Future Trends in Biotechnology Antibodies and What is … · Future Trends in Biotechnology –...

Future Trends in Biotechnology –Antibodies and What is Next?

Venture Capital Club Munich

Dr. Axel Wiest MPHMunich, July 21, 2010

Agenda

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• Executive Summary

• Boehringer Ingelheim

• Status Biotech 2010

• Antibody Success Story

• Unmet Medical Need / Technical Challenges

• Future Technology Trends

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• Boehringer Ingelheim’s strategic corporate venture fund fills in the gaps

• From “ Traditional Pharma/Size Matters/Blockbuster Medicine” to “Targeted Therapy/Individualized Medicine”

• The pharma innovation gap calls for innovative biotech solutions

• Monoclonal antibodies have achieved medical successes, but no “magic bullet” (yet)

• Various antibody improvements and new molecule classes are in development

• Next-generation biologicals/therapeutics will have to address efficacy, safety and costs

• In the future, several classes of therapeutic entities are likely (in development)

• Next-generation small molecules/chemicals (not covered)

• Next-generation monoclonal antibodies and derivatives

• Engineered binding proteins, e.g., protein scaffolds

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Executive SummaryExecutive Summary

Agenda

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Boehringer Ingelheim is one of the top 20 leading research-driven pharmaceutical companies in the world

Founded in Ingelheim am Rhein in 1885 by Albert Boehringer (1861 — 1939), with 28 employees

Boehringer Ingelheim 2009Among the top 20 leading R&D pharmaceutical companies

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Employees worldwide: 41,534

Research and development at 12 sites in 7 countries

Production sites in more than 15 countries

Affiliated companies worldwide: 142 in 50 countries

- Research and development 16.7 %

- Production 29.9 %

- Marketing and Sales 39.0 %

- Administration 12.7 %

- Average number of trainees 1.7 %

Net sales: EUR 12.721 billion

R&D expenditure: EUR 2.215 billion

Investments in tangible assets: EUR 630 million

Boehringer Ingelheim Venture Fund Strategic fund with focus on early technologies

• Investment focus on early technologies

• New therapeutic platforms (e.g. RNA silencing, regenerative medicine)

• New generation vaccines

• New generation protein and antibody technologies

• New molecular targets and/or first-in-class compounds

• Disease-related biomarkers

• Size: 100m€

• Initial investments of up to 2m€, total of up to 10-15m€ per venture

• Global scope

• Added-value expertise beyond capital investment:

• Confidentiality assured to protect our portfolio companies and entrepreneurs

• On request: value through BI’s extensive drug discovery, scientific and managerial expertise and access to selected relevant experts and knowledge

• Seasoned team: please contact via www.boehringer-ingelheim-venture.com

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Agenda

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The big picture view: From „Traditional Pharma“ to „Targeted Therapy/Individualized Medicine“

2010 ?Time

Efficiency gainsand valuecontributions

Basic researchand moleculardiagnostics arealready on thenext s-curve

“Targeted therapy/Individualized

medicine”

„Traditional Pharma“„Size Matters“

“Blockbuster Medicine”

Innovation is key to create medically differentiated products/benefit to patients Innovative products continue to command high prices / reimbursement and yield

high value returns8

R&D Investments versus new drug approvalsPharma’s innovation gap calls for biotech solutions

26 2522

28

53

39

30

35

2724

1721

31

2018

24

0 $

5 $

10 $

15 $

20 $

25 $

30 $

35 $

40 $

45 $

50 $

55 $

0

10

20

30

40

50

60

70

Phar

ma

R&

D (

$ b

illio

n)

New

Dru

g A

pp

rova

ls (

NM

Es)

New Drug Approvals (NMEs) PhRMA Member R&D Spending

PharmaInnovation

Gap

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Source: Burrill & Company9

10

DNARNA RNA

pAH9

6915 bp

Km

iNOS

SV40 polyA

CMV

Km Prom.

Col E1 ori

BGH poly A

Gene TherapyAntisense RNA Antisense RNA Monoclonal Antibody

Protein Substitution

Antigen/Receptor

Protein

The idea is to “hit the disease” at the molecular levelMonoclonal antibodies bind to extracellular antigens

The number of biopharmaceuticals in clinicaldevelopment grows strongly - antibodies in the lead

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+28 % +17 % -14 %+20%

Also, the biopharma market grows above average (CAGR 1998 – 2015: 14% vs. 4% Pharma)

Source: EvaluatePharma; vfa; BCG

122

102

33

162

Nu

mb

er o

f pro

ject

s

Agenda

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Antibodies as part of our immune system have set the standard. They …

binding sitebinding site

potential binding to immune cells

(effector function)

• …play an important role in the body‘s immune response to bacteria, viruses and cancer cells

• …are proteins produced after contact with substances (antigens) unknown to the immune system

• Antibodies recognize their target cells specifically and bind them via binding sites in accordance with the „key/lock principle"

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Human Immunogloblulin G (IgG)

The quantum leap: Milstein and Köhler developmonoclonal antibodies in mid-70s (Nobel Prize 1984)

Spleen Cells

(antigen+)

Myeloma Tumor Cells

(antigen-)

2) Fusion in Polyethylene Glycol

HybridomaUnfused

Myeloma

Cells

Fused

Myeloma

Cells

Fused

Spleen

Cells

Unfused

Spleen

Cells

Cell Death Cell DeathProliferation

3) Clonal expansion of a single cell

4) Monoconal antibodies:

Homogenous regarding

single antigen specificity

activity, affinity

1) Vaccination of mouse with antigen

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World market of monoclonal antibodiesThe medical success translates into an economic one, too

