1

Creating New

Immunotherapies

to Fight Disease

Non-Confidential

January 2019

2

Forward Looking Statements

This presentation contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933,

Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-

looking statements are not based on historical fact and include statements regarding Alpine’s platform technology, potential

therapies, potential milestone and royalty payments, future development plans, clinical and regulatory objectives and the timing

thereof, expectations regarding the sufficiency of cash to fund operations into 2020, expectations regarding the plans of its

collaborator, expectations of future collaborations, and expectations regarding the potential efficacy and commercial potential of

Alpine’s and its collaborator’s product candidates. Forward-looking statements generally include statements that are predictive in

nature and depend upon or refer to future events or conditions, and include words such as “may”, “will”, “should”, “would”,

“expect”, “plan”, “intend”, and other similar expressions among others. These forward-looking statements are based on current

assumptions involving risks, uncertainties, and other factors that may cause actual results, events, or developments to be

materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of

which are beyond our control, include, but are not limited to: Alpine’s discovery-stage and pre-clinical programs may not

advance into the clinic or result in approved products on a timely or cost-effective basis or at all; Alpine may not achieve

additional milestone payments pursuant to its collaborations; the impact of competition; adverse conditions in the general

domestic and global economic markets; as well as the other risks identified in our filings with the Securities and Exchange

Commission. These forward-looking statements speak only as of the date hereof, Alpine undertakes no obligation to update

forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements.

“Variant Immunoglobulin Domain”, “vIgD”, “Transmembrane Immunomodulatory Protein”, “TIP”, “Secreted Immunomodulatory

Protein”, and “SIP” are registered trademarks or trademarks of Alpine Immune Sciences, Inc. in various jurisdictions.

All rights reserved.

3

Leading the Next Generation of Immunotherapies

Platform Technology

Powerful platform technology

to be leveraged for strategic

partnerships and licensing

opportunities

Alpine’s lead programs in inflammation and oncology targeted to enter the clinic in 2019

Management Team

Proven development,

regulatory, and commercial

success in both autoimmune

diseases and oncology

Investors

Premier Life Sciences

investors

ALPN-101

Dual ICOS/CD28 antagonist

for inflammatory diseases

targeted to begin clinical

studies Q1-2019

ALPN-202

Dual PD-L1/CTLA-4 antagonist,

and CD28 agonist for oncology

indications targeted to enter the

clinic Q4-2019

Cell Therapy Enhancement

Engineered expression of

costimulatory ligands or

selective checkpoint

antagonists

Using Directed Evolution to Create Powerful Multifunctional Immunotherapies

44

POWERFUL

SCIENTIFIC PLATFORM

5

Turning Immunoglobulin Superfamily (IgSF) Proteins Into Novel Therapeutics

• IgSF is the largest human protein superfamily, with

765 members identified1

• Named for the Ig domain (70-110 amino acids)

found in antibodies

• Includes many targets which have evolved as

critical regulators of immunity, e.g.

1Nature 409:860 (2001)

Group Examples

Checkpoint PD-1, PD-L1, CTLA-4, TIGIT, Lag-3,

VISTA, CD47

Costimulatory CD28, ICOS, CD80, CD86, CD2

Antigen Receptor-

Related

CD3, TCR, BCR, MHC, CD19, CD4, CD8

Cytokine Receptors IL-1R, IL-6R, CSF1RNat Rev Immunol 2:116 (2002)

The CD28 Protein FamilyA Critical IgSF Subfamily

X

6

Variant Ig Domains (vIgDs) are IgSFs Engineered via Directed Evolution to

Acquire Target Specificity and Optimize Immune Modulation

Bead and/or flow cytometric

selection

vIgD

Fc-fusion protein

generation

Counter-structure binding

assays

Functional assays

IgSF ECD Yeast Display

LibrariesIgSF Protein

Optimized vIgD

Limited counter-structureswith low/moderate affinity

Random and/or targeted mutagenesis

Assess in vivo andin vitro pharmacology

Analyze yeast outputs for desired binding

Sequence yeast outputs to identify unique variant hits

Mammalian cell line production

A tailored non-

antibody domain

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vIgDs Facilitate Multiple Potential Therapeutic Formats

