OmniAb®Naturally optimized human antibodies®

Industry’s only multi‐species, genetically engineered platforms for generation of mono‐ and bispecific fully human antibodies

2

2020 top‐20 forecast ($B)

Evaluate Pharma February 2016

14.0

5.8

0.9

13.9

6.0

7.0 6.8

2.6

3.6

0.4 0.0

7.3

5.45.8

1.9

4.0

0.6

1.92.5

0.8

15.9

10.2

8.47.7

6.96.4

5.7 5.6 5.6 5.5 5.3 5.1 5.0 4.8 4.8 4.5 4.5 4.3 4.0 4.0

0

2

4

6

8

10

12

14

16

18

Hum

ira (T

NF)

Revlim

id

Opd

ivo (PD‐1)

Harvo

ni

Prevna

r

Avastin

 (VEG

F)

Hercerptin

 (Her2)

Soliris (C

5)

Tecfidera

Orkam

bi

Entresto

Rituxan (CD20

)

Enbrel (T

NF)

Remicad

e (TNF)

Xtan

di

Janu

via

Keytruda

 (PD‐1)

Eliquis

Eylea (VEG

F)

Triumeq

2020 top-20 product forecast- $91B in 2015, $124B in 2020- 50% antibodies by count- 53% antibodies by $

3

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)

2000sCatumaxomab (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

Infliximab (Janssen)Basiliximab (Novartis)Rituximab (Roche)Abciximab (Janssen)

Palivizumab (AZ)Trastuzumab (Roche)Zenapax (Roche)

1980s OKT3 (Janssen)

56 animal vs 3 phage‐derived approved mAbs

$80B 2015E$150B 2020E

BioPharm Insight Mar 2016

4

US antibody phase IIIs doubling in 5 years

26 25 25

29

33

39

53

0

10

20

30

40

50

60

2010 2011 2012 2013 2014 2015 2016

Reichert Nov 2015

5

US antibody clinical programs

85110

37

12595

16

0

50

100

150

200

250

Phase I Phase II Phase III

Non‐cancer

Cancer

Reichert Nov 2015

6

Therapeutic antibody programs

1,021preclinical

342phase I

276phase II

137phase III

15 filing

49 distinct generic names

(including combos & company sharing)

BioPharm Insight August 2015

OmniAb®Naturally optimized human antibodies®

8

Platforms for hmAb discovery

VH

CH3

CH2

hinge

VL

VH C

CH1

CH2

CH3

hinge

Ligand unlimited licenses TENEO sequence license

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

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Inactivation of endogenous rat Ab expression

Zn‐finger technology– Exclusive license for rat Ig knockout– One cut per genome– Double strand break repair– Mutation

Target sequence (exon of coding gene)

Non‐homologous end‐joining (NHEJ)

deletion insertion

Gene disruption

Double strand break

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Micro‐injection, ZNF‐targeted mutagenesis

X

One‐cell embryoExtract DNA to look for ZFN activity

ZFN1/ZFN2

Transfer to pseudopregnant 

females

Newborns

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Science‐first rat Ig gene knock‐out

Science2009, July 24, 325: 433‐

European Journal of Immunology2010, 40: 2932–2941

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Improved genetic engineering

AbgenixMedarexHematechKirinTherapeutic Human Polyclonals

Old, suboptimal New, improved

Suboptimal BCR signaling Normal BCR signaling

RegeneronKyMabOmniAb

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Transgenic V(D)J immunoglobulin loci

