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Yeast Display-Based Antibody Discovery and Optimization Technologies Avantgen Company Overview

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Yeast Display-Based Antibody Discovery and Optimization Technologies Avantgen Company Overview Advantageous Technologies, Exceptional Results Yeast Display-Based Antibody Discovery and Optimization Technologies AvantGen Company Overview • Services and Collaborations – San Diego-based leader in providing antibody discovery and optimization services based on its state-of-the-art yeast display technology platform • Rapid discovery of human antibodies • Exceptional antibody humanization and optimization • Rabbit mAb generation for IHC and PK/PD studies • Core technologies – Superior antibody yeast display platform • Proprietary, inducible, secretable display motif – Comprehensive human antibody database – Large collection of human antibody libraries • Team – Proven expert R&D and business leaders in therapeutic antibodies 2 Yeast Display is a Superior Platform • Widely recognized as a preferred technology platform for rapidly discovering and optimizing mAbs of exceptional quality for therapeutic development • Can also be used to optimize and humanize antibodies originating from in vivo immunization or in vitro phage display approaches 3 Core Platform Technology Advantages Comparison of in vitro Antibody Discovery and Optimization Platforms Features Phage Display Yeast Display Antibody Format Limited Extensive Display Diversified Limited/Biased Excellent Libraries ¹ Developability Low High ¹ Yeast System Provides Improved Display of Diversity Across Diverse Human Antibody V Families vs. Phage Phage Display Yeast Display 4 Core Platform Exceptional Human Antibody Libraries • Constructed to mimic natural sequence variation in human antibodies to reduce immunogenicity and increase developability • Informed by deep-sequencing of human antibody repertories from > 500 individuals • Largest known collection of yeast display libraries (>100 billion clones in Fab, scFab, and scFv formats) • Most potentially problematic sequence motifs have been removed from the library Glycosylation sites Cleavage sites Isomerization sites Oxidation sites Deamidation sites Free cysteines 5 Rapid and Efficient Discovery of Human Antibodies for Therapeutic Development Individual yeast clones seeded into 96-well plates. Culture SNs used for 96 well assays 10 weeks to identify 10s-100s suitable clones 6 Core Platform Antibody Optimization Fold Sample ID K (M) K (1/Ms) K (1/s) Full R^2 D on off Improvement WT 5.24E-07 2.75E+05 1.44E-01 0.99 1 Clone A 2.60E-10 6.08E+04 1.58E-05 0.99 2000 Clone B <1.0E-12 8.28E+04 <1.0E-07 0.99 >1000 • Focused libraries are constructed based on our proprietary database for the specific antibody clones to be optimized • Libraries are displayed with AvantGen’s yeast display system and screened with ultra-high throughput FACS • Affinity improvement (correlates with drug potency) of >1,000 fold can be achieved by just one round of library construction and screening 7 Core Platform Antibody Affinity Maturation Target: Receptor with 12-transmembrane regions Antigen: Soluble form not available Screening: Using cell lysate prepared from transiently transfected cells that express target-GFP fusion protein WT clone Affinity matured Clone, F10 Antibody display only Antibody display and Antibody display and Antibody display and in the presence of 10% in the presence of 10% in the presence of 10% cell lysate (target-GFP) cell lysate (target-GFP) cell lysate (target-GFP) Plus WT soluble IgG as Plus control soluble IgG as competitor competitor 8 Yeast Display Platform Extension: Rabbit mAbs • Coupling rabbit immunization and yeast display library screening to generate rabbit mAbs • Ultra high specificity capable of recognizing ̶ Single point mutation ̶ Post modification sites ̶ Differential cleavage sites ̶ Anti-idiotype antibodies • High affinity clones: pM to sub-nM range 9 Novel Rabbit Monoclonal Antibodies Generated with AvantGen’s Platform Antigen Clone Affinity Peptide sequence (nM) AVG300 D4 0.01 LALQAQPVPDELVTK AVG301 E11 0.01 DITSDTSGDFR AVG308 A6 0.04 Phospho-peptide specific VADPDHDHTGFLTEyVATR AVG309 H4 0.04 Phospho-peptide specific KD =40 pM RPHFPQFsYSASGTA AVG308: VADPDHDHTGFLTEyVATR AVG310: VADPDHDHTGFLTEYVATR y indicates phosphorylated residue 10 Isoform-Specific Rabbit Monoclonal Antibodies HbS: VHLTPVEKSAV HbA: VHLTPEEKSAV HbC: VHLTPKEKSAV HbF: GHFTEEDKATITS 11 Rabbit Monoclonal Antibodies for IHC and PK Studies (Anti-Idiotype) Anti-target Fab, clone E12 4 3.5 3 2.5 2 1.5 1 0.5 Isotype control Rabbit anti-target 0 clone B4 1 2 3 1. Target: Human Fab Scale bar = 50 mm 2. Irrelevant human Fab A 3. Irrelevant human Fab B 12 Typical Timelines* Project Method/Goal Timeline Antigen-Specific 2 months Novel Fully Human Antibody Discovery Antigen- and epitope-specific 2-3 months (e.g., blocking