Revival of Bispecific Antibodies

Patrick A. Baeuerle Micromet, Inc.

Empowering Antibodies for Cancer Therapy: Three Major Trends

Conventional (IgG1) Herceptin Rituxan Erbitux Campath

Antibody Drug Conjugates

Fc-engineered (ADCC)

Bispecifics (T cell-engaging)

T-DM1 SGN-35

GA101 MEDI-563

Removab ANYARA Blinatumomab

Bispecific Antibodies
q First reports on bispecific antibodies in the mid eighties q 2009: First bispecific antibody obtains market approval (Removab by Fresenius Biotech/Trion Pharma) q 2010- : Have now industry meetings with focus on bispecific antibodies q Most large biopharma players became public about early-stage bispecific antibody developments q Major promise of bispecific antibodies is enhancement of antibody efficacy by combining two activities in one molecule Neutralization of two ligands by one mAb Inhibition of two receptors by one mAb Crosslinking of two receptors on one cell Redirecting cytotoxic immune cells q Reduced effort vis--vis antibody combination approach by avoidance of dual development effort and cost

Bispecific Antibody Deals since 2009

q BiTE antibodies for cancer therapy (Micromet)
Bayer Schering Pharma (2009); 1 solid tumor target Sanofi-aventis (2009); 1 solid tumor target Boehringer Ingelheim (2010); 1 multiple myeloma target

$900M

q DART antibodies (MacroGenics)

Pfizer (2010); 2 cancer targets Boehringer Ingelheim (2010); up to 10 target combinations

not. discl. $2.1B

$250M

q Fcab and MAb2 antibodies (F-star)

Boehringer Ingelheim (2010); up to 7 targets

q Fc-engineered IgG1 (Xencor)

AMGEN (2011); CD19/CD32B dual-specific IgG for immune modulation $500M

Deal Volume of >$3.5B for Bispecifics in 2009-2011

More than 35 Bispecific Antibody Formats in Current Development Classifications

Class I: Asymmetric IgG-Like

Triomab/Quadroma Trion Pharma/ Fresenius Biotech
Anti-EpCAM Anti-HER2 Anti-CD20 Anti-GD2 Anti-CD3

Knobs-into-Holes Genentech

CrossMAbs Roche

Electrostatically-matched AMGEN
Anti-CD32B/Anti-CD64 Anti-CD32B/Anti-FcRI

LUZ-Y Genentech

Rat IgG2b/Mouse IgG2a

+- +

Cleavable Leucine Zipper Domains

Strand Exchange Engineered Domain (SEED)body EMD Serono

Anti-GD2

Biclonic Merus

Fab-Exchanged Genmab

Common Light Chain IgG/IgA Chimeric CH3 Domain

IgG4 Hinge IgG4 CH3 Domain

Class II: Symmetric IgG-Like

Dual Targeting (DT)-Ig GSK/Domantis Two-in-one Antibody Genentech
Anti-HER2/Anti-VEGF Anti-EGFR/Anti-HER3 Anti-DR5/Anti-VEGF

Crosslinked MAbs Karmanos Cancer Center

Anti-IL-4/Anti-IL-13 Anti-VEGF/Anti-EGFR

Anti-CD3

Single Domain Antibody OKT-3

Chemical Crosslinker

mAb2 F-star
Anti-CD20/ Anti-TNF

CovX-body CovX/Pfizer
Anti-VEGF/Anti-Ang-2 Bivalent Ligand

Herceptin or Rituxan

Reactive Lysine in CDR3 Fcab

Anti-HER2 Anti-CD20

Two Extra vH In CH3 Domain

Class III: IgG Fusions

Dual Variable Domain (DVD)-Ig Abbott
Anti-IL-1/Anti-1 Anti-IL-12/Anti-IL-18 Anti-TNF/PGE2 Anti-CD20/Anti-CD3 Extra vH/vL

IgG-like Bispecific Eli Lilly

Anti-EGFR/Anti-VEGFR2 Anti-EGFR/Anti-IGF-1R Anti TRAIL-R/Anti-LTR

Extra vH/vL

Ts2Ab MedImmune/AZ
ScFv 1

BsAb ZymoGenetics

HERCULES Biogen Idec

TvAb Roche

Anti-IL-12/Anti-IL-18 Anti-IL-1/Anti-IL1 Anti-EphA2/4/Anti-Ephrin 2

Anti-IL- 17A/Anti-IL-23 Anti-PDGFR/Anti-VEGF-A Anti-LTR/Anti-TRAIL-R Anti-VEGF/Anti-Ang-2

ScFv 2

ScFv

Class IV: Fc Fusions

ScFv/Fc Fusions Academic Institution SCORPION Emergent BioSolutions/ Trubion ZymoGenetics/BMS

ScFv 1

ScFv 2

ScFv 1 Anti-CD79B/Anti-DR Fc Part Fc Part Anti-CD19/Anti-CD37 Anti-VEGF-A/Anti-PDGFR2