Formats: vIgD Fc Fusion V-mAb Cell Therapy

Enhancement

Structure 70-110 aa vIgD-Ig Fc Multi-vIgD-Fc vIgD-mAb fusion vIgD ± TM

Example

Schematic

Purpose(s) Base domain Single domain

therapeutic

•Multi-functional, multi-domain therapeutic

•Target- (e.g., tumor-) specific immune activity

Potentiation of

engineered

immunotherapy

Examples • ICOSL vIgD

•CD80 vIgD

•ALPN-101

•ALPN-202

•NKp30-ICOSL-Fc

(B7-H6-specific)

•PDL1-CD155-Fc

•Trastuzumab-ICOSL

(anti-HER2)

•CD86 vIgD TIP

•PD-1-CD28

“Switch” TIP

TCR/

CARFc mAbFc

TIP Transmembrane Immunomodulatory Protein

Lead Programs

88

TWO LEAD PROGRAMS

ALPN-101 & ALPN 202

9

ALPN-101

Autoimmune/Inflammatory Diseases

10

ALPN-101: a First-In-Class Dual CD28/ICOS Antagonist for Multiple

Inflammatory Disease Indications

CD28 and ICOS:

Key T cell Costimulatory

Pathways

ICOSCD28

ICOSLCD80

CD86

T cell

APC

Currently Available

Therapeutics Block

Only the CD28 Pathway

ICOSCD28

ICOSLCD80

CD86

CTLA4-Ig

ICOSCD28

ICOSLCD80

CD86

ALPN-101

ICOSL vIgD-Fc*

ALPN-101 (ICOSL vIgD-Fc)

Blocks Both CD28 & ICOS

Pathways

*Effectorless IgG1 Fc†Orencia 2017 sales = $2.5B (Source: BMS)

†

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Inhibition of Both CD28 and ICOS Pathways

Likely Required to Treat Many Serious Inflammatory Diseases

Naïve T cell

CD28+ ICOS-

CD28+ ICOS+

T cell activation:

ICOS

CD28 (some cells) CD28- ICOS+CD28lo ICOS+

Activated / Effector / Memory / TFH cellsVarious populations

CD28

ICOS

During activation, T cells lose CD28 dependence but

upregulate ICOS – the most closely related IgSF member

Activation / Time

CD28 ICOS

Rela

tive O

vera

ll C

ostim

ula

tory

Dependence / E

xpre

ssio

n

Relative Redundancy of CD28 and ICOS

- Lupus (Arthritis Rheum 62:3077, 2010)

- Sjögren’s (Mod Rheumatol 26:891, 2016)

- Myositis (Ann Rheum Dis 77:55, 2018)

- GvHD (Transpl Immunol 43-44:54, 2017)

- IBD (Gastroenterology 143:62, 2012)

- Multiple Sclerosis (Mult Scler 23:686, 2017)

CD28 blockade (abatacept) has been

only modestly or not effective in:

- Lupus (Arthritis Rheumatol 70:1071, 2018)

ICOS blockade (prezalumab) has

been only modestly effective in:

- GvHD (JCI Insight 1:e86660, 2016)

- Arthritis (Nature 542:110, 2017)

- Sjögren’s (Arthritis Rheumatol 70:774, 2018)

- Myositis (Brain 127:1182, 2004)

- IBD (Gastroenterology 126:829, 2004)

- Multiple Sclerosis (PLoS One 8:e57820, 2013)

ICOS+ / TFH cells have been

implicated in:

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ALPN-101 Harbors Broad Potential in Multiple Therapeutic AreasSuperior Efficacy in Diverse Disease Models vs. Active Comparators

GI: Inflammatory Bowel Disease

Heme/Onc: Acute Graft-Versus-Host Disease Rheumatology: Rheumatoid, Psoriatic, Juvenile Idiopathic Arthritis