antibody) CDR grafting 2 months Antibody Humanization Epitope-guided selection of CDR-H3 focused library 2-3 months Affinity Optimization Affinity improvement: 10 to 1000-fold 2-3 months Rabbit Monoclonal Rabbit immunization, library construction and 5-6 months Antibody Generation screening /sub-nM binders * Time to positive hits, excluding the time needed for subcloning and antibody production 13 Excellent Collaborative Record 14 Accomplished Leadership • Xiaomin Fan, Ph.D. – Founder, President & CEO – Founded AvantGen in 2006; Inventor of the company’s technology platforms – Previously, Scientist/Sr Scientist/Group Leader, Targeted Molecules Corp. • Therapeutic antibody programs partnered with Sanofi; currently in Phase II and I trials – Ph.D., University of Kansas; Post-doc, University of Pennsylvania • Tom Smart – Head, Corporate Development – Biopharma business leader with multiple Board and CEO appointments – Prior C-level and BD positions at therapeutic antibody technology pioneers AnaptysBio, Chairman & CEO (NASDAQ: $2B mkt cap); XOMA, CBO; Cell Genesys (Abgenix/Amgen), and other business roles at Genetics Institute (Pfizer) and Searle (Pfizer) – BS, Cornell University; MBA, University of Chicago Booth School of Business • Catherine Woods, Ph.D. – Vice President of Research – Joined AvantGen in 2007; Broad and extensive experience (>20 years) in the pharmaceutical and biotech industry – Previously, Exec Director, Research, Targeted Molecules Corp; Assoc. Director, Clinical Research/Sr Director, Biological Research & Tech Transfer, Alliance Pharmaceutical Corp; Research Fellow, Merck Research Laboratories – Ph.D., University of California, Davis; Post-doc, California Institute of Technology 15 Case Studies Internal projects pursed to highlight the performance advantages of AvantGen’s human antibody discovery and optimization platform 1. Anti-CD16a based NK cell engager platform 2. Anti-BCMA antibodies for multiple myeloma therapy 16 Significant Interest in NK Cell Engagers August 27, 2018 Globe Newswire Affimed Announces Collaboration with Genentech to Develop Novel NK Cell Engager- based Immunotherapeutics for Multiple Cancer Targets Affimed will receive $96 million upfront and committed funding and is eligible for up to an additional $5.0 billion including milestone payments, and royalties on sales October 1, 2018, Cision PR Newswire Dragonfly Therapetics Announces New Multi-Target Collaboration with Merck to Use Dragonfly's Proprietary TriNKET™ Platform to Develop Novel Drug Candidates for Patients with Solid Tumors Dragonfly to earn up to $695 million in up front and milestone payments per program as well as royalties on sales of approved products 17 Example From an In-house Project • Target antigen: CD16a • Part of effort to generate NK cell engager platform – identify highly specific anti- CD16a antibody clones • Affinity to CD16a is important for the clinical efficacy of anti-cancer therapeutic antibodies • CD16a expressed on natural killer cells, macrophages, subpopulation of T-cells • A single nucleotide polymorphism creates higher Fc-binding (176V) and low Fc- binding (176F) forms. 60% populaon has 176F and 40% with 176V → bind both • CD16b expressed in 70% of leukocytes (CD16b+ granulocytes) → avoid binding Ideal profile of the antibody candidates CD16A(176V) CD16A(176F) CD16B Activate NK cells X 18 Alignment of CD16a and CD16b CD16a and CD16b have 98% homology Ideal antibody would exhibit high affinity and specificity against both allotypes of CD16a (176F and 176V), without cross-reactivity to CD16b The three green residues represent the only specific differences between the two CD16a allotypes and the two CD16b allotypes 19 Discovery of CD16a Specific Human Antibodies Screening of AvantGen’s yeast display human antibody libraries Enrichment sort MACS Enrichment sort For both 176V and 176F binders FACS Subtractive sort Removal of CD16b binders ELISA CD16a-expressing-293F FACS analysis of CD16b-expressing-293F individual clones Untransfected293F 20 The Anti-CD16a Antibody Clones are of High Affinity/Specificity Antibody DNA subcloned from yeast into mammalian expression vector; purified antibody from ExpiCHO cells used to determine KD values 21 HPLC Analysis of IgG1-A2 and IgG1-Affimed After Protein A Chromatograph Purification Histidine in the buffer Histidine in the buffer IgG1-A2 IgG1-Affimed 22 Affinity Comparison of Anti-CD16A Clone A2 and Affimed’s Antibody by Octet A2/Affimed have comparable binding affinity to CD16A, with no detectable cross-reactivity to human CD16B Human CD16A Human CD16B Cyno CD16A IgG1-A2 1.28 nM Not detectable 6.6 nM IgG1-Affimed 1.70 nM Not detectable 15.2 nM 23 Clone A2 in a Bispecific Format Activates CD16a Reporter Cells in a Target Cells-Dependent Manner aCD19 aCD16A scFv-scFv format 24 Design of Protease-Cleavable Bivalent NK Cell Engager Protease cleavage site (28 mg/mL
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