Slide 1: Opening The Barn Door To Antibody Diversity
1 Opening The Barn Door To Antibody Diversity Bill Harriman, PhD SVP Antibody Discovery Discovery on Target October 18, 2022
Slide 2: The OmniAb Technology Suite
2 The OmniAb Technology Suite The only platform leveraging four species Robust solutions for bispecific antibodies Human frameworks with ultralong CDR-H3s Industry-leading broadest offering See Dev’s poster #51 Proven success At OmniAb booth
Slide 3: Platforms to Generate Custom Antibody Repertoires
3 Platforms to Generate Custom Antibody Repertoires BIOLOGICAL INTELLIGENCE™: INTERPLAY BETWEEN RATIONAL GENETIC DESIGN AND POWERFUL IN VIVO PROCESSES Naïve repertoire Immune repertoire Building the Animal System Repertoire Shaping Repertoire Mining V gene building blocks Antigen design Phenotypic s
Slide 4: OmniAb Program Count Continues to Grow
4 OmniAb Program Count Continues to Grow PROGRESSION AND PERFORMANCE IN PROGRAMS BY STAGE OF DEVELOPMENT As of 2016 As of 09/30/22 Phase 3: 2 Phase 2: 2 Approved: 3 Phase 1: 18 Preclinical: 1 Preclinical: 12 21 282 Discovery: 245 Discovery: 20 Substantial progress in all phases, increase in discover
Slide 5: Animal Platforms
Omni Animal Platforms
Slide 6: Rodent Platforms
6 Rodent Platforms Light chain loci Heavy chain locus VL J CL VH DH JH EµCµCγ1 Cγ2b ε α • Endogenous Ig genes inactivated + Fully human LC Human V, D, J Rat constant • Expression of full human V gene diversity VJ C • Streamlined conversion into fully human VDJ C molecule mRNA Human Antibody Well-val
Slide 7: OmniChicken
7 OmniChicken® POWERED BY EVOLUTION 300 million years Primordial target gene 95 million years Chicken orthologue Murine orthologue Human orthologue Greater evolutionary distance yields greater immunogenicity and more antibody diversity
Slide 8: Engineering of Ig Loci
8 Engineering of Ig Loci ADAPTATION TO CHICKEN GENE CONVERSION PROCESS Gene conversion Engineered locus Germline VH3-23 VK3-15 or VL1-44 // CDR-focused diversity Gene conversion Diversified B-cells Human V’s selected for: // • High expression level, stability, ubiquity // • High sequence diversity i
Slide 9: Common Light Chain Platforms
9 Common Light Chain Platforms STANDARD IGG FORMAT TO DE-RISK DOWNSTREAM DEVELOPMENT1 OF BISPECIFIC MABS Rearranged IgVK3-15/JK1 IgKC IgVK3-15/JK1 JK2-5 // Rearranged human VK3-15 light chain “Germlining” human VK3-15 light chain combined with diversifying heavy chain combined with diversifying heav
Slide 10: OmnidAb: Heavy Chain Only Transgenic Chickens
10 OmnidAb™: Heavy Chain Only Transgenic Chickens HCO STRATEGY USING TRUNCATED LIGHT CHAIN (TLC) tLC transgene tLC Chicken VH sdAb (hu Fc) See Abheepsa’s poster #50 tLC transgene + tLC human VHH sdAb VHH transgene (hu Fc) • Normal chicken heavy chain can express as VH alone • VHH transgene in develo
Slide 11: OmniTaur: Ultralong CDRH3s Create Novel Binding Domains
11 OmniTaur™: Ultralong CDRH3s Create Novel Binding Domains UNIQUE STRUCTURAL FEATURES OF ULTRALONG H3 ANTIBODIES CDRH3 Human Cow • Novel structure may enable targeting epitopes unreachable by standard antibodies • Long H3 domains can be expressed on human VH Stanfield, et.al. Sci Adv (2020) 6(20):
Slide 12: OmniTaur mAbs Share a Structural Theme with Bioactive Natural Peptides
12 OmniTaur™ mAbs Share a Structural Theme with Bioactive Natural Peptides “Picobody™” Natural peptide Shk peptide mAb RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC Cow antibody “knob” Long H3 mAbs potentially combine high biological potency with high target specificity SCPDGYRERSDCSNRPACGTSDCCRVSVFGNCLTT
Slide 13: mAb Binding Modes to Ion Channel Kv1.3
13 mAb Binding Modes to Ion Channel Kv1.3 H3 LENGTH IMPACTS TYPES OF MOLECULAR INTERACTION Long H3 mAb binds within pore Nanobodies (~15KD) bind turret loops Selvakumar et al, 2022 doi: https://doi.org/10.1101/2022.04.19.488765
Slide 14: OmniAb Antibody Repertoires
14 OmniAb Antibody Repertoires UNSURPASSED OPTIONS AVAILABLE TO ADDRESS DIVERSE PARTNER OBJECTIVES Structural and Benefits for therapeutics Host V genes immunological features discovery and development Full human V gene diversity Diverse V gene usage and mixed Widely accessible and flexible workflow
Slide 15: Screening Platforms
Omni Screening Platforms
Slide 16: Discovery Platforms
16 Discovery Platforms Create Diverse Screen Antibody Identify the Antibody Pools Candidates Right Antibody Immunization Isolate B-cells Expression Validation Sequence Bioinformatics Hybridoma Workflow Fusion Screen enrichment Single-cell B-cell optional NGS Workflow Our powerful single B-cell scree
Slide 17: Screening Technology: GEM Assay
17 Screening Technology: GEM Assay GEL ENCAPSULATED MICROENVIRONMENT Target 2 Dual bead GEM B-cell Target 1 Cell-based GEM Izquierdo et al. Microscopy, 2016, 1-12
Slide 18: Screening Technology: xPloration
18 Screening Technology: xPloration® 1 | Loading 2 | Assay + Machine Vision 3 | Recovery & Single-Cell NGS Bright Field Enzymatic Fluorescent Reactions Antibodies 1.5 million, 40 µm 6 million, 20 µm Label-free Enzyme Inhibitions Cell Surface Binding GFP Immune Reporter Activation cAMP Signaling 20 h
Slide 19: OmniAbs
OmniAbs
Slide 20: Deeper Characterization Identifies New Clonotype Families
20 Deeper Characterization Identifies New Clonotype Families Each dot represents an antibody Technology GEM xPloration Information NGS • xPloration® expands on majority of clonotypes identified by GEM assay • Multiple new clonotype families identified • Next-generation sequencing (NGS) adds support
Slide 21: The OmniAb Platform
21 The OmniAb Platform Create Diverse Screen Antibody Identify the Antibody Repertoires Candidates Right Antibody Create Diverse Pools of High-Quality Screen Millions of Cells to Find Further Characterize, Select & Naturally Optimized Antibodies Potential Therapeutic Candidates Optimize the Right An