Preventative Dosing Therapeutic Dosing

Neurology: Multiple Sclerosis

MOG Adoptive Transfer Experimental

Autoimmune Encephalomyelitis

Company data

Human Xenogenic NSG

CD45RBhi Colitis

Collagen-

Induced

Arthritis

ICOSL vIgD-Fc

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Initial Indications for ALPN-101 are Psoriatic Arthritis and Acute GvHD

PsA offers a considerable

commercial opportunity

• ~250-300K patients per year affected with

moderate to severe psoriatic arthritis

• TNFs, IL-17s, and IL-12/23s expected to dominate

market. Competitive pipeline offering few novel

MOAs

• Orencia’s revenues are projected at $250M+ U.S. in

2025 despite modest effects

• ALPN-101 has shown ability to differentiate from

Orencia in multiple preclinical models

GvHD has significant unmet needs.

The opportunity is relatively small

but rapidly evolving

• ~4K Acute GvHD patients per year

• Predominately a T Cell mediated disease

• 30-50% do not respond to available therapies

• Preclinical data strongly support activity of

ALPN-101 in this disease population

• Single dose of ALPN-101 has been shown to be

effective in aggressive preclinical model

Psoriatic Arthritis (PsA) Acute GvHD

New therapeutic options needed for a host of other potentially ICOS/CD28 mediated diseases:

Lupus, Sjogren’s syndrome, Inflammatory Bowel disease (IBD), Ophthalmology (Uveitis/Dry Eye),

and Pulmonary Fibrosis

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Initial Clinical Strategy for Lead Program ALPN-101

Phase 1 Healthy

Volunteer

Phase 1b Psoriatic Arthritis

Phase 1b Acute Graft-versus-Host Disease

✓ Preclinical development

✓ GMP manufacturing with sufficient drug substance to complete initial Phase 1 Studies

Phase 2 / Pivotal Trials

Expansion into other indications

Key Biomarker and

Safety Data (PK/PD)

Preliminary Data

Readout to support Ph2

2019 2020 2021 2022 2023

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ALPN-101 Development and Lifecycle Vision

Heme/OncAcute GvHD

TransplantationAllograft Rejection

Rejection Prophylaxis

Heme/OncChronic GvHD

GvHD Prophylaxis

RheumatologyPsoriatic Arthritis

RheumatologySjögren’s Syndrome

Systemic Lupus Erythematosus RheumatologySystemic Sclerosis

Inflammatory Myositis

Vasculitis

RheumatologyJuvenile Idiopathic Arthritis

Rheumatoid Arthritis

GastroenterologyCrohn’s Disease

Ulcerative Colitis

NeuroscienceMultiple Sclerosis

OphthalmologyUveitis

PulmonologyInterstitial Lung Disease

• Broad, diverse market potential

• Initial core investments in

rheumatology and heme/onc will

enable most efficient proof-of-concept

• Compatible with self-sustained or

partnered development

16

ALPN-202

Oncology

17

ALPN-202 is a Dual PD-L1/CTLA-4 Antagonist with PD-L1 Dependent

T-Cell Activation (e.g., Costimulation)

Greater than 70% of Patients

Receiving PD-1/L1 Therapy

Do Not Respond,

Likely Due to Insufficient T

Cell Activation, e.g.

Costimulation

ALPN-202 is a first-in-class molecule with the

potential to improve response rates through

necessary costimulation

ALPN-202 Driven Immune Response

ALPN-202(CD80 vIgD-Fc)

Fc

CD80 vIgDs

PD-1 CD28

PD-L1

TCR/CD3

Complex

MHC

Tumor cell

T cell

ALPN-202

TCR/CD3

Complex

MHC B7

CTLA-4

Tumor cell

T cell

CD28

ALPN-202

181 10 100 1000 10000 1000001000000

0

20000

40000

60000

[pM]

MF

I

Fc Control

ALPN-202

Ipilimumab(anti-CTLA-4)

1 100 10000 10000000

5000

10000

15000

20000

25000

IL-2

(p

g/m

L)

ALPN-202

WT CD80-Fc

Durvalumab (anti-PD-L1)

Nivolumab (anti-PD-1)

