Bispecific Anticalin Fusion Proteins for Localized Targeting of Immune Cells for Application in Immuno-Oncology

Christine Rothe, Ph.D.

PEGS Europe Summit, Nov 4, 2016

Forward Looking Statements

Statements in this presentation that are not descriptions of historical facts are forward-looking statements that are based on management’s current expectations and assumptions and are subject to risks and uncertainties. In some cases, you can identify forward-looking statements by terminology including “anticipates,” “believes,” “can,” “continue,” “could,” “estimates,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “projects,” “should,” “will,” “would” or the negative of these terms or other comparable terminology. Factors that could cause actual results to differ materially from those currently anticipated include, without limitation, risks relating to the results of our research and development activities, including uncertainties relating to the discovery of potential drug candidates and the preclinical and clinical testing of our drug candidates; the early stage of our drug candidates presently under development; our ability to obtain and, if obtained, maintain regulatory approval of our current drug candidates and any of our other future drug candidates; our need for substantial additional funds in order to continue our operations and the uncertainty of whether we will be able to obtain the funding we need; our ability to retain or hire key scientific or management personnel; our ability to protect our intellectual property rights that are valuable to our business, including patent and other intellectual property rights; our dependence on third-party manufacturers, suppliers, research organizations, testing laboratories and other potential collaborators; competition in our industry; regulatory developments in the U.S. and foreign countries; as well as those risks more fully discussed in the “Risk Factors” section of our Current Report on Form 8-K filed with the SEC on December 18, 2014, the Company’s annual report on Form 10-K for the fiscal year ended December 31, 2014, the Company’s quarterly reports on Form 10-Q, and the other reports we file with the SEC. In light of these risks, uncertainties and assumptions, the forward-looking statements regarding future events and circumstances discussed in this report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. The forward-looking statements included in this presentation speak only as of the date hereof, and except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations.

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Company and Technology

Overview

Pieris Pharmaceuticals, Inc.

Anticalins are a novel class of protein therapeutics, proprietary to Pieris, with several degrees of validation

Human data demonstrating desired drug-like properties

– 26 solid tumor patients with VEGF-A antagonist

– 36 healthy volunteers with hepcidin antagonist

Proven track record for successful collaborations with Pharma

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Human Lipocalins – Scaffold for

Novel Anticalin® Therapeutics

Human lipocalin High-affinity (pM) “template” Anticalin bound to

Small target

Highly diverse phage display libraries (>1011) of potential drug candidates

Human, natural Automated selection and Medium

binding proteins target

screening technology

Low molecular

weight Deep protein engineering

(~1/8 of mAb size)

know-how to yield ideal Extracellular drug candidates

Non-immunogenic

Very stable “cup- Large like” structure target

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Going Beyond Anticalin Proteins – Multispecific Drug Candidate Formats

Pure Anticalin formats

Anticalin Duocalin Tricalin Tetracalin

mAb-Anticalin formats

Fc-Anticalin formats

Molecules designed for optimal target engagement and drug-like properties Binding site geometry can be adjusted to biological need

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Anticalin® Product Pipeline

Product Target(s) Indication Partner Discovery Preclinical Phase 1 Phase 2

PRS-080 Hepcidin Anemia pegylated Anticalin

Fully PRS-060 IL4Ra Asthma inhalable Anticalin Owned PRS-343 CD137/HER2 IO mAb-Anticalin fusion PRS-300s n.d. IO bi-/multispecifics

PRS-110 cMet Oncology Co- PRS-NN n.d. n.d.

Partner funded* Develop- Major rights retained ment PRS-NN n.d.

Ophthal- Stelis mology

PRS-NN n.d. Stelis

Daiichi n.d. n.d.

Fully Sankyo Partner funded n.d. n.d.

Partnered Milestones & Royalties Sanofi n.d. n.d.

