OmniAb Naturally optimized human antibodies

Transcription

1 OmniAb Naturally optimized human antibodies Industry s only multi species, genetically engineered platforms for generation of mono and bispecific fully human antibodies

2 top 20 forecast ($B) Evaluate Pharma February top-20 product forecast - $91B in 2015, $124B in % antibodies by count - 53% antibodies by $ Humira (TNF) Revlimid Opdivo (PD 1) Harvoni Prevnar Avastin (VEGF) Hercerptin (Her2) Soliris (C5) Tecfidera Orkambi Entresto Rituxan (CD20) Enbrel (TNF) Remicade (TNF) Xtandi Januvia Keytruda (PD 1) Eliquis Eylea (VEGF) Triumeq

3 56 animal vs 3 phage derived approved mabs Murine (5) Chimeric (8) Humanized (26) Human phage (3) Human transgenic (14) 2016 Infliximab US (Celltrion) Elotuzumab (BMS) Mepolizumab (GSK) Daratumumab (Janssen) 2015 Blinatumomab (Amgen) Unituxin (United) Idarucizumab (BI) Nucala (GSK) Necitumumab (Lilly) Alirocumab (REGN) Evolocumab (Amgen) Secukinumab (Novartis) 2014 Siltuximab (Janssen) Pembrolizumab (Merck) Vedolizumab (Takeda) Numax (AZ) Adalimumab IN (Cadila) Nivolumab (BMS) Ramucirumab (Lilly) 2013 Infliximab EU (Celltrion) Trastuzumab Emtansine (Roche) Obinutuzumab (Roche) Mogamulizumab (Kirin) Trastuzumab IN (Biocon) Itolizumab IN (Biocon) 2012 Pertuzumab (Roche) Raxibacumab (GSK) 2011 Brentuximab vedotin (SGEN) Belimumab (GSK) Ipilimumab (BMS) 2000s Catumaxomab (Fresenius) I 131 Tositumomab (GSK) Ibritumomab Tiuxetan (Biogen) Cetuximab (Lilly) Tocilizumab (Roche) Certolizumab Pegol (UCB) Eculizumab (Alexion) Ranibizumab (Roche) Bevacizumab (Roche) Natalizumab (Biogen) Nimotuzumab (Daiichi) Efalizumab (Roche) Omalizumab (Roche) Alemtuzumab (Sanofi) Gemtuzumab (Pfizer) Adalimumab (AbbVie) Denosumab (Amgen) Golimumab (Janssen) Ustekinumab (Janssen) Canakinumab (Novartis) Ofatumumab (GSK) Panitumumab (Amgen) 1990s 1980s OKT3 (Janssen) Infliximab (Janssen) Basiliximab (Novartis) Rituximab (Roche) Abciximab (Janssen) Palivizumab (AZ) Trastuzumab (Roche) Zenapax (Roche) $80B 2015E $150B 2020E BioPharm Insight Mar

4 US antibody phase IIIs doubling in 5 years Reichert Nov

5 US antibody clinical programs Non cancer Cancer Phase I Phase II Phase III 37 Reichert Nov

6 Therapeutic antibody programs 1,021 preclinical 342 phase I 276 phase II 137 phase III 15 filing 49 distinct generic names (including combos & company sharing) BioPharm Insight August

7 OmniAb Naturally optimized human antibodies

8 Platforms for hmab discovery V L V H C H 1 hinge C H 2 C H 3 C V H hinge C H 2 C H 3 Ligand unlimited licenses TENEO sequence license 8

9 OmniAb platform development Inactivation of endogenous rat Ig genes Heavy chain J locus Light chain Cκ Light chain Cλ Recombinant immunoglobulin loci Kappa light chain Lambda light chain Heavy chain 9

10 Inactivation of endogenous rat Ab expression Zn finger technology Exclusive license for rat Ig knockout One cut per genome Double strand break repair Mutation Double strand break Target sequence (exon of coding gene) Non homologous end joining (NHEJ) deletion insertion Gene disruption 10

11 Micro injection, ZNF targeted mutagenesis X Transfer to pseudopregnant females Newborns ZFN1/ZFN2 Extract DNA to look for ZFN activity One cell embryo 11

12 Science first rat Ig gene knock out Science 2009, July 24, 325: 433 European Journal of Immunology 2010, 40:

13 Improved genetic engineering Old, suboptimal New, improved Abgenix Medarex Hematech Kirin Therapeutic Human Polyclonals Regeneron KyMab OmniAb Suboptimal BCR signaling Normal BCR signaling 13

14 Transgenic V(D)J immunoglobulin loci Human light chain locus VL VL 1 J Ck + VH VH 1 Human heavy chain locus D J E Cm Cd C 2b E A VJ C m RNA Human Antibody Easy Conversion 14

15 Rat and mouse transgenesis X One cell embryo Microinject DNA construct Implant in hormonetreated female Transgenic offspring 15