Fc Control

No PD-L1

1 100 10000 10000000

5000

10000

15000

20000

25000

[pM]

IL-2

(p

g/m

L)

With PD-L1

1 10 100 1000 10000 10000010000000

1000

2000

3000

[pM]

MF

I

Fc Control

ALPN-202

Atezolizumab(anti-PD-L1)

Three Primary Mechanisms of Action of ALPN-202

1. PD-L1 Antagonism

2. CTLA-4 Antagonism

3. PD-L1-Dependent Costimulation

(CD28 Agonism)

Primary T cells + K562 ± hPD-L1

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ALPN-202 Exhibits Potent Efficacy in vivoAnti PD-L1 Superiority as Judged by Tumor Responses and Gene Signatures

ALPN-202-pretreated

Naive

PD-L1 inhibitor-superior, Efficacy as Monotherapy …with Evidence of Anti-Tumor Immunity

Superior Intra-Tumoral Inflammatory Signatures

0 10 20 30 400

500

1000

1500

2000

Day

Me

dia

n T

um

or

Vo

lum

e (

mm3

)

Fc Control

ALPN-202

durvalumab (anti PD-L1)

p < 0.0001

ALPN-202 vs

durvalumab

Mice dosed

0/11 mice tumor free

2/11 mice tumor free

8/11 mice tumor free

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ALPN-202 Phase 1 Strategy

Demonstrate Early Monotherapy Activity and Enable Combo Development

• Population: advanced malignancies (all-comer)

- May enrich for any translationally justified tumors

- Consider 1st line PD-(L)1 on-label tumors in combo

• Design

- “Subtherapeutic”: Single patient cohorts

- “Active” doses: 3+3 dose escalation,

• Assessments

- ORR, DOR, PFS, OS

- Retrospective biomarker analysis

Monotherapy Dose

EscalationMonotherapy Dose Expansion

PD-1 Combo Dose

EscalationPD-1 Combo Dose Expansion

Combo within or as separate protocol

Single arm

PD-1 resistant

tumors/patients

3-way combo

PD-1 labeled

indication(s)

Monotherapy

Efficacy

Observed

Combo

Appropriate

2121

FOCUS ON

DELIVERING VALUE

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Enhancement of

Cell-Based

Immunotherapies

TIP/SIP Program

Improved Cell

Proliferation &

Persistence

Enhanced

T Cell Killing

Engagement of

Bystander T cellsIncreased Tumor

Immunogenicity

23

TIP/SIP: vIgD-Based Enhancement of Engineered Cell-Based Therapies

24

vIgD TIPs Potently Augment Engineered T Cell ActivityExample: CD86 vIgD TIPs with HPV E6 TCR

vIgD TIPs exhibit superior proliferation, cytokine production, and cytotoxicity over TCR as well

as TCR + wild-type IgSF TIPs. Reproduced across multiple targets and CAR/TCR systems.

Improved Cytotoxicity

Increased T cell Cytokine Production

Enhanced T cell Proliferation

25

Switch vIgD TIPs Improve T Cell Activity, Proliferation, and Cytotoxicity

0 10000 20000 30000 40000 500000

1000

2000

3000

4000

CD4+ T Cells Proliferation

Target Cell #

Cell c

ou

nt

0 10000 20000 30000 40000 500000

5000

10000

15000

20000

CD8+ T Cell Proliferation

Target Cell #

Cell c

ou

nt

Enhanced T cell Proliferation Improved Cytotoxicity

Increased T Cell Cytokine Production

0 10000 20000 30000 40000 500000

1000

2000

3000

4000

5000

IFN Release 24 Hours

Target Cell #

pg

/ml

2:1 1:1 1:20

20

40

60

Killing of Caski Cells at 24 Hours

E:T Ratio

% K

illin

g o

f T

arg

et

Cells TCR only

H1646 PD1-CD28

H1646 PD1-CD28.4-1BB

H1646 PD1-CD28.ICOS

H1646 PD1-CD28.ICOS.4-1BB

H1646 PD1-No ICD

Intracellular CD28, ICOS, and 4-1BB ICDs alone or in combination

PD-1 vIgD ECD TMD CD28/ICOS/4-1BB ICD

26

ALPN-101 & ALPN-202 Recent Scientific Presentations

December 1, 2018

Therapeutic Candidate ALPN-101, a

Dual ICOS/CD28 Antagonist, Potently

Suppresses Human/NSG Mouse

Xenograft Graft Vs. Host Disease

(GvHD) in a Dose Ranging Study and

Reduces Disease Activity in a Mouse

Model of Hemophagocytic

Lymphohistiocytosis (HLH)

