Immune Responses, On Cue™

Copyright © 2019 Cue Biopharma, Inc.

Nasdaq: CUE November 2019

Corporate Presentation

Forward-Looking Statements

This presentation has been prepared by Cue Biopharma, Inc. (“we,” “us,” “our,” “Cue” or the “Company”) and is made for informational purposes only and does not constitute an offer to sell or a solicitation of an offer to buy securities, nor shall there be any sale of any securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. The information set forth herein does not purport to be complete or to contain all of the information you may desire. Statements contained herein are made as of the date of this presentation unless stated otherwise, and neither this presentation, nor any sale of securities, shall under any circumstances create an implication that the information contained herein is correct as of any time after such date or that information will be updated or revised to reflect information that subsequently becomes available or changes occurring after the date hereof.

This presentation contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, that are intended to be covered by the “safe harbor” created by those sections. Forward-looking statements, which are based on certain assumptions and describe our future plans, strategies and expectations, can generally be identified by the use of forward-looking terms such as “believe,” “expect,” “may,” “will,” “should,” “would,” “could,” “seek,” “intend,” “plan,” “goal,” “project,” “estimate,” “anticipate,” “strategy,” “future,” “likely” or other comparable terms. All statements other than statements of historical facts included in this press release regarding our strategies, prospects, financial condition, operations, costs, plans and objectives are forward-looking statements. Examples of forward-looking statements include, among others, statements we make regarding anticipated results of our drug development efforts, including study results, our expectations regarding the timing of milestone events, regulatory developments and expected future operating results. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, our limited operating history, limited cash and a history of losses; our ability to achieve profitability; our ability to secure required U.S. Food and Drug Administration (“FDA”) or other governmental approvals for our product candidates and the breadth of any approved indication; negative or inconclusive results from our clinical studies or serious and unexpected drug-related side effects or other safety issues experienced by participants in our clinical trials; delays and changes in regulatory requirements, policy and guidelines including potential delays in submitting required regulatory applications to the FDA; our reliance on licensors, collaborations and strategic alliances; our ability to obtain adequate financing to fund our business operations in the future; and the other risks and uncertainties described in the Risk Factors and in Management's Discussion and Analysis of Financial Condition and Results of Operations sections of our most recently filed Annual Report on Form 10-K and any subsequently filed Quarterly Report(s) on Form 10-Q. Any forward-looking statement made by us in this presentation is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

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Vision and Approach

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Vision

Harness the specificity and diversity of the immune system to cure complex human diseases and fundamentally transform patient lives

Approach

Deploy our Immuno-STATTM platform based on rational protein engineering to develop biologics that selectively and specifically

modulate disease-relevant T cells in a patient’s body

4

The opportunity vs challenges:

• Challenges for effective T cell responses in cancer immunotherapy include:• Antigen access and availability• Antigen uptake and processing by the “desired” antigen presenting cells (APCs)• Generation of optimal T cell epitopes by the APCs: dependency on antigen presentation and co-stimulatory signals?• Productive encounter between “charged” APCs and relevant precursor tumor-specific T cells• Need for T cells to re-engage APCs in tumor lesions• Specificity and selectivity of T cell activation: impact on patient safety• Manufacturability and safety considerations with cell therapy approaches

• The Immuno-STAT platform generates biologics that address all of the above hurdles

• CUE-101, the first clinical candidate, is exemplary of the platform and is anticipated to provide the clinical PoC for future therapeutic applications of the platform across numerous indications

• Cue Biopharma has developed a robust pipeline following CUE-101 that focuses on diverse tumor specificities and biological signals to harness the breadth of the anti-tumor T cell repertoire

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Guiding Principle: Immune Balance is a Cornerstone of Health

An optimal immune response has the potential to provide transformative clinical benefit

• E.g., Eradication of tumors in some patients by immune-modulating therapies

Sustained and robust responses in the patient requires:• Selectivity• Specificity• Safety• Sustainability

The Immuno-STATTM platform is engineered to address all of the above needs in a singular biologic

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We have rationally engineered Immuno-STAT biologics to selectively target, activate and/or modulate the activity of disease-relevant T cells

The Immuno-STAT Concept: Emulating Nature’s Cues To Modulate The Activity and Fate of T cells

Source: Dustin ML. “The Immunological Synapse”

HLA HLA

Immuno-STAT Framework

• “Ready-to-engage” biologic that specifically targets and selectively modulates disease relevant T cells

• Not dependent on barriers of natural antigen presentation via antigen presenting cells (in contrast to vaccines etc.)

• Control specificity and selectivity of signals to avoid systemic activation (in contrast to rhIL-2, bi-specifics etc.)

• Administered directly to the patient and does not involve ex-vivo manipulation of T cells (in contrast to cell therapy approaches)

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Key Points for Superior DifferentiationSignal 1A stabilized peptide-HLA complex (pHLA) to engage disease relevant T cells

Signal 2A co-stimulatory or

inhibitory signal to control the activity of target T cells

Fc BackboneProvides stability and ease of manufacturability

Fc

HLAHLA

Immuno-STAT Platform Modularity: Unlimited potential to generate therapeutic molecules for many diseases and patients

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Fc

HLA

“Swap” peptide epitopes to target different diseases#1

Ability to target distinct biological signals, including cytokines and cell-surface receptors

#3

Incorporate different HLA alleles to target diverse global patient populations

#2HLA

HLA

Fc#4 Fc engineering to dial-in or dial out biