OmniAb December 22, Naturally optimized human antibodies

Transcription

1 OmniAb December 22, 2016 Naturally optimized human antibodies

2 Market Naturally optimized human antibodies

3 Antibodies, Leading Therapeutic Class Global sales ($B) Top-20 product forecast, Half antibodies (blue) - Half non-antibodies (orange) - Sales growth from $91B to $124B - 53% of sales from antibodies Evaluate Pharma February 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

4 Murine (5) Chimeric (9) Humanized (33) Human phage (5) Human transgenic (19) Human (1) Review Romosozumab (UCB) Inotuzumab (Pfizer) Ocrelizumab (Roche) Sirukumab (Janssen) Dupilumab (Regeneron) Brodalumab (Amgen) Sarilumab (Regeneron) Xilonix (Xbiotech) 2016 Obiltoxaximab (Elusys) Infliximab EU (Bioepis) Infliximab US (Celltrion) Elotuzumab (BMS) Mepolizumab (GSK) Atezolizumab (Roche) Reslizumab (Teva) Ixekizumab (Lilly) Olaratumab (Lilly) Bezlotoxumab (Merck) Daratumumab (Janssen) Necitumumab (Lilly) 2015 Dinutuximab (United) Idarucizumab (BI) Mepolizumab (GSK) Necitumumab (Lilly) Alirocumab (REGN) Evolocumab (Amgen) Secukinumab (Novartis) 2014 Blinatumomab (Amgen) Siltuximab (Janssen) Pembrolizumab (Merck) Vedolizumab (Takeda) Numax (AZ) Adalimumab IN (Cadila) Nivolumab (BMS) 2013 Infliximab EU (Celltrion) Trastuzumab Emt. (Roche) Obinutuzumab (Roche) Mogamulizumab (Kirin) Trastuzumab IN (Biocon) Itolizumab IN (Biocon) Adotrastuzumab (Roche) Ramucirumab (Lilly) 2012 Pertuzumab (Roche) Raxibacumab (GSK) 2011 Brentuximab vedotin (SGEN) Ipilimumab (BMS) 00s 90s Catumaxomab (Fresenius) I 131 Tositumomab (GSK) Ibritumomab Tiu. (Biogen) Cetuximab (Lilly) Infliximab (Janssen) Basiliximab (Novartis) Rituximab (Roche) Abciximab (Janssen) Tocilizumab (Roche) Certolizumab Pegol (UCB) Eculizumab (Alexion) Ranibizumab (Roche) Bevacizumab (Roche) Natalizumab (Biogen) Nimotuzumab (Daiichi) Efalizumab (Roche) Omalizumab (Roche) Alemtuzumab (Sanofi) Gemtuzumab (Pfizer) Palivizumab (AZ) Trastuzumab (Roche) Zenapax (Roche) Belimumab (GSK) Adalimumab (AbbVie) Denosumab (Amgen) Golimumab (Janssen) Ustekinumab (Janssen) Canakinumab (Novartis) Ofatumumab (GSK) Panitumumab (Amgen) $80B 2015E $150B 2020E 80s OKT3 (Janssen) Reichert Oct

5 US antibody phase IIIs Doubling in 5 years Reichert Nov

6 US antibody clinical programs Non cancer Cancer Phase I Phase II Phase III Reichert Oct

7 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

8 Business Naturally optimized human antibodies

9 OmniAb Advantage OmniRat Industry only rat Freedom to operate Industry first head tohead with wildtype OmniMouse Industry only dual species Freedom to operate No Regeneron law suit OmniFlic Only rat for bispecifics Freedom to operate TeneoSeek avoids hybridoma limitations Animal hosting Global master colonies All species and genetic makeups OmniDeep Gateway to diverse CROs OmniAb All non confidential info Options Front or back loaded Royalty ranges Rat or mouse only Partner control Indications Territories Combinations Sublicensing Agreement Easy 20 pages Partner proven 9 9

10 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 genetic 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 10

11 OmniDeep Industry only rat for monospecific hmab discovery OmniDeep Global network of antibody discovery CROs, hybridoma free One of few mouse hmab platforms with FTO Industry only rat for bispecific hmab discovery 11

