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AbCheck Combining affinity, stability, functionality & drugability

on customized antibody formats

Company PresentationMarch - 2011

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Profile

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AbCheck utilises three synergistic platforms for the discovery and generation of human antibodies:

Proprietary Phage Display libraries and Yeast Display of full-length IgG or novel formats

combined into the unique AbSieve technology

Highly validated proprietary Phage Display libraries ensure fast and reliable discovery of highly specific and high affinity human antibodies for virtually every possible target protein

Track record of more than 25 successful antibody discovery projects

Three different proprietary libraries with a combined diversity of 1010 human antibodies

In-licensed Yeast Display technology allows screening of all antibody formats and improves drugability of drug candidates

Selects improved drug candidates from a huge number of variants

Selection in the most relevant format including full-length IgGs, customer specific and novel antibody formats

Services range from antibody discovery to lead optimization

Attractive tailor-made deal structures and with no royalty obligations to its partners

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Three paths to success

Phage Display

o Proven commercially – fast, robust and flexibleo Proprietary libraries with a combined diversity of 1010

provide a reliable source of highly specific human antibodies

o Monovalent display for isolation of high affinity binders

o Allows cell panning, selection of internalizing antibodies, epitope-focused selections and much more

o Isolated VH/VL pairs constitute “binding units” and can be used in every antibody format from IgG to customer specific and novel formats

Yeast Display

o Displays functional full length IgGs , tandem scFvs , scFvs and in all probability new customer specific and novel antibody formats

o Eukaryotic ER proof reading mechanism selects-out misfolded antibodies

o Display efficiency correlates with expression yields and stabilities of soluble antibodies

o Highest level of control by real-time, quantitative selection of antibody clones by FACS

o Enables antibody engineering in the relevant antibody format

AbSieve•Yeast Display of enriched AbCheck phage display libraries in two to three panning rounds

•Batch recloning of enriched pool

•Yeast Display and FACS-based selection in the most relevant format

•Expression of soluble antibodies - including full length IgGs - enables direct screening for functionality

•Apply to existing antibodies for improvement in affinity, expression, stability and functionality

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AbCheck Workflow - Overview

AbSieve: Combined strength of Phage and Yeast display

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AbSieve: Increased probability of antibody success

AbSieve combines the strength of highly validated phage display libraries with the advanced possibilities of yeast display to address antibody specifications beyond affinity.

Ready-to-use and highly validated phage display libraries with 1010 different molecules are optimal tools to discover new antibodies in minimal time.

Monovalent display on the phage allows selection of high-affinity antibodies to monomeric, dimeric or oligomeric soluble targets or targets in their native environment on the cell surface.

Improved drugability through yeast display, selecting for enhanced soluble expression levels and stability of antibodies.

The yeast proof reading mechanism guarantees expressability in eukaryotic systems.

Yeast Display in combination with FACS allows real-time monitoring and full control of the selection process.

Screening in the final drug format avoids any drop outs caused by changes in the format.

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Significantly increased probability of

reaching market by identifying antibodies

to exact specifications

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Proprietary Libraries

AbCheck uses three validated distinct human librariesNatural library derived from immune system’s antibody gene repertoire Further info

Fully synthetic library Further Info

Semi-synthetic library combining aspects of both natural and synthetic antibody libraries Further info

Comprising a total of about 1010 sequentially and structurally diverse antibodies. Advantages

Higher probability of isolating very specific human antibodies against every target High diversity; approximately 1010 not only in sequence, but also in structural diversityAntibodies tuned to best target specific properties

ValidationTrack record of more than 25 successful antibody discovery projectsMore than 10 antibodies from AbCheck libraries in pre-clinical programs, one in the clinicOutstanding screening expertise including:

Several complex cell surface receptors as well as GPCRSubnanomolar affinitiesExtreme specificities

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Library validation + panning procedure

Affinities

Monovalent binding affinities within the low nanomolar region obtained from primary screens

Low koff rates even for monovalent scFv

Transfer into bivalent IgG usually increases binding strength by orders of magnitude

Several means of affinity maturation can be applied to enhance the affinity even further

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Library validation + panning procedure

Extreme Specificities

Efficient counter-selection strategies were successfully applied to isolate antibodies with extreme specificities:

Isoform specific antibodies: We have isolated an antibody to the Fc receptor CD16A (FcRIIIa) that does not bind

the CD16B isoform despite 96% sequence identity between the two isoforms.