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Anticalin® Product Pipeline

Product Target(s) Indication Partner Discovery Preclinical Phase 1 Phase 2

PRS-080 Hepcidin Anemia pegylated Anticalin

Fully PRS-060 IL4Ra Asthma inhalable Anticalin Owned PRS-343 CD137/HER2 IO mAb-Anticalin fusion PRS-300s n.d. IO bi-/multispecifics

PRS-110 cMet Oncology Co- PRS-NN n.d. n.d.

Partner funded* Develop- Major rights retained ment PRS-NN n.d.

Ophthal- Stelis mology

PRS-NN n.d. Stelis

Daiichi n.d. n.d.

Fully Sankyo Partner funded n.d. n.d.

Partnered Milestones & Royalties Sanofi n.d. n.d.

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PRS-300 Series: Multispecifics for

Immuno-Oncology

Pieris’ Immuno-Oncology Approach –

Localized Immune Activation

Monospecific Targeting Pieris’ Bispecific Approach

Tumor Tumor- Cell targeting mAb

Immune system- targeting Anticalin

T cell

Mellman et al. Nature 480, 480-489; 2011

Challenges Potential benefits

Systemic mAbs often show narrow Enhanced tolerability with reduced therapeutic window “off-tumor” effects

mAbs are poor agonists for certain activating Tumor-mediated clustering drives signaling receptors and depend on Fc receptor by activating receptors clustering Increased efficacy in patients unresponsive to tumor-targeted therapies

Pieris is pursuing both activating and inhibitory IO targets

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Costimulatory T cell Engagement in Tumor

Microenvironment

T cell costimulation in tumor No T cell costimulation in periphery

Tumor Cell

Tumor target

MHC-peptide

Clustering No clustering

Costimulatory T cell receptor receptor

Costimulatory Primary signal TcR signal

T- Cell No activation Activation

Targeted Mode of Action

Clustering of bispecific molecules in tumor microenvironment drives costimulatory T cell engagement Maintaining T cell receptor-mediated tumor antigen specificity on activated T cells

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PRS-343

HER2-CD137 Bispecific Anticalin Fusion Proteins

PRS-343: HER2-CD137 Bispecifics

Multiple Formats Under Preclinical Evaluation

CD137 – a TNFR Costimulatory Target

Preclinically and clinically validated

Marker for tumor-reactive T cells

Activation leads to tumor elimination in vivo Signaling included in clinical CAR-T cells

mAbs struggle to find therapeutic window

Activity depends on Fc receptor interaction Doses required for T cell activation have led to toxicity

PRS-343

HER 2 – Validated but not fully exploited

Upregulated on several solid tumors with significant unmet medical need

Bladder, gastric, ovarian, breast cancer

Restricted expression on normal tissue favors immunotherapy approach

Bispecific immunotherapy approach may expand responding population

HER2+ tumors with lower expression levels not adequately addressed with current therapy

CD137-targeting Anticalin

HER2-targeting mAb (trastuzumab derived)

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CD137 Targeting Lead Anticalin® Has Demonstrated Agonistic Properties

Binding to CD137

Affinity: KDhCD137 = 2nM

“Non-competitive” CD137 engagement preserves ligand-binding capability to CD137L

Biophysical properties

100% monomeric expression TM = 74°C (DSC)

Fully stable after 1 week at 37°C in PBS, hu or mu plasma

In vitro functional testing

IL-2 Production Assay

CD137 Anticalin

Control

Dose dependent T-cell activation in ex vivo human donor cell assay by CD137 clustering

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HER2-CD137 Bispecific Formats Retain Target Binding Capacity

?-HER2 CD137 Ac

HER2 CD137

Bispecific formats show similar binding to CD137 and HER2 as building blocks

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HER2-CD137 Bispecific Formats Bind Both Targets at the Same Time

Dual binding ELISA data

Dual binding

detection Biotin

assay format

titration

coating

Simultaneous target engagement confirmed for all bispecific formats

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PRS-343 Bispecifics Exhibit

Favorable Biophysical Properties

Storage Stability

Time 0 Time 7day

Freeze / Thaw Stability

Reference Reference Reference Reference

PBS at 37°C

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Plasma and Storage Stability Confirmed

