Biotechnology Center of ExcellenceJanssen Research & Development, LLC

Engineering Multi-functionality

into Antibodies

Engineering Multi-functionality

into Antibodies

Barry Springer, Ph.D.V.P. and Head of Biologics Technology, Strategy, and External PartneringJanssen R&D, Pharmaceutical Companies of J&J

Texas FreshAIR Immuno-Oncology October 23, 2014

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Antibody Engineering Technologies are Transforming the Immuno-Onc Strategy and Approach

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Bispecific or Bifunctional Abs in the ClinicNames of Biologics Company Targets Platform Indication Current PhaseStelara Janssen IL12 & IL23, 

bifunctionalbinding to p40 subunit

IgG1 Psoriasis Approved

20‐2b 20‐2b INFalphaR/CD20 dock & lockNon‐hodgkinsLymphoma Ph II

ABT122 Abbott TNF/IL‐17 DVD‐AbRheumatoid arthritis Ph 1

ABT981 Abbott IL‐1 alpha & beta DVD‐Ab Osteo Arthritis Ph 1

AFM13 Affimed CD30/CD16a TandAbHodgkins Lymphoma

Ph 1/2a (AFM13‐101)

Blinatumomab (MT103) Amgen (Micromet) CD3/CD19 BiTE ALL, NHL Ph 2MT‐110 Amgen (Micromet) CD3/EpCAM BiTE Solid tumors Ph 1

MT‐111 (MEDI‐565)  Amgen (Micromet) CEA/CD3 BiTEGastrointestinal cancer Ph 1

MT‐112 (BAY2010112) Bayer/Amgen PMSA/CD3 BiTE Prostate Cancer Ph 1 CTA submitted

CVX241 CovX (Pfizer) VEGF/Ang2 mAb peptide fusionAdvanced Solid Tumors Ph 1

ETI‐204 (Anthim) Elusys Therapeutics RCB CR1 x Anthrax Chemically fused antibodies Anthrax infection Ph 2Catumaxomab (Removab) Fresenius/Trion CD3/EpCam mouse/rat Malignant Ascities ApprovedErtumaxomab Fresenius/Trion HER2/CD3 mouse/rat Breast cancer Ph 2FBTA05, With Donor Lymphocyte Infusion Fresenius/Trion CD20/CD3 mouse/rat? B‐cell lymphoma Ph 2

GSK‐2434735 GSK IL‐13/IL4 domain antibody (Domantis) Asthma Completed Ph 1

COVA‐322 Covance TNF/IL-17 IgG1 ‐ FynomerRheumatoid arthritis Ph 1

Multi-specifics in the Pharma Pipeline

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In the beginning….STELARA® (ustekinumab)

• Approved for moderate to severe plaque psoriasis in 72 countries

• Offers unprecedented convenience with only 4 doses per year

• Winner of Prix Galien award US and International for best biotech product

First in Class Human Anti-IL-12/23 p40 Monoclonal Antibody

Kauffman CL, et al. J Invest Dermatol 2004;123:1037-1044.

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Multiple Platforms Producing Multi-Specifics at Janssen

• Bispecific Abs – Genmab DuoBody platform

• Ab-alternative scaffold hybrids

– Centyrins

– Fynomers

• Alternative Scaffolds

• Peptides

Bivalent,bispecific

Tetravalent,bispecific

Tetravalent,trispecific

Tetravalent,tetraspecific

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Genmab DuoBody Bispecific Antibody Technology

Cancercell

T cell

T cell mediated LYSISIgG1 Bivalent,monospecific

IgG1 Bivalent,bispecific

Mildreduction

andre-oxidation

**

**

**

Labrijn et al. 2013 Efficient generation of stable bispecific IgG1by controlled Fab-arm exchange PNAS 110:5145-5150

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Oncogenic Drivers in Lung Adenocarcinoma

• Primary EGFR mutations (ex19del, L858R) occur in ~17% non-Asian and ~50% Asian patients with lung adenocarcinoma

• Patients treated 1st line with EGFR tyrosine kinase inhibitor (TKI) erlotinib, gefitinib, afatinib

• 70% response rate but all acquire resistance and relapse

Modified from Blakely and Bivona, Cancer Discovery; 2012, 2:872-875; with adaptations from R. Herbst

EGFR

KRAS

Other

PI3K

METINSR

PDGFREPHA/B

HER2

ALK

VEGFRROS

BRAF

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JNJ-372 Binds EGFR and cMet With High Affinity and Inhibits Ligand Binding to Each Receptor

JNJ-372 binds EGFR-ECD with KD = 1.4 nM, 25x tighter binding than EGF ligand

JNJ-372 inhibits binding of EGF to EGFR-ECD

JNJ-372 binds cMet-ECD with KD = 39 pM, 820x tighter binding than HGF ligand

JNJ-372 inhibits binding of HGF to cMet-ECD

EGFR cMet

HGF

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Bispecific Shows Increase in Potency Compared to Combination of Monospecific mAbs