12 OmniAb access options Unlimited license Platform access Clinical milestones Royalties Individual target license Target fee Clinical milestones Royalties Unlimited buy out Buy out fee Single or multi year NO milestones or royalties 12

13 Partners 29 user groups 24 with unlimited access for milestones and/or royalties 3 fully paid up in single transaction 2 academics Strategic partners Three animal breeders and knock out providers Four CROs US, Europe and Japan 13

14 OmniAb Antibody Development >100 successful antibody campaigns >10,000 fully human high affinity binders Good manufacturability, high affinity, expected PK First Phase I trial in INDs in INDs in

15 Animals Naturally optimized human antibodies

16 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 platform license TENEO sequence license 16

17 Platform development Improved genetic engineering based on proven technology 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 17

18 Novel and proprietary knockout technology Inactivation of rat antibody expression Sangamo Zn finger technology Exclusive license for Rat Ig knockout Zn finger nuclease One cut per genome DSB repair Mutation DSB Non Homologous End Joining (NHEJ) Target sequence (exon of coding gene) deletion insertion Gene Disruption 18

19 Micro injection, ZNF targeted mutagenesis X Transfer to pseudopregnant females Newborns ZFN1/ZFN2 Extract DNA to look for ZFN activity One cell embryo 19

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

21 OmniRat/OmniFlic/UniRat Rat antibody expression 100% inactivated New KO Technology Heavy chain J locus deletion Kappa light chain mutation Lambda constant region deletion 21

22 Transgenic immunoglobulin loci Representing the human V(D)J repertoire Human LC locus VL VL 1 J Ck + Heavy chain locus VH VH 1 D J E Cm Cd C 2b E A VJ C m RNA Human Antibody Easy Conversion 22

23 Transgenic immunoglobulin loci Representing the human V(D)J repertoire Human LC locus VL VL 1 J Ck + Heavy chain locus VH VH 1 D J E Cm Cd C 2b E A VJ C m RNA Human Antibody Easy Conversion 23

24 Rat and mouse transgenesis X One cell embryo Microinject DNA construct Implant in hormonetreated female Transgenic offspring 24

25 OmniRat and OmniMouse Functional recombinant immunoglobulin loci Productive rearrangement of all functional human V H, D H, J H and V L, J L Normal human frequencies of V, D, J gene usage Normal human CDR3 length Normal B cell development High expression of human antibodies Normal hypermutation and affinity maturation Sprague Dawley Brown Norway Lewis B6/SJL 25

26 Antibodies Naturally optimized human antibodies

27 Immunization Standard (every 3 4 weeks +/ adjuvant) Rapid (2x/week for 4 weeks) Rapid (1x at base of the tail) DNA prime/protein boost Cell prime/dna boost Addition of T cell epitope Sprague Dawley Brown Norway Lewis B6/SJL 27

28 Two species = more antibodies = 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% 28

29 Anti ß gal response in OmniRat & OmniMouse OmniMouse OmniRat 29

30 Kinetics and epitope binning of anti PG mabs 30

31 Hybridoma generation 5 different antigens OMT rats make antibodies as well as normal rats 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 mabs confirmed by Biacore

32 Journal of Immunology

33 9% 63% 41% 23% 10% 20% 33

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36 High number of unique binders Target Homology human/rat # screened clones # binders # unique binders 1 99% % %

37 Good diversity against conserved targets 20 IGHV, 11 IGKV, and 12 IGLV different germ lines isolated from 3 screening campaigns Some V genes are specific to one target selection 37

38 OmniRat vs phage display antibody binding 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 38

39 DNA immunization Start from electronic cdna sequences Polyclonal sera (8 weeks) Monoclonal antibodies (4 months) POLYCLONAL MONOCLONAL Cloning of human CEACAM5 cdna into our specially designed vectors cdna immunisation (GENOVAC Antibody Technology ) of OmniRat and Wistar rats. Immune response against the native antigen Fusion and hybridoma generation Screening and sub cloning Serum and supernatant test on native protein. Cross reactivity tests. No need for isolated protein or peptide during the process or for screening 39

