg/ml) EC50 (pg/ml) EC50 (pg/ml) donor 1 3.7 3.5 2.7 donor 2 3.0 1.4 1.6 24 Rapid Production of Biotherapeutics 2 DAYS 4 6 8 Sutro Technology Synthetic DNA • • • • 50 µg protein HTS plate format 5g protein 5-L reactor 100 g protein 100-L reactor Direct linear scale-up from HTS to production scale Uses standard bioreactors & downstream equipment Minimal, rapid process development Gene sequence to drug substance in days Scalable and Efficient a [rhGM-CSF], mg/L 800 250 uL 300 mL 600 4L 100L 400 200 0 0 200 400 600 Time, min Zawada et al, (2011) Biotech. & Bioeng. Xpress CF™ Manufacturing: GMP Facility a Critical Element Intellectual Property • Exclusive license to broad patent estate relating the ProteinSAR™ platform, enabled by Xtract CF™ and Xtract CF+™ • 12 U.S. and 33 foreign issued patents • 14 U.S. and 23 foreign pending patent applications 28 Management Team Management Team Board of Directors William J. Newell, JD, CEO Mike Ross, PhD Trevor Hallam, PhD, Chief Scien6fic Officer Dan Janney Jeremy Bender, PhD, MBA, Chief Business Officer John Freund, MD Ed Albini, Chief Financial Officer Armen Shanafelt, PhD Henry Heinsohn, VP Development & Manufacturing Bryan Lawlis, PhD Aaron Sato, PhD, VP Research Dan Petree Aerovance (President), QLT, Axys Pharmaceu9cals Astra Zeneca (VP Biologics – Respiratory & Inflamma9on) Smith Kline & French, Glaxo, Roche, Rhone Poulenc Rorer, Pala9n (Lead numerous programs to and through Ph 2 clinical development) Allos Therapeu9cs (VP – Corporate Development) Boston Consul9ng Group Itero Biopharmaceu9cals (CFO), Novacea (CFO), Genentech, Lynx (CFO), Carbylan Biosurgery, Peat Marwick Mitchell & Co. Genentech, Genencor, Corning Medical & Scien9fic Oncomed (Sr. Dir. -‐ An9body Engineering)., Dyax Corp (led 4 oncology progarms into clinic at OncoMed) SV Life Sciences, Managing Partner Alta Partners, Managing Director Skyline Ventures, Founder Lilly Ventures, Venture Partner Itero Biopharmaceu9cals (CEO) Four Oaks Partners, Managing Director William J. Newell, CEO Sutro Biopharma, Inc. 29
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