ScFv 2

Dual Affinity Retargeting Technology (Fc-DART) MacroGenics

Stabilized Diabodies

Dual(ScFv)2-Fab National Research Center for Antibody Medicine

ScFv 1 ScFv 2 Anti-CD20 Epitope 1/ Anti-CD20 Epitope 2

Extra Disulfide Bond VH1-VH2 Fc Part Fc Part

Class V: Fab Fusions

F(ab)2 Medarex/AMGEN
Anti-HER2/ Anti-CD64

Dual-Action or Bis-Fab Genentech

Anti-EGFR/ Anti-HER3R Thiobody Fab 1 Fab 1 Thiobody Fab 2

Fab 2 Chemical Crosslinker

Fab-Fv UCB-Celltech

Polyethylenglycol Fab

Dock-and-Lock (DNL) ImmunoMedics

Anti-CD22/ Anti-CD20 Anti-CEA/Anti-Hapten

Bivalent Bispecific Biotecnol

VH/VL Anti-BCL1 Anti-Albumin

Fab 1

DDD2 S . AD2 S . S S

Fab 1 Fab C ScFv 1 CH1 ScFv 2

Fab 2 Anti-CD3 Anti-BCL1

Class VI: ScFv- and Diabody-based

Bispecific T Cell Engager (BiTE) Micromet
Anti-CD19 Anti-EpCAM Anti-CEA Anti-EGFR Anti-EphA2 Anti-MCSP Anti-PSMA Anti-CD3

Tandem Diabody (Tandab) Affimed

Anti-CD30/Anti-CD16A Anti-CD19/Anti-CD3

Dual Affinity Retargeting Technology (DART) MacroGenics

Anti-CD32B/Anti-CD16A Anti-CD32B/Anti-CD79B Anti-CD19/Anti-CD3

Single-chain Diabody Academic

Anti-CEA/Anti-CD3 FAP-alpha/Anti-CD3

ScFv 1

Diabody 1

Diabody ScFv 2 Linker Extra Disulfide Bond

Diabody

Linker

Diabody 2

TCR-like Antibodies AIT, ReceptorLogics

Antibody Recognizing Peptide/MHC Complex ScFv 1

Human Serum Albumin ScFv Fusion Merrimack

Anti-HER2 Anti-HER-3

COMBODY Epigen Biotech

Single Domain Antibody

Anti-HLA-A2

ScFv 1

ScFv 2

COMP48 Domain ScFv Anti-CD3

ScFv 2 Anti-CD3

Human Serum Albumin

Class VII: IgG/Non-IgG Fusions

Superantigen Fusion Protein Active Biotech
Anti-5T4

Immunocytokines EMD Serono, Philogen, ImmunGene, ImmunoMedics

Cytokine (IL-2)

Fab

ScFv Engineered Bacterial Superantigen

Anti-EBD Domain

Anti-CD20 Anti-EpCAM Anti-GD2

Immune Mobilising mTCR Against Cancer (ImmTAC) Immunocore

Anti-gp100/HLA-A2 High Affinity T Cell Receptor

Cytokine (IL-2, IL-12, IFN-2)

ScFv

Anti-CD3

Alternative Solution for Multitargeting

Oligoclonal Antibodies Symphogen
(3-26 mAbs) (3-5 MAbs)

Merus

Anti-Rhesus D Anti-EGFR

Shared Light Chain

+
Shared Light Chain

Non-Ig Scaffolds Are Suitable for Making Small Multifunctional Antibody-like Molecules
Adnectins Adnexus/BMS
Anti-VEGF-R2 (CT-322) Fibronectin Type III Domain-based (10Fn3)

Anticalins Pieris
Lipocalin-based

Affilins SCIL Proteins

Ubiquitin-based

Trans-bodies BioRexis/Pfizer
Transferrin -based

Affibodies Affibody

DARPINs Molecular Partners

TrimerX Anaphore (Borean)

MicroProteins Selecore
Cys-rich Domainbased

Protein A Domain-based

Tetranectinbased Ankyrin Repeat-based

Fynomers Covagen
Fyn SH3 Domainbased Anti-IL-17

Avimers Avidia/AMGEN
EGFR A Domainbased

Centyrins Centyrex/ J&J Ventures

KALBITOR (Ecallantide) Dyax

Kunitz Domainbased

Centyrin-based (Ig-like)

+ AlphaBodies by Complix

Outlook
q Bi/multispecific antibodies are en vogue q Bi/multispecificity has been recognized as key technology for empowering antibodies q More than 35 formats of bi- and multispecific antibodies and derived constructs are under early development by majority of biopharma companies q Six bispecific antibody deals made over last 2 years with cumulative volume in excess of $3.5B q >Empowering antibodies by bi/multispecificity goes beyond use in cancer therapy => Many developments are in inflammatory disease areas q Antibody mixtures emerge as alternative for multi-targeting (>$200M investment in Symphogen) q Bi/multispecific biologicals based on alternative scaffolds are also in the works