16 OmniRat makes Abs like normal rats 5 different antigens Single immunization on day 0 Lymph node fusion on day fusions 5 highest affinity Abs Animal Antigen Cells* fusions titer hybrids IgGs** Kd*** SD PG LN nm OmniRat PG LN nm OmniRat hghr LN , 3, 2 ND SD TAU/KLH LN # nm OmniRat TAU/KLH LN # nm SD HEL LN nm OmniRat HEL LN , 2, nm SD OVA LN nm OmniRat OVA LN , 30, 0, nm Similar titers Similar # of hybridomas 502 mabs confirmed by Biacore 16

17 9% 63% 41% 23% 10% 20% 17

18 OmniRat range of pharmacological profiles Phage displayderived IgG OmniRat derived IgG OMT A1 OMT A2 Target 1 K D *= 1.9 nm K D = 2.3 nm K D = 219 nm OMT B1 OMT B2 OMT B3 Target 2 K D *= nm K D *= 0.02 nm K D *= 0.13 nm K D = 0.33 nm OMT C1 OMT C2 OMT C3 OMT C4 Target 3 K D = 15 nm K D = 0.07 nm K D = 0.01 nm K D = 7 nm K D *= 4 nm * Estimated affinities 18

19 OmniRat produces anti GPCR antibodies Immune serum (1:1000 dilution) of a representative animal is tested on mammalian cells transfected with the cdna encoding for the target antigen (human = green curves, mouse = blue), on a stable cell line, or with an irrelevant construct (red curves) Three fusions with ten immunized animals 11 positive hits out of 1824 tested samples (0.6%) 34 positive hits out of 1920 tested samples (1.8%) 2 positive hits out of 1920 tested samples (0.1%) Parallel immunization with KO mice unsuccessful 19

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21 Two species, better epitope coverage Different antibody titers Different immune response genes SD vs BN vs LEW vs Mouse Bl6/SJL Human antigen rat antigen mouse antigen Different V genes (human vs rat vs mouse) Blocking Antibodies: OmniMouse vs OmniRat vs Mouse vs Rat Isotype Switching Increased IgM+/decreased IgG+ B cells in OmniRat Mouse vs Rat Fc Mouse Rat Epitope coverage Gene Human/Mouse Human/Rat Mouse/Rat CD30* 54.0% 50.1% 83.4% CD22* 58.7% 56.9% 77.7% CD % 61.3% 80.9% CD % 43.4% 63.4% CD % 41.0% 64.9% IL 1 beta 64.7% 63.8% 86.9% 21

22 Kinetics and epitope binning of anti PG mabs 22

23 OmniDeep sequence based discovery Platform is a unique combination of Antibody repertoire deep sequencing Custom bioinformatics analysis High throughput vector assembly Recombinant expression and screening 23

24 OmniDeep screening strategy Primary screen: All prominent CDR3 sequence families (ELISA, affinity, functional) Secondary screen: Complete lineages of primary hits (affinity, functional) hit Primary Screen: diverse CDR3 sequences Guided by lineage rank analysis Secondary Screen: unique sequences per lineage Includes rare sequences in lineages of interest hit 24

25 PDL1 antibody discovery in OmniFlic 6 OmniFlic rats, injected with PDL1 Lymph nodes from 2 legs x 2 tech reps of each = 4 total samples/rat Deep sequencing and analysis done on each sample Candidates expressed as fully human IgG with fixed light chain 25

26 Antibody repertoire lineage rank analysis Each column an independent sample PDL1 OmniFlic rats Each row is a unique CDR3 family Heat map key: Red= highest frequency sequence Blue= lowest frequency sequence 26

27 OmniAb multidimensional advantage Scarce therapeutic targets n Single monoclonal technology Single platform epitope coverage, affinity, specificity, etc. Suboptimal antibody discovery for each scarce clinical target OmniAb OmniRat OmniMouse OmniFlic Multiple species and backgrounds o Broader epitope coverage o Higher affinity o More specificity choices Bispecific antibodies o Simultaneously address two therapeutic targets o Engage effector functions o Strong intellectual property Greater antibody discovery for each scarce clinical target 27

28 Partners 24 partners 18 with unlimited access for milestones and/or royalties Three fully paid up LLC style One academic, anti PD 1 for China and OmniFlic for CART Strategic partners Three animal breeders and knock out providers Four CROs US, Europe and Japan 28

29 OmniAb access options Unlimited license Annual access fee Clinical milestones Royalty on sales Individual target license Target fee Clinical milestones Royalty on sales Unlimited buy out Buy out fee Single or multi year NO milestones or royalties 29

30 OmniAb Only rat for monospecific hmab discovery OmniAb Only multispecies for mono and bispecifics One of few mouse hmab platforms with FTO Only rat for bispecific hmab discovery 30