40 Receptor protein complex Immune serum (1:1000 dilution) of a representative animal is tested on mammalian cells transfected with the cdna encoding for the target antigen (green curves) or with an irrelevant construct (red curves) Three fusions with 7 immunized animals 505 positive hits out of 960 tested samples (53%) 1122 positive hits out of 1632 tested samples (69%) 792 positive hits out of 864 tested samples (69%) 40

41 GPCR 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 10 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 41

42 Anti CD3 (human and cyno) 42

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47 Transgenic animals for hmab discovery OmniFlic with rearranged human L chain expressed with any (human) IgH locus Fixed L chain IgG antibodies 47

48 OmniFlic anti PDL 1 48

49 Immune response cellular perspective Multiple injections, 5 6 week immunization time course Harvest cells from lymph nodes Millions of naïve B cells in circulation Affinity maturation in GCs of LNs ~2M total B cells per LN ~20K ag specific B cells per LN (1%) ~200 ag specific CDR3 families per animal (based on GC model of normal rodent) Our analysis is focused on LN derived B cells Plasma or memory cell differentiation 49

50 OmniFlic antibody discovery methods Sequence Analysis HC Repertoire Cloning Display, Select Ab Characterization Immunization & LN harvest Isolate Antigen Specific B cells HC Repertoire Cloning & Expression Ab Characterization Deep sequencing, Ranking Gene Assembly & Expression Ab Characterization 50

51 Cloning, expression and selection in yeast RT PCR cloning V J or C V H DJ H V2 V3 V4 V6 XhoI expression and identification Aga2 S S S S Aga1 HA Bio ````` ``` V H DJ H yeast cell fixed V L J L 51

52 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 52

53 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 53

54 Example: PDL1 antibody discovery in OmniFlic 6 OmniFlic rats, injected with PDL1 LN tissue from 2 legs X 2 tech reps of each = 4 total samples per rat Deep sequencing and analysis done on each sample Candidates expressed as fully human IgG with fixed light chain 54

55 HCAb Repertoire Rank Analysis Adj only rats Adj+antigen rats LN samples used for hybrid/yeast display Antigen-selected samples Blue= hybridoma /yeast display sequences from rat #6 Blocks of red= high freq seqs unique to one antigen rat 55 high freq seqs found in multiple antigen rats but not in adj-only rats high freq seqs found in antigen rats and adj-only rats

56 Selection of antibodies for primary screen High frequency sequences chosen from 2 categories CDR3 families found in multiple rats CDR3 families found in individual rats 234 total heavy chain sequences 106 unique CDR3 sequence families Expressed as fully human IgG with fixed LC in HEK cells ELISA screen 56

57 Primary screen: PDL1 ELISA binding & affinity Each row is a unique VH sequence expressed as IgG with fixed LC 127 of 234 total abs positive by ELISA 62 of 106 unique CDR3 families positive by ELISA 1.3 nm highest affinity 2 different CDR3 sequences with ligand blocking activity in cell based assay Red= strong binding Blue= negative binding 57

58 PDL1 ligand blocking sequence families Primary Screen Secondary Screen Primary Screen Identified 2 antigen specific antibody families with ligand blocking activity Secondary Screen Identify family members with higher affinity and fewer sequence liabilities 58

59 PDL1 ligand blocking family #1 affinity (nm) CDR seq liability met,nglyc 2.7 met 4.0 met 5.0 nglyc nglyc 9.0 nglyc 10.0 deam,met 13.7 met,nglyc met from primary screen deam from primary screen nglyc

60 PDL1 ligand blocking family #2 affinity (nm) CDR seq liability 4.4 isom,cys 4.9 isom from primary screen 5.9 isom 6.1 isom 6.3 isom 6.9 isom 6.9 isom 7.8 isom,cys 8.0 isom 10.1 isom 11.3 isom 11.8 isom,cys 12.3 isom 17.5 nglyc 20.6 deam,isom 23.5 isom 61.4 isom 62.8 isom 67.0 deam,isom 82.0 deam,isom 92.0 isom deam,isom isom deam,isom deam,isom deam,isom deam,isom deam,isom deam,isom 60

61 OmniAb Naturally optimized human antibodies