omniab® · pdf file · 2017-10-04evaluate pharma february 2016 0 2 4 6 8 10 12...

Naturally optimized human antibodies®

OmniAb®December 22, 2016


Market

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Antibodies, Leading Therapeutic Class

Evaluate Pharma February 2016

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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

Top-20 product forecast, 2015-2020- Half antibodies (blue)- Half non-antibodies (orange)- Sales growth from $91B to $124B- 53% of sales from antibodies

Global sales ($B)

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$80B 2015E$150B 2020E

Murine (5) Chimeric (9) Humanized (33) Human phage (5) Human transgenic (19) Human (1)

ReviewRomosozumab (UCB)Inotuzumab (Pfizer)Ocrelizumab (Roche)

Sirukumab (Janssen)Dupilumab (Regeneron)Brodalumab (Amgen)Sarilumab (Regeneron)

Xilonix (Xbiotech)

2016Obiltoxaximab (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)

00sCatumaxomab (Fresenius)I‐131 Tositumomab (GSK)Ibritumomab Tiu. (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)

Belimumab (GSK)Adalimumab (AbbVie)

Denosumab (Amgen)Golimumab (Janssen)Ustekinumab (Janssen)Canakinumab (Novartis)Ofatumumab (GSK)Panitumumab (Amgen)

90s

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

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

80s OKT3 (Janssen)

Reichert Oct 2016

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US antibody phase IIIs – Doubling in 5 years

26 25 25

29

33

39

53

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10

20

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2010 2011 2012 2013 2014 2015 2016

Reichert Nov 2015

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US antibody clinical programs

90115

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150 115

17

0

50

100

150

200

250

300

Phase I Phase II Phase III

Non‐cancer

Cancer

Reichert Oct 2016

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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


Business

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OmniAb Advantage

OmniRat– Industry‐only rat– Freedom‐to‐operate– Industry‐first head‐to‐

head with wildtypeOmniMouse– Industry‐only dual species– Freedom‐to‐operate– No Regeneron law suitOmniFlic– Only rat for bispecifics– Freedom‐to‐operate– TeneoSeek avoids

hybridoma limitations

OmniAb– All non‐confidential info– www.omniab.comOptions– Front‐ or back‐loaded– Royalty ranges– Rat‐ or mouse‐onlyPartner control– Indications– Territories– Combinations– SublicensingAgreement– Easy 20 pages– Partner proven

Animal hosting– Global master colonies– All species and genetic makeupsOmniDeep– Gateway to diverse CROs– www.omnideep.com

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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 genetic 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

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OmniDeep™

Industry‐only rat for

monospecific hmAb discovery

One of few mouse hmAb platforms with

FTO

OmniDeep™Global network of antibody

discovery CROs, hybridoma‐free

Industry‐only rat for

bispecific hmAb discovery

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OmniAb access options

• Platform access• Clinical milestones• Royalties

Unlimited license

• Target fee• Clinical milestones• Royalties

Individual target license

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

Unlimited buy‐out

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Partners29 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

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>100 successful antibody campaigns– >10,000 fully human high affinity binders

Good manufacturability, high affinity, expected PKFirst Phase I trial in 20153 INDs in 20165‐10 INDs in 2017

OmniAb Antibody Development


Animals

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Platforms for hmAb discovery

VH

CH3

CH2

hinge

VL

VH C

CH1

CH2

CH3

hinge

Ligand unlimited platform license TENEO sequence license

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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

Improved genetic engineering based on proven technology

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Novel and proprietary knockout technology

Sangamo Zn‐finger technology– Exclusive license for Rat Ig knockout

Zn‐finger nuclease– One cut per genome– DSB repair– Mutation

Inactivation of rat antibody expression

Target sequence (exon of coding gene)

Non Homologous End‐Joining(NHEJ)

deletion insertion

Gene Disruption

DSB

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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 immunology gene knock‐out

Science2009, July 24, 325: 433‐

European Journal of Immunology2010, 40: 2932–2941

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OmniRat/OmniFlic/UniRat

New KO Technology–Heavy chain J‐locus deletion–Kappa light chain mutation–Lambda constant region deletion

Rat antibody expression 100% inactivated

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Transgenic immunoglobulin lociRepresenting the human V(D)J repertoire

m‐RNA Human Antibody

Human LC locus

VL…………… VL1 J Ck +

VJ C

VH………VH1 D J E Cm Cd C2b E A

Easy

Conversion

Heavy chain locus

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Transgenic immunoglobulin lociRepresenting the human V(D)J repertoire

m‐RNA Human Antibody

Human LC locus

VL…………… VL1 J Ck +

VJ C

VH………VH1 D J E Cm Cd C2b E A

Easy

Conversion

Heavy chain locus

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Rat and mouse transgenesis

X

One‐cell embryo

Microinject DNA construct

Implant in hormone‐treated female

Transgenic offspring

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OmniRat and OmniMouseFunctional recombinant immunoglobulin loci– Productive rearrangement of all functional human VH, DH, JH and VL, JL– Normal human frequencies of V‐, D‐, J‐gene usage– Normal human CDR3 length

