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From personalized to individualized immunotherapy -the next major step in developing

medicines of the future

Prof. Dr. Dolores J. Schendel

CEO/CSO: Medigene AGManaging Director: Medigene Immunotherapies GmbH

"Safe Harbor" Statement

This presentation contains forward-looking statements, whichare based on our current expectations and assumptions.Due to various risks and uncertainties including changes inbusiness, economic competitive conditions, regulatory reforms,foreign exchange rate fluctuations and the availability offinancing, actual results, performance or achievements coulddiffer materially from those included in the forward-lookingstatements. These and other risk factors are discussed in theCompany’s public reports. The company does not assume anyobligations to update or revise any of these forward-lookingstatements, even if new information becomes available in thefuture.

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Immunotherapy ̶ the future of cancer therapy

3

Classical Mainstays

Surgery

Radiation

Chemotherapy

Newer

Treatments

Hormone therapies

Small moleculetargeted therapies

Antibody therapies

Cancer

Immunotherapies

Stem cell transplantation

Immune response modifiers

DC vaccines

Latest developments:

Adoptive cell therapies

CARs and TCRs

Before 1990 1990-2010 From 2010

4

Biomarkers of interest to understand the move from personalized to individualized immunotherapy of cancer

T cells residing

in the tumor

microenvironment

Tumor mutations

allowing formation of

neoantigens for T cell

recognition

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Adaptive immune reactions within a tumor influence clinical outcome in colon carcinoma

5Galon et al., Cancer Research, March 2007

Cold Hot

Localization of CD3-positive T cells impact on disease-free survival

6Galon et al., Science, September 2006

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Type of CD3 T cell infiltrate influences rate of relapse in patients with colon carcinoma

7

High density Th1/cytotoxic memory T lymphocytes in

tumor center and at invasive margin of the primary

tumor associated with low risk of relapse and

metastasis and overall survival.

Tumors from patients without recurrence had higher

immune cell densities (CD3, CD8, GZMB and

CD45RO).

The correlation between a robust lymphocyte

infiltration and patient survival has been well

documented in melanoma, ovarian, head and neck,

breast, urothelial, colorectal, lung cancer.

From Galon et al., Science, September 2006:

mRNA levels of seven genes from Th1 adaptive cluster, from maximal (red) to minimal (blue) expression levels.

Immune checkpoints halt T cell responses via two central pathways: CTLA-4/B7 and PD-1/PD-L1

8Wolchock J, et al. J Clin Oncol 2013;31(15 suppl); abstract 9012

T cell Tumor cell

MHCTCR

PD-L1PD-1T cellDendritic

cell

MHCTCR

CD28

B7 CTLA-4- - -

Activation(cytokines, lysis, proliferation,

migration to tumor)

B7+++

+++

CTLA-4 pathway PD-1 pathway

Periphery Tumor microenvironment

++ +

PD-L2PD-1

- - -

- - -

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Clinical benefit from immune checkpoint blockade

9

Selected immune checkpoint inhibitors in clinical trials:

Anti-CTLA-4 antibody: Ipilimumab (Yervoy)

Anti-PD-1 antibody: Nivolumab (Opdivo)/Pembrolizumab (Keytruda)

Anti-PD-L1 antibody: Atezolizumab (Tecentriq)

Robert et al., N Engl J Med, 2011 Robert et al., N Engl J Med, 2015 Garon et al., N Engl J Med, 2015

Ipilimumab inmetastatic melanoma

Pembrolizumab inNSCLC

Nivolumab in untreated melanoma

(without BRAF mutation)

Cancers vary widely in mutational burden

10

Alexandrov et al., Nature 2013

Antithetical observation: The best responses to checkpoint blockade occur in patients who have tumors with highest mutational burdens

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Mutations alter the array of peptides presented at the tumor cell surface for T cell recognition

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Neoantigens are formed when mutant peptides bind to a patient’s HLAmolecule and are presented at the surface of a tumor cell.

