Sutro Biopharma, Inc. · NASDAQ:STRO
Sutro Biopharma — 14th Annual World ADC San Diego 2023
25 slides from Sutro Biopharma's conference presentation, Oct 12, 2023
Slide 1: Discovery of Novel Linker Payloads for Site-Specific ADCs with Improved Efficacy and Therapeutic Index
Discovery of Novel Linker Payloads for Site-Specific ADCs with Improved Efficacy and Therapeutic Index Krishna Bajjuri Sr Director, Chemistry Sutro Biopharma 14th Annual WADC, San Diego 2023
Slide 2: Presentation Outline
Presentation Outline • Brief overview of the diverse classes of Sutro’s linker payloads platform employed in the discovery and development of DAR4/8 site-specific ADCs • Discovery of novel tumor-selective linkers and payloads explored in enhancing the efficacy and therapeutic index of α-ROR1 ADC (ST
Slide 3: Expanding Sutro's Various Classes of Payload Platform for ADCs
Expanding Sutro’s Various Classes of Payload Platform for ADCs Maytansine Hemiasterlin Analog Exatecan/Gly-Exatecan PNU anthracycline class • Used on two Sutro • Sutro novel payload • Topo1 Inhibitor • Topo1-inhibitor, multiple clinical programs asset used in two • Close analog to Daiichi effects on
Slide 4: Hemiasterlins: From Natural Product to ADC Payload
Hemiasterlins: From Natural Product to ADC Payload Isolation & SAR characterization Tet Letters, 1994, 4453 Tetrahedron, 1995, 10653 Hemiasterlin hemiasterella minor • Co-crystallization of SC209 is binding to the vinca-site of two α,β-tubulin interdimer interface • Sutro’s tubulin inhibitor class p
Slide 5: CPT Derivatives and DNA Targeting Cytotoxins Explored as ADCs
CPT Derivatives and DNA Targeting Cytotoxins Explored as ADCs Camptothecins (DNA topoisomerase I inhibitor) CPTs induce DNA damage through trapping of Topoisomerase 1 Camptothecin Camptotheca acuminata Camptothecin (CPT) derivatives • SN-38 (SC2609) • Poor solubility • Exatecan (SC3386) • Less poten
Slide 6: Legumain (LGMN) Expression in Human Tumors for ADC Linker
Legumain (LGMN) Expression in Human Tumors for ADC Linker • The Cys protease Legumain, also known as Asparaginyl endopeptidase, specifically cleaves Asn amide bonds at acidic pH • Legumain is overexpressed in the majority of human solid tumors • This protease is known to be upregulated in multiple c
Slide 7: Legumain Protease Cleavable Hemiasterlin and Topo1i LP's for ADCs
Legumain Protease Cleavable Hemiasterlin and Topo1i LP’s for ADCs LGMN cleavable hydrophilic Hemiasterlin LP LGMN cleavable hydrophilic Exatecan LP Hemiasterlin Payload (SC209) • Selective to the LGMN • Stable to hNE • It is stable to serine proteases and or other cysteine proteases Exatecan Payload
Slide 8: β-Glucuronidase (β-Glu) Overview
β-Glucuronidase (β-Glu) Overview • β-Glu is overexpressed in the majority of known solid and blood cancers • β-Glu is only active and present in cancer cell lysosomes and tumor necrotic regions • Active only at acidic pH • Non peptide based, stable to hNE & or to other serine/cysteine proteases • Mi
Slide 9: Design of Novel Proprietary Tumor Specific β-Glucuronide Linker for ADCs
Design of Novel Proprietary Tumor Specific β-Glucuronide Linker for ADCs Lysosomal release of various β-Glucuronidase Cleavable Exatecan Linker Payloads Linker % of Expected Payload Payload release from Lysosomal Several β-Glu cleavable linkers have been explored across Incubation @ 24h diverse vect
Slide 10: β-Glucuronidase Enzyme Release of Optimized Hydrophilic β-Glu Linker Payloads
β-Glucuronidase Enzyme Release of Optimized Hydrophilic β-Glu Linker Payloads β-Glu enzyme cleaves novel hydrophilic β-Glu cleavable Exatecan (SC3417) and β-Glu cleavable Hemiasterlin (SC3425) LPs SC3425 at 10 μM 10 9 8 Concentration (μM) 7 Exatecan 6 SC209 Hemiasterlin 5 4 SC3425 DBCO- DBCO-PEGylat
Slide 11: Human Neutrophil Elastase (hNE) Stability of Various Linker Payloads
human Neutrophil Elastase (hNE) Stability of Various Linker Payloads hNE Cleavage of Different pAMF/Cys Quenched Linker Payloads 120% 100% SC572Cys SC3417pAMF % intact linker remaining 80% SC3418pAMF SC3420pAMF 60% 40% 20% 0% 0 20 40 60 80 100 120 140 Time (min) • hNE cleavage was observed for SC572
Slide 12: ROR1 Background
ROR1 Background • Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a cell- surface, onco-fetal protein whose expression is correlated with oncogenic properties such as enhanced proliferation, survival, and chemoresistance • ROR1 expression is highly associated with epithelial- mesenchymal t
Slide 13: ROR1 is an Attractive ADC Therapeutic Target for Solid/Hematological Malignancies