October 21, 2018

ALPN-101, a Dual ICOS/CD28

Antagonist, Potently Suppresses

Disease in Multiple Mouse Models of

Autoimmunity

October 21, 2018

Therapeutic Candidate ALPN-101, a

Dual ICOS/CD28 Antagonist,

Demonstrates In Vivo Efficacy in an

Experimental Autoimmune

Encephalomyelitis (EAE) Model

November 9, 2018

ALPN-202, a combined PD-L1/CTLA-4

antagonist and PD-L1-dependent

CD28 T cell costimulator, elicits potent

intratumoral T cell immunity superior to

and differentiated from PD-L1 inhibitor

monotherapy

December 2, 2018

Oral Presentation from Indiana Univ.

Collaborators

ICOSL+ Plasmacytoid Dendritic Cells

As Biomarker and Inducer of

Graft-Versus-Host Disease

December 1, 2018

“Switch” Transmembrane

Immunomodulatory Proteins (TIPs)

Consisting of High-Affinity PD-1

Extracellular Domains (PD-1 vIgDs)

and Costimulatory Intracellular

Domains Potently Enhance the Activity

of TCR-Engineered T Cells

27

Pipeline of Potential Novel Therapies

PROGRAM DISCOVERY IND-ENABLING PHASE 1 COLLABORATOR

Autoimmune/Inflammatory Diseases

ALPN-101 (Dual ICOS/CD28 antagonist)

Undisclosed Programs

Immuno-Oncology

ALPN-202 (PD-L1/CTLA-4 Antagonist & CD28 Agonist)

Undisclosed Programs

Cellular Therapy Enhancement (Undisclosed Targets)

PsA

GvHD

28

Strong Financial Position

$62 millioncash equivalents as of

September 30, 2018

$25 millionraised January 2019

Sufficient

cash runway to fund operations

into 2021

~13.9 million shares outstanding as

of August 2018

Analyst Coverage

29

Strong Leadership Team with Deep Clinical, Regulatory, and

Commercial Expertise

LEADERSHIP TEAM PRINCIPAL INVESTORS

Stanford Peng, M.D., Ph.D. EVP of R&D, Chief Medical Officer

Ryan Swanson VP of Immunology & Co-Founder

Paul RickeyChief Financial Officer

Mark Litton, Ph.D.President & Chief Operating Officer

Kristine Swiderek, Ph.D.Senior VP of Research

Mitchell H. Gold, M.D. Executive Chairman & CEO

30

Leading the Next Generation of Immunotherapies

Platform Technology

Powerful platform technology

to be leveraged for strategic

partnerships and licensing

opportunities

Alpine’s lead programs in inflammation and oncology targeted to enter the clinic in 2019

Management Team

Proven development,

regulatory, and commercial

success in both autoimmune

diseases and oncology

Investors

Premier Life Sciences

investors

ALPN-101

Dual ICOS/CD28 antagonist

for inflammatory diseases

targeted to begin clinical

studies Q1-2019

ALPN-202

Dual PD-L1/CTLA-4 antagonist,

and CD28 agonist for oncology

indications targeted to enter the

clinic Q4-2019

Cell Therapy Enhancement

Engineered expression of

costimulatory ligands or

selective checkpoint

antagonists

Using Directed Evolution to Create Powerful Multifunctional Immunotherapies

31

Thank You

COPYRIGHT © 2019 ALPINE IMMUNE SCIENCES, INC. ALL RIGHTS RESERVED.