Finn O. N Engl J Med 2008;358:2704–2715

Long-term benefit of CTLA-4 checkpoint blockade is associated with high mutational burden in melanoma

12Snyder et al., N Engl J Med, December 2014

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Neoantigens impact on long-term benefit of CTLA-4 checkpoint blockade in melanoma patients

13Snyder et al., N Engl J Med, December 2014

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Mutational load & neoantigens in NSCLC impact clinical benefit with PD-1 checkpoint blockade

Nonsynonymous mutation

burden associated with

clinical benefit of anti-PD-1

therapy

High neoantigen burden

correlates with PFS

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Tumors with high mutation, many cytotoxic T cells, and strong inhibition respond to PD-1/PD-L1 blockade

15Bobisse et al., Ann Tansl Med, May 2016

Adoptive cell transfer of tumor-infiltrating lymphocytes can lead to regression in melanoma

16Gattinoni et al., Nat Rev Immunol, 2006 .

Enigma: What is the specificity of T cells present among TIL that deliver the greatest clinical benefit?

National Cancer Institute, www.cancer.gov

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Clinically effective TIL contain high avidity T cells that see neoantigens present in autologous melanoma

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Robbins et al., Nature, June 2013

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Adoptive cell transfer of neoantigen-specific T cells for treatment of melanoma - medicine of the future

Dudley M E & Rosenberg S A, Nature Reviews Cancer, September 2003

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Adoptive T cell therapy with patient T cells modified to express neoantigen-specific TCRs

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TCR-modified

patient T cells with neoantigenspecificity

12

4

5

Isolation of

patient T cells

vector

mediated

TCR transfer

3

Can we help patients who have no TIL and have tumors with low mutational burdens?

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Differential

NGS analysis

Tumor tissue Normal tissue

Selection of potentially relevant

tumor-specific mutations

Autologous mDCs Naïve T cell repertoire

of healthy donors

Fast, flexible and efficient method to define neoantigens for vaccines andgenerate TCRs directed against individual tumor mutations

Mutation 1

Mutation 2

Mutation 3

Mutation 4

Mutation 5

Mutation ..

ivt-RNA

+

(outsourced to others)(use of outsourced and

in-house bioinformatic tools)

www.illumina.com

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multimer

CD

8

Donor

1D

onor

2D

onor

3D

onor

4

0

0.2

0.4

0.6

0.8

1

IFN

-γre

lease

[O

D]

0

0.2

0.4

0.6

0.8

1

IFN

-γre

lease [

OD

]

0

0.2

0.4

0.6

0.8

1

IFN

-γre

lease

[O

D]

0

0.2

0.4

0.6

0.8

1

IFN

-γre

lease

[O

D]

Specificity-screen of T-cell clonesSort of

multimer+ T cells

Next Generation Sequencing of

TCRs

+ -

Four healthy donors yield T cells specific for mutation-1 presented by HLA-A2

21Mutated epitope Wild type epitope

www.illumina.com

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TRAV13-1*02

TRAV13-1*02

TRAV13-1*02

TRAV13-1*02

TRAV38-2/DV8*01

TRAV27*01

TRAV38-2/DV8*01

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TRAV12-2*02

TRAV12-2*02

TRAV38-2/DV8*01

TRAV40*01

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TRAV19*01

TRAV19*01

TRAV35*02

TRAV35*02

TRAV29/DV5*01

TRAV5*01

TRAV5*01

TRAV12-2*01

TRAV3*01

TRAV38-2/DV8*01

TRAV38-2/DV8*01

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TRAV38-2/DV8*01

TRAV29/DV5*01

TRAV29/DV5*01

TRAV29/DV5*01

TRAV25*01

TRAV38-2/DV8*01

TRAV38-2/DV8*01

TRAV38-2/DV8*01

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TRAV24*01

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

TRAV38-1*03

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TRAV12-2*01

TRAV12-2*01

TRAV12-2*01

TRAV12-2*01

TRAV12-2*01

TRAV38-2/DV8*01

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TRAV14/DV4*01

TRAV14/DV4*01

TRAV34*01

TRAV34*01

TRAV27*01

TRAV22*01

TRAV19*01

TRAV38-2/DV8*01

TRAV9-2*01

TRAV38-2/DV8*01

TRAV8-2*01

donor 1 donor 2 donor 3 donor 4

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Mutation-1-specific T cell responses seenwith individual donors are complex

N= 10 TCRs

N= 13 TCRs

N= 20 TCRs

N= 5 TCRs

1 mutation4 healthy blood donors

306 screened T cell clones256 antigen-specific clones (84%)

48 neoantigen-specific TCRsfor the patient!