Specific binding to deletion mutants without binding to the wild type protein:Specific targeting of deletion mutants is challenging, because the only unique epitope

is at the fusion site of the fragments upstream and downstream of the deleted part.

Conformation-specific antibodies:By depleting the libraries of binders to the non-activated platelet receptor GPIIb/IIIa

we were able to isolate antibodies to the activated form of the receptor.

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Library validation + panning procedure

Functionality

Most of the therapeutic applications require not only binding of the antibody but depend on agonistic or antagonistic activity. From our libraries we have isolated antibodies with different functions beyond binding:

Agonistic antibodies: Binding of the anti CD16A antibody to the receptor activates NK cells and is very

efficient in inducing ADCC.

Blocking antibodies:The isolated anti GPIIb/IIIa antibody inhibits binding of fibrinogen to activated

thrombocytes.

Antagonistic antibodies:We have isolated an anti IL13R antibody that interrupts the IL13 signalling cascade.

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Library validation + panning procedure

Diversity

Our libraries have a combined complexity of 1010 antibodies. In the natural library all VH and VL families are included giving the maximal possible structural diversity. The synthetic library extends the diversity beyond the limits of naturally occurring antibody sequences. A combination of natural and synthetic diversity proved in further increasing the diversity.

In a typical project 5 to 10 different antibodies meet the requested specifications.

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Our Discovery Capabilities

Lead Optimisation

Phage or Yeast DisplaySublibraries for lead optimisation can be created for phage or yeast display

AddressingAffinity, expression levels, stability and functionality

Possible in different antibody formatsYeast Display platform allows lead optimisation of IgGs or other antibody formats

De novo isolation of antibodies

Phage DisplayReady-to-use highly validated phage display librariesStrong experience in panning strategies including cell panning

AbSieveChange to final drug format during the selection processFACS-based selections

Characterisation

Affinity and specificityELISA & flow cytometry titrations Biacore

StabilityAssessed in thermofluor assays

In vitro functionalityTarget specific cell-based assays

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Partner Benefits

Three discovery platforms ensure three paths to the best antibodies

AbSieve is based on highly productive and validated technologies

Drugable antibodies delivered in very competitive time frames to virtually any target

Three distinct proprietary libraries expressing about 1010 human antibodies

Significantly increased probability of identifying antibodies to exact specifications

Proven track record of isolating more than 25 different human antibodies

Strong IP position allowing flexible, tailored deal structure

No royalty obligations to third parties

Senior team with a proven track record in the discovery and research of therapeutic antibodies

Proven, highly enabling technologies combined with attractive cost structures

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The Human antibody discovery specialist in commercially validated yeast and phage technologies

Antibody discovery for virtually all targets in all formats

Higher probability of reaching market by screening in final antibody drug format

The unique AbSieve technology delivers drugable antibodies within highly efficient timelines

Three commercially validated diversified antibody libraries

AbCheck offers tailored deals with no royalty obligations

Thank you

Summary

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Senior Management

Dr. Volker Lang (Managing Director)16 years experience in the biotechnology sector, spanning basic research, industryR&D, Business Development and Licensing, commercial operations and managementBackground as scientist and project manager combined with extensive experience inthe commercialization of biotechnology productsConsiderable CMC/Production experience in his previous positions as Chief Business Officer (Affimed Therapeutics AG) and Vice President Corporate Development (Scil Technology GmbH)

Dr. Vera Molkenthin (Chief Scientist and Head of Discovery)Many years experience in the selection of antibodies using phage displayPhD from the Faculty of Biology in Mainz with main focus on construction of a phagedisplay library and the selection of stabilizing mutationsHead of Screening at Affimed with responsibility for the management of the screeninggroup, with special emphasis on generation of highly diverse antibody libraries, anddesign and execution of the most appropriate selection procedure for a particulartarget

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Contact

Volker Lang, PhD(Managing Director)

Phone: +420 378 05 1500 V.Lang@AbCheck.eu

AbCheck s.r.o.