% activity

Plasma stability confirmed

Storage stability confirmed

binding qELISA); *blotted with an off-set on

the y-axis for better visualization

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HER2-CD137 Bispecifics Mode of Action – Relevance of Fc-g Receptor Interaction

Desired Detrimental

Tumor-target driven T-cell activation NK mediated ADCC of T cells Non-tumor target driven random activation of T cells

T cell ADCC Activation

CD137

FcgR+

NK Cell T cell T cell

Killing cell

HER2

CD16 CD137 CD16 CD137 CD32

HER2+ tumor cell CD64

…

Desired mode of action is HER2-dependent CD137 clustering and activation on T cells Trastuzumab IgG1 backbone could induce undesired side effects of ADCC directed against T cells and non-tumor localized activation of T-cells via FcgR positive cells in the periphery

PRS-343 bispecifics contain trastuzumab with an engineered IgG4 backbone to minimize FcgR binding

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Engineered IgG4 Backbone Ensures Reduced FcgRI

& FcgRIII Interaction – FcRn Interaction Retained

FcgRI FcgRIII FcRn

Trastuzumab (IgG1)

Control fusion (IgG1) HC-C-Term. (IgG4engineered) LC-C-Term. (IgG4engineered) LC-N-Term. (IgG4engineered) HC-N-Term. (IgG4engineered)

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PoC: T Cell Activation by HER2-CD137

Bispecifics is HER2 Target-Dependent

Assay Design IL-2

IFN-g?

Costimulatory HER2 – CD137 T cell Bispecifics lead to activation

Activation

Excess of trastuzumab blocks Signal 1 Signal 2 binding of Bispecifics and T cell activation

a-CD3

antibody SKBR3 tumor cell

culture dish

Her-2 positive SKBR3 cells were grown on 96-well culture dishes, precoated with aCD3 antibody T cells from healthy donor PBMCs were added together with HER2—CD137 bispecifics to activate T cells Excess of trastuzumab inhibits binding of HER2 – CD137 bispecifics and activation of T cells

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PoC: T Cell Activation by HER2-CD137 Bispecifics is HER2 Target-Dependent

IL-2 response IL-2 response with Her2 blockade Assay design

Construct

A

Construct B

Activity is HER2 target+ dependent

Addition of excess trastuzumab

Construct Trastuzumab

prevents bispecific binding to

C

HER2-positive cells and results in a loss of activity

Geometry impacts activity of HER2-CD137 Bispecifics

Construct

D Three constructs are capable of activating T cells

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Pharmacokinetics of HER2-CD137 Bispecifics in Mice are Comparable to Trastuzumab

Pharmacokinetics in mice PK assay set up

trastuzumab

Construct A

detection Biotin titration coating

Bispecifics Trastuzumab

10mg/kg of bispecifics or trastuzumab were injected i.v. in male CD-1 mice (3 mice per timepoint) Terminal half-lives of bispecifics range from 15-21 days compared to 13 days for trastuzumab

Beneficial half-life of parental antibody is preserved for all bispecifics or even exceeded

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Summary and Path Forward

PRS-343: HER2-CD137 Bispecifics

– Exhibit excellent binding and drug-like properties with long half lives in mice

– Induce strong T cell activation via tumor target-dependent costimulatory T cell engagement

– Expected to allow potent local activation of tumor-specific T cells with low toxicity

PRS-343 Path to Clinic

– Drug candidate nomination planned for YE 2015

– Initiate IND enabling studies in 2016

– Aim to perform clinical trial in HER2-positive cancer in 2017

Pieris’ IO pipeline focusing on multiple targets

Pieris is pursuing both activating and inhibitory IO targets

Each immunomodulatory target combinable with different tumor targets

Bispecifics approach for tumor localized immune activation

Variable bispecific geometry facilitates optimal engagement for all receptors

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Pieris Pharmaceuticals, Inc.

255 State Street Boston, MA 02109 USA info@pieris.com

Pieris Pharmaceuticals, GmbH.

Lise-Meitner-Strasse 30 85354 Freising (Munich) Germany info@pieris.com

Thanks to the Pieris Team!

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