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Proof-of-Principle: T cell responses detected against 4 of 7 selected neoantigens

� 7 predicted neoantigen-derived epitopes from 6 proteins

� 4 healthy blood donors used for DC-T cell co-cultures

� Specific T cell clones found for 4/7 neoantigen-epitopes

� TCRs found in response of each donor ranged from afew to many unique sequences

� 3/7 mutation-spanning epitopes in 2 proteinsdid not stimulate T cell responses in any donor(possibly due to sub-optimal binding to HLA-A*02:01)

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Results of differential

NGS analysis availableSet up in vitro cultures

Sort and

expand T cells

Test

clones

+ NGS

TCR sequences

available

Preparation

Priming

Expansion

Selection

3 weeks

3 weeks

2 weeks

1 week

Proof-of-Technology: Medigene utilizes automation for high-throughput identification of lead candidates

Selection of T cells

Screening of TCR candidates

High-throughput TCR analysis

1 2 3 4 5 6 7 8 9weeks 0

www.tecan.com

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Take-home messages

25

Proof-of-Principle

Proof-of-Technology

Process and steps of automation allow neoantigen-specific TCRs

to be identified in approximately 6 weeks (+ 3 wks for tumor NGS)

Medigene’s in vitro DC priming approach reveals mutation-specific T

cell responses

→ Identification of immunogenic neoantigens for DC vaccines

Medigene’s de novo process yields abundant T cell clones

→ Fast and efficient sources of TCRs for adoptive T cell therapies

26

From personalized to individualized immunotherapies

Spontaneous anti-tumorT cell responses are present in tumors

T cell responses intumor microenvironment

Th1/CTL responses are best

Efficacious T cellsrecognize neoantigens

T cells drive checkpoint inhibition

Checkpoint blockadereallows T cell responses

1

2

3

4

5

Tumors varyin mutational burden

High numbers of mutationsyield more neoantigens

More neoantigens supportbetter spontaneous

T cell responses

1

2

3

Tumor mutationsleading to neoantigens

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From personalized to individualized immunotherapies

Tumor mutations

leading to neoantigens

Spontaneous anti-tumorT cell responses are present in tumors

Immune responses in

tumor microenvironment

Th1/CTL responses are best

Efficacious T cellsrecognize neoantigens

T cells drive checkpoint inhibition

Checkpoint blockadereallows T cell responses

1

2

3

4

5

Tumors varyin mutational burden

High numbers of mutationsyield more neoantigens

More neoantigens supportbetter spontaneous

T cell responses

1

2

3

Conclusion:Neoantigen-based immunotherapies

will become the medicine of the future!

Acknowledgments

Medigene Immunotherapies GmbH

Dr. Christian Ellinger

Dr. Markus Dangl

Dr. Christiane Geiger

Dr. Slavoljub Milosevic

Dr. Silke Raffegerst

Dr. Daniel Sommermeyer

Dr. Carina Wehner

Dr. Manon Weis

Dr. Susanne Wilde

28

Dr. Daniel Sommermeyer

Dr. Christian Ellinger

Dr. Slavoljub Milosevic

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Medigene AG

Lochhamer Straße 11

82152 Planegg / Martinsried

Germany

Listed on Frankfurt Stock Exchange (MDG, Prime Standard)

T +49 - 89 - 20 00 33 - 0

F +49 - 89 - 20 00 33 - 2920

investor@medigene.com

www.medigene.com

Medigene AG

Lochhamer Strasse 11

82152 Planegg / Martinsried

Germany

Listed on Frankfurt Stock Exchange (MDG1, Prime Standard)

T +49 - 89 - 20 00 33 - 0

F +49 - 89 - 20 00 33 - 2920

investor@medigene.com

www.medigene.com

Thank you