Vedeckotechnicky park Plzen

Teslova 3

CZ-301 00 Plzen

www.AbCheck.eu

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Appendix

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Fully human libraryIn vivo created diversity of antibody sequences comprising sequential as well as structural diversityNew combinations of VH and VL chains from multiple healthy donorsNo bias due to amplification of the VH chains by IgM specific primingSpecial assembly technology guarantees > 70% functional clones

Natural Antibody Library

Reliable and rapid selection of highly specific and high affinity antibodies on recombinant proteins or cells

Back to Libraries

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Fully Synthetic Library

Synthetic libraryGenerated by introducing randomized sequences in the antibody binding site of selected frameworksEnsuring reliable folding and high expression yieldsDiversity generated in vitro thereby Avoiding counter selection against anti-self antibodies

Back to Libraries

Semi-synthetic libraryCombining the advantages of the natural and synthetic libraryDiversity and reliable folding and high expressionIncreasing the diversity of binding molecules even further

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Semi-Synthetic Library

Back to Libraries

The following four slides define the yeast display library AbCheck utilises for antibody discovery

SECANT platform is the proprietary technology of Celexion LLC

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Yeast Display Explained:

TM

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• The SECANT™ platform is a next-generation antibody display system that can handle large and complex proteins

• First yeast system to display full-length IgG antibodies• Proven to display tandem scFv, bispecific and proprietary scaffolds

• Enables high throughput assay of 108 to 109 variants for • De Novo Antibody Discovery• Complex Scaffold Engineering• Scaffold Reformatting• Affinity Maturation• Stability/Solubility/Folding Control• Humanization

• The SECANT™ platform will accelerate discovery timelines by allowing faster characterization and higher throughput

• SECANT™ platform is compatible with many types of proteins and libraries• Full length IgG and scFv, fibronectin, receptor ectodomains, superoxide dismutase, human serum albumin, vitamin D-binding protein

SECANT™ Platform Overview

Source: CelexionSource: Celexion

SECretion and CApture Tech. (SECANT™)

1. The gene for the variant protein to be engineered (the “gene of interest“) is expressed as a fusion to a biotin acceptor peptide (BAP). A co-expressed biotin ligase attaches biotin to the BAP tag on the expressed protein.

1. The gene for the variant protein to be engineered (the “gene of interest“) is expressed as a fusion to a biotin acceptor peptide (BAP). A co-expressed biotin ligase attaches biotin to the BAP tag on the expressed protein.

2. Avidin is attached to the outer wall of the host cell.2. Avidin is attached to the outer wall of the host cell.

Source: CelexionSource: Celexion

SECANT™ platform (continued)

4. The captured proteins can be assayed for binding, expression, or enzymatic activity by labeling with a fluorophore-tagged ligand, antibody, or substrate. Protein functionality can then be assayed and the best clones isolated by FACS.

4. The captured proteins can be assayed for binding, expression, or enzymatic activity by labeling with a fluorophore-tagged ligand, antibody, or substrate. Protein functionality can then be assayed and the best clones isolated by FACS.

3. The biotinylated protein of interest is secreted into the extracellular space where it binds to the surface-localized avidin. Approximately 105 proteins can be captured on the yeast surface in this manner.

3. The biotinylated protein of interest is secreted into the extracellular space where it binds to the surface-localized avidin. Approximately 105 proteins can be captured on the yeast surface in this manner.

Source: CelexionSource: Celexion

SECANT™ platform can display functional, full-length IgG

Source: CelexionSource: Celexion