0

5000

10000

15000

20000

25000

30000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

USD

bn

Oncology Immunology Inflammatory Cardiovascular

Monoclonal AntibodiesCAGR

1998 – 2010: 36%

Year

Total MAb market

(USD bn)0.69 2.11 2.79 4.10 5.43 7.77 10.4 13.0 15.8 18.7 21.5 24.8 28.6

5

10

15

20

25

30

(US

D b

n)

Source: IMS; Datamonitor

Agenda

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For instance, the number of people with chronic conditions in the United States is rapidly increasing

Source: Partnership for solutions 2004, Chronic Conditions: Making the case for Ongoing care17

Enthusiasm

Idea

Hysteria

Reality

Disillusionment

Adaptation

Development

Increased

efficiency

The typical ups and downs of innovative technologies Monoclonal antibodies are no exception

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Challenges

• Lack of tissue and blood brain barrier penetration limits application to extra-cellular targets

• Limited success in solid tumors

• CNS diseases off-limits

• Limited to intravenous application

• Limited number of clinically relevant target create competitive environment

• Neutralization of clinical targets requires high dosages of monoclonal antibodies (costs) and investments in production volumes

Monoclonal antibodies are large moleculesStill plenty of challenges to overcome

Small molecules0,6 kD

Monoclonal Antibody150 kD

Agenda

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Efficacy (examples)

• Enhanced ADCC*, CDC** (improved product quality)

• Antibody Drug Conjugates (ADC)

• Dual targeting / T-cell engaging

• Oral activity to increase patient convenience and compliance

• Prolonged half life / increasing stability

• Increased affinity to improve receptor binding

• Improved tissue penetration to reach additional targets (e.g. CNS)

Safety (examples)

• Decreased immunogenicity to avoid neutralization of therapeutic

• Increased specificity to discriminate btw. target and off-target activities

Decreased investments, cost-effective development and production (examples)

• Disposables

• High titer expression systems

The wish list: In search of ever improving efficacy, safety, cost-effective development and production…

* ADCC: Antibody Dependent Cellular Cytotoxicity; **CDC: Complement Dependant Cytotoxicity

….and/or new molecule classes

see following slides

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Natural Killer Cell (NK)

Antigen PresentingCell (APC)

Cytotoxic T-Lymphocytes(CTLs)

a)

b)c)

d)

(a) Immediate effectmAb to antigen on the tumor cell surface, providing the target for Fc receptors on thesurface of NK cells. Cross-linking of receptorstriggers release of perforin and granzymesthat lyse the tumor cell

(b-d) Delayed and prolonged (memory) effectCell debris is taken up by APCs (b), which present thetumor antigens to B cells, triggering the release ofpatient‘s antibodies with specificities for numerousepitopes on the target antigens (c) and CTLs that arecapable of recognizing and killing cells that express the target antigen (d)

MonoclonalAntibody

(mAb)

Tumor Cell/Surface Antigens

Fc receptor

Patient‘sAntibodies

Efficacy/ADCC: The additional activation of the patient’s immune system is key to fight tumor cells

Efficacy/ADCC: Glycoengineering leads to ~100 fold increase of in-vitro tumor cell killing

-20

0

20

40

60

80

100

0,0001 0,001 0,01 0,1 1

Anti T-cell Mab

Potelligent® Mab Conventional Mab

0

20

40

60

80

100

0,0001 0,001 0,01 0,1 1

Cyt

otox

icit

y(%

)

Rituximab

Potelligent® Mab Conventional Mab

Mab concentration (µg/mL)Source: Biowa, Potelligent® Technology

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Efficacy/Antibody Drug Conjugates: Linking the antibody to toxic substances to kill the tumor cell

AntibodyDrug-conjugate

Tumor Antigen

Cell nucleus withDNA Lysosom

Cancer cell

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Antibodydesign

Thera-peutic areas

Target antigen

Removab®

EpCAM+ T-Cell

Immune effectorcells

Mal. AscitesOvarian CAGastric CA

EpCAM

Ertumaxomab

HER2neu+

T-Cell

Metastatic Breast CA

HER2neu

FBT-A05

CD-20+ T-Cell

B-CLLNHL

CD 20

Efficacy/Dual Targeting: Trifunctional antibodies activateT-cells and other immune cells effectively



Source: Fresenius Biotech/Trion Pharma25

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Monoclonal antibodies’ efficacy against cancer may be limited by their large size, which prevents them from penetrating into tissue (e.g., solid tumors)

Monoclonal Antibody

(IgG)

Single domain

fragments

Fv

VLVH

Bis-scFv

(bispecific)

Single chain

fragments

scFv

Diabody

(bivalent)

Heavy chains

Light chains

Fv

Fab

Fc

Fab Fragments

Fab

F(ab)2 (bispecific)

adhesive

domains

F(ab)2

Nanobodies

Antibody Derivatives/Mimetics

Antibody derivatives/mimetics try to combine the benefitsof antibodies and small molecules (in development)

Anti-Tumor Antibody

Proprietary α-CD3 Single-chain Antibodies

Linker

Single-chainAntibody

BiTE®

Tumor Cell

T-Cell

BiTE®

Target Antigen

CD3 receptor

Efficacy/Dual Targeting: Micromet‘s platform technology(BiTE®) demonstrated first clinical proof of concept

27Source: Micromet; BiTE® Bispecific T-Cell Engager

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New molecule classes: various protein scaffolds on the horizon (in development)

Ubiquitin

Features of these engineered binding proteinsSmall (10 - 30 Kda), high affinity, high pH & temperature stability, short half lifeTargets: e.g., solid tumors, CNS

Anticalin CrystallinDARPin

Aptamers Fynomers TetranectinsAffibodies

Many thanks for your attention!

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Boehringer Ingelheim Biopharmaceuticals:From Mind to Market in a One-Stop-Shop Approach with trendsetting technologies

in process science, engineering and manufacturing

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