ROR1 is an Attractive ADC Therapeutic Target for Solid/Hematological Malignancies ROR1 Expression Across Various Solid Tumors Skin Pancreatic Colon Ovarian Lung Breast Adrenal Prostate Uterus Bladder Testicular Normal Tumor • ROR1 is a favorable target for an ADC due to its low expression in normal
Slide 14: α-ROR1 nnAA pAMF Labeled Ab Discovered Using Sutro's CF Platform Technology
α-ROR1 nnAA pAMF Labeled Ab Discovered Using Sutro’s CF Platform Technology • α-ROR1 STRO-003 Ab, high affinity binding to ROR1 • Fully human IgG1 aglycosylated Ab • 8 pAMF nnAA incorporated at LC and HC • Binding to ROR1 Ig domain • Cross reactive to human/cyno/rodent • No binding to ROR2 Optimize
Slide 15: Design/Optimization of Novel Linker Payload for α-ROR1 ADC
Design/Optimization of Novel Linker Payload for α-ROR1 ADC • ROR1 is expressed on multiple hematologic and solid tumors but not on normal tissues • Heterogenous expression, low receptor copy number (ranging between 50,000-150,000) • Payload selection Tubulin vs DNA targeting • Low/not a substrate fo
Slide 16: Payload Selection for α-ROR1 ADC
16 Relative Cell Viability 0. (Cellular ATP content, % of control) 00 0 100 120 20 40 60 80 01 0. 01 Relative Cell Viability 1 0. (Cellular ATP content, % of control) 0 0 100 150 50 00 1 nM 10 0. 0 0 01 10 0. 00 01 0 10 0. 1 SC3386 (Exatecan) 00 0 00 1 nM Relative Cell Viability 0. (Cellular ATP con
Slide 17: In vitro Potencies of α-ROR1 DAR8 ADCs with Different Linker/Payloads
In vitro Potencies of α-ROR1 DAR8 ADCs with Different Linker/Payloads NTERA-2 MCF-7 SP10978 2188-D04 + SC3411 (charge-PEG-tripeptide (ROR1+++) (ROR1-ve) cathepsin sensitive Exatecan) DAR8 150 150 SP10979 2188-D04 + SC3417 (PEGylated bGlu Exatecan) DAR8 (Cellular ATP content, % of control) (Cellular
Slide 18: PK Summary of α-ROR1 DAR8 ADCs in Non-Tumor Bearing Mice
PK Summary of α-ROR1 DAR8 ADCs with Different Linker/Payloads in Non-Tumor Bearing Mice : Terminal Conjugate Description t1/2 (day) ROR1 2188-D04-SC239 SP10873 7.56 (DAR8) ROR1 2188-D04-SC3403 SP10926 12.0 (DAR8) ROR1 2188-D04-SC3418 SP10980 8.67 (DAR8) ROR1 2188-D04-SC3417 SP10979 10.2 (DAR8) ROR1
Slide 19: α-ROR1 DAR8 ADCs in MDA-MB-231 Breast Cancer Model
α-ROR1 DAR8 ADCs with Various Linker/Payloads in MDA-MB-231 Breast Cancer Model with Moderate ROR1 Expression Tumor Growth Curves Dose % TGI 2000 LP SC# Description (qw x4) (Day 42 or 43) Tumor volume (mm3) DAR8 hydrophilic β-glu Exatecan 1500 Linker Payload 106% SC3417 5 mg/kg 1000 DAR8 CatB (tripe
Slide 20: α-ROR1 DAR8 SP11321 Anti-Tumor Activity in NSCLC PDX Models
α-ROR1 DAR8 SP11321 (β-glu Exatecan) ADC Shows Greater Anti-Tumor Activity in High and Low ROR1 Expressing NSCLC PDX Models than SP11322 ADC ROR1 high PDX models were dosed at 10 mg/kg q7dx5. ROR1 low ROR1 negative 100 % tumor volume chage 50 SD 0 -50 PR -100 Vehicle SP11321 SP11322 DAR8 hydrophilic
Slide 21: α-ROR1 DAR8 SP11321 Stable in Circulation and Well Tolerated in NHP
α-ROR1 DAR8 SP11321 was Stable in Circulation and Well Tolerated in NHP up to 45 mg/kg SP-011321 @ 45 mg/kg • Non-human primates were dosed with SP11321 every three weeks in a repeat dose toxicity (Q3wx2 at 10, 20, 45 100 mpk) and toxicokinetic study 10 Concentration (μM) Monkey Plasma 1 • SP11321 w
Slide 22: α-ROR1 DAR8 SP11321 Demonstrated a Wide Safety Window in Non-Human Primates
1000 α-ROR1 DAR8 SP11321 Demonstrated a Wide Safety Window in Non-Human Primates retic (10^9/uL) 100 • α-ROR1 DAR8 SP11321 (β-glu Exatecan Linker Payload) was well tolerated in a multi-dose non-GLP NHP study up to 45 mg/kg 10 • No observed neutropenia or thrombocytopenia, no changes observed in WBCs
Slide 23: SP11321 α-ROR1 DAR8 ADC
SP11321 α-ROR1 DAR8 ADC • High affinity ROR1 specific Ab; incorporating eight para- azidomethyl-phenyl alanine (pAMF) nnAA residues at optimal sites allowing for precise conjugation for enhanced efficacy and safety • Optimized novel hydrophilic tumor selective and stable β- glucuronidase cleavable E
Slide 24: Sutro's Site-Specific TAA ADCs Utilizing Novel β-Glucuronidase Cleavable Exatecan Linker Payload
Sutro’s Site-Specific TAA ADCs Utilizing the Novel Hydrophilic β-Glucuronidase Cleavable Exatecan Linker Payload (SC3417) TAA1 β-glu Exatecan ADC in vivo data in breast cancer TAA2 β-glu Exatecan ADC in vivo data in breast cancer CDX model CDX model MDA-MB-231 Growth Curves MDA-MB-231 Growth Curves
Slide 25: Acknowledgments
Acknowledgments Many thanks to Sutro’s dedicated scientists across different cross functional teams as well as the managers who made valuable contributions! NON-CONFIDENTIAL 25
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