m‐RNA   Human Antibody

Human light chain locus

VL……………   VL1 J         Ck +

VJ C

VH………VH1 D            J     E Cm Cd C2b   E   A

Easy

Conversion

Human heavy chain locus

15

Rat and mouse transgenesis

X

One‐cell embryo

Microinject DNA construct

Implant in hormone‐treated female

Transgenic offspring

16

OmniRat makes Abs like normal rats

Animal Antigen Cells* fusions titer hybrids IgGs** Kd***

SD PG LN 1 38400 3520 38 0.3‐1.0 nM

OmniRat PG LN 1 12800 1600 148 0.7‐2.4 nM

OmniRat hGHR LN 3 4800 704‐1024 18, 3, 2 ND

SD TAU/KLH LN 1 20000 1728 99# 0.6‐2.4 nM

OmniRat TAU/KLH LN 1 4800 1880 118# 0.5‐3.2 nM

SD HEL LN 1 12800 1564 26 0.02‐0.1 nM

OmniRat HEL LN 3 25600 288‐640 0, 2, 7 0.6‐1.5 nM

SD OVA LN 1 9600 1488 10 1.1‐4.8 nM

OmniRat OVA LN 4 8000 512‐2240 0, 30, 0, 1 0.7‐1.5 nM

5 different antigens

Single immunization on day 0Lymph node fusion on day 21

16 fusions

Similar titers

Similar # of hybridomas

502 mAbs confirmed by Biacore

5 highest affinity Abs

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

18

OmniRat range of pharmacological profiles

Target 1

* Estimated affinities

Target 2

Target 3

KD*= 1.9 nM

OMT‐A1

KD= 2.3 nM

KD= 15 nM KD= 0.01 nM

OMT‐C2

KD*= 0.001 nM KD*= 0.02 nM

OMT‐B1

OMT‐C3

KD= 7 nM

OMT‐C4

KD*= 4 nM

OMT‐C1

KD= 0.07 nM

KD*= 0.13 nM

OMT‐B2

KD= 0.33 nM

OMT‐B3

OMT‐A2

KD= 219 nM

Phage display‐derived IgG

OmniRat‐derived IgG

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)

Parallel immunization with KO mice unsuccessful

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%)

20

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

RatMouse

Epitope coverage

Gene Human/Mouse Human/Rat Mouse/RatCD30* 54.0% 50.1% 83.4%CD22* 58.7% 56.9% 77.7%CD14 63.7% 61.3% 80.9%CD80 39.2% 43.4% 63.4%CD52 36.1% 41.0% 64.9%

IL‐1 beta 64.7% 63.8% 86.9%

22

Kinetics and epitope binning of anti‐PG mAbs

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

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– Primary screen: All prominent CDR3 sequence families (ELISA, affinity, functional)– Secondary screen: Complete lineages of primary hits (affinity, functional)

Primary Screen:100‐400 diverse CDR3 sequences

Guided by lineage rank analysis

SecondaryScreen:50‐300 unique sequences per lineage

Includes rare sequences in lineages of interest

hit

hit

OmniDeep screening strategy

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6 OmniFlic rats,injected with PDL1

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

PDL1 antibody discovery in OmniFlic

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1 2 3 4 5 6 PDL1 OmniFlic rats

Each

row

is a

uni

que

CD

R3

fam

ily

Each column an independent sample

Heat map key:Red= highest frequency sequenceBlue= lowest frequency sequence

Antibody repertoire lineage rank analysis

27

OmniAb “multidimensional advantage”

Scarce therapeutic targets 1 2 3 . . . 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 backgroundso Broader epitope coverageo Higher affinityo More specificity choices

• Bispecific antibodieso Simultaneously address two therapeutic targetso Engage effector functionso Strong intellectual property

• Greater antibody discovery for each scarce clinical target

28

Partners24 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

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OmniAb access options

• Annual access fee• Clinical milestones• Royalty on sales

Unlimited license

• Target fee• Clinical milestones• Royalty on sales

Individual target license

• Buy‐out fee• Single‐ or multi‐year• NO milestones or royalties

Unlimited buy‐out

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OmniAb

Only rat for monospecific 

hmAb discovery

One of few mouse hmAb platforms with 

FTO

OmniAbOnly multi‐species for mono‐ and bispecifics

Only rat for bispecific hmAb 

discovery