-2 -1 0 1 2 30

1000

2000

3000

4000n=3

Treatment Conc. log[nM]

pER

K s

igna

l

EGFR monospecific

cMet monospecific

55-fold increase in potencyIC50 = 0.64 nM

Bispecific JNJ-372

IC50 = 35 nM+Combination

H292 CellsEGFR wt; MET wt

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JNJ-372 in EGFR Mutant/ MET Amp PDX Model Compared to Erlotinib + MetMab

Patient Explant Model

LU858EGFR: L858R;MET amp 

0 10 20 30 40 500

500

1000

1500

2000

2500

Dosing phase

Mea

n tumou

r volum

e / mm

3 Vehicle

Erlotinib

Afatinib

MetmabErlotinib+Metmab

JNJ-372

Days

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JNJ-372: Three Mechanisms of Action

Receptor degradation

Inhibition of ligand-driven EGFR/cMETsignaling

ADCC

JNJ-372 treatment results in degradation of both EGFR and cMet in vivo

JNJ-372 inhibits EGF-stimulated pEGFR and HGF-stimulated pMet

JNJ-372 inhibits pERKand pAKT

Enhanced ADCC with low fucose JNJ-372 in vitro

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CentyrinsAn alternative scaffold with excellent biophysical properties

• Structural homology to antibody variable domains

• Consensus sequence of Fn3 domains of hTenascin C

• Small (10 kDa), simple, highly stable single domain proteins• No cysteines, glycosylation• Rapidly selected using in vitro CIS-display• Can be formatted in multi-specific molecules• Cost-effective and simple purification

FG

BC

DE

CD

EF

AB

Multiple libraries

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0.1 1 10 100 1000 10000 1000000

10000

20000

30000

40000

50000

60000

Biologic (nM)

pEG

FR (

RC

LU)

0.1 1 10 100 1000 10000 1000000

10000

20000

30000

40000

Biologic (nM)

pMet

(R

CLU

)

0.01 1 100 10000 10000000

5000

10000

15000

20000

25000

30000

Biologic (nM)

pER

K (

RC

LU)

Biologic IC50 value of pMet

IC50 value of pEGFR

IC50 value of pERK

High affinity EGFR binder 1 >10,000

Low affinity cMet binder 610 >10,000

Mixture 438 1 368

Bi-specific 1 5 6

EGFR high C

cMetlow

Bispecific Centyrin: CNTX158Selective tumor targeting due to avidity

(ECB1)

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High-High (25 mg/kg)

High-Low (25 mg/kg)

Low-High (25 mg/kg)

Low-Low (25 mg/kg)

High-Low (2.5 mg/kg)

High-Low (0.25 mg/kg)

PBS

Bi-specific Centyrins Inhibit Growth of Tumor Cells in a Xenograft Model

Proliferation of lung tumor cells

Dose CentyrinIP (25 mg/kg)

Implant 2x106 tumor cells

X

α-EGFR: KD ~ 0.4 nM(Loop Library)

α-cMet: KD ~ 0.2 nM(Sideways Library)X = Half-life extension domain

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Combine Centyrins and mAbs to create bi- and/or multispecific mAbtyrins

IL17 targeting Centyrin

IL 13 mAb

Multispecific Ab Engineering: mAbtyrins

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• Anti-IL13 activity unaffected by centyrin

• mAbtyrin has activity similar to anti-IL17 mAb

Oncology Discovery• Sheri Moores (co‐lead)• Mark Anderson• Barbara Bushey• Kristen Chevalier • Amanda Cavanaugh • Frank McCabe• Jeffrey Nemeth• Leopoldo Luistro• Diana Wiley • Ricardo Attar• Rob Kramer

Oncology Biomarkers• JP Karkera• Dana Gaffney• Katherine Bell• Gabriela Martinez• Christopher Moy

AcknowledgementsBiologics Research 

• Mark Chiu (co‐lead)• Audrey Baker• Eric Beil• Deidra Bethea• Ken Boakye• Randall Brezski• Marguerite Campbell• Susanne Corisdeo• Natalie Fursov• Wei Gao• Leslie Gardner• Ron Gervais • Jiang Haiyan• Peter Haytko• Katherine Heeringa• Victoria Hull• Stephen Jarantow• Thomas Kelly• Eilyn Lacy• Steve Lang • Tom Nesspor• Steven Orcutt• Jose Pardinas• Steve Pomerantz • Dennis Powell

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Centyrex (internal venture)• Karyn O’Neil• Steve Jacobs

Biologics Research• Kevin Smith• Keri Soring• Stacey Spencer• Justin Sprenkle• Annmarie Winkis• Sam Wu

Photo by John Masucci

Development Team • Matt Lorenzi • Joe Erhardt• Kevin Emes• Leonid Freytor• Sherin Manuel Chacko• Javier Pintado• Houjun Yang• Amy Han• Adam Dinerman• Parul Doshi• Vijay Peddareddigari• Carla de Boer• Sylvie Laquerre

Genmab• Joost Neijssen• Janine Schuurman• Riemke van Dijkhuizen • Paul Parren

Thank You!

Art Credit:Space-filling model of STELARA® (ustekinumab), an antibody therapy approved for the treatment of adults with moderate to severe plaque psoriasis, and being investigated for multiple immune-mediated inflammatory diseases