Normal B‐cell developmentHigh expression of human antibodiesNormal hypermutation and affinity maturation

• Sprague Dawley• Brown Norway• Lewis

• B6/SJL


Antibodies

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ImmunizationStandard (every 3‐4 weeks +/‐ adjuvant)Rapid (2x/week for 4 weeks)Rapid (1x at base of the tail)DNA prime/protein boostCell prime/DNA boostAddition of T‐cell epitope

• Sprague Dawley• Brown Norway• Lewis

• B6/SJL

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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

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%

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Anti‐ß gal response in OmniRat & OmniMouse

OmniMouse

OmniRat

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Kinetics and epitope binning of anti‐PG mAbs

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Hybridoma generationOMT rats make antibodies as well as 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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Journal of Immunology 2013

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

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High number of unique binders

Target Homology human/rat

# screened clones

# binders # unique binders

1 99% 7896 511 1752 98% 6768 337 1303 67% 2880 297 49

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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

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OmniRat vs phage display antibody binding

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

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DNA immunization

MONOCLONALPOLYCLONAL

Polyclonal sera (8 weeks) Monoclonal antibodies(4 months)

No need for isolated protein or peptide during the process or for screening

Start from electronic cDNA sequences

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.

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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%)

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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)

Parallel immunization with KO mice unsuccessful

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%)

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Anti‐CD3 (human and cyno)

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Transgenic animals for hmAb discovery

Fixed L‐chain IgG antibodies

OmniFlic with rearranged human L‐chain expressed with any (human) IgH locus

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OmniFlic anti‐PDL‐1

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Immune response – cellular perspectiveMultiple injections, 5‐6 week immunization time course Harvest cells from lymph nodes

Millions of naïveB 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)

Plasma or memory cell differentiation

Our analysis is focused onLN‐derived B‐cells

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Immunization & LN harvest

Immunization & LN harvest

Deep sequencing, Ranking

Deep sequencing, Ranking

Gene Assembly & Expression

Gene Assembly & Expression

Ab Characterization

Ab Characterization

Display, Select Display, Select

Sequence AnalysisSequence Analysis

Ab Characterization

Ab Characterization

Isolate Antigen Specific B‐cellsIsolate Antigen Specific B‐cells

HC Repertoire Cloning & Expression

HC Repertoire Cloning & Expression

Ab Characterization

Ab Characterization

HC Repertoire Cloning

HC Repertoire Cloning

OmniFlic antibody discovery methods

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Cloning, expression and selection in yeast

expression and identification

RT‐PCR

VH D JH

V

V2

V3

V4

V6

J or C

XhoI

cloning

fixed VL JL

````````

VH DJH

S SS S

Aga1

Aga2 HA

yeast cell

Bio

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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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OmniDeep screening strategy– 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

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6 OmniFlic rats,injected with PDL1

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

Example: PDL1 antibody discovery in OmniFlic

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HCAb Repertoire Rank Analysis

1 2 3 4 5Adj only rats Adj+antigen rats

LN samples used for hybrid/yeast display

Blue= hybridoma/yeast display sequences from rat #6

Blocks of red= high freq seqs unique to one antigen rat

high freq seqs found in multiple antigen rats but not in adj-only rats

Antigen-selected samples

high freq seqs found in antigen rats and adj-only rats

1 2 3 4 5 6 7

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Selection of antibodies for primary screenHigh‐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

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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 bindingBlue= negative binding

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PDL1 ligand‐blocking sequence families

Primary Screen– Identified 2 antigen‐specific

antibody families with ligand blocking activity

Secondary Screen– Identify family members with

higher affinity and fewer sequence liabilities

Primary Screen Secondary Screen

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affinity (nM) CDR seq liability1.31.32.2 met,nglyc2.7 met4.0 met5.0 nglyc6.36.87.88.08.28.4 nglyc9.0 nglyc

10.0 deam,met13.7 met,nglyc13.714.4 met from primary screen16.118.421.923.225.4 deam29.038.548.249.0 from primary screen49.553.7 nglyc79.5

PDL1 ligand‐blocking family #1

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PDL1 ligand‐blocking family #2affinity (nM) CDR seq liability

4.4 isom,cys4.9 isom from primary screen5.9 isom6.1 isom6.3 isom6.9 isom6.9 isom7.8 isom,cys8.0 isom

10.1 isom11.3 isom11.8 isom,cys12.3 isom17.5 nglyc20.6 deam,isom23.5 isom61.4 isom62.8 isom67.0 deam,isom82.0 deam,isom92.0 isom

870.0 deam,isom980.0 isom

1665.0 deam,isom1750.0 deam,isom1920.0 deam,isom2480.0 deam,isom2670.0 deam,isom2710.0 deam,isom

OmniAb®Naturally optimized human antibodies®

omniab® · pdf file · 2017-10-04evaluate pharma february 2016 0 2 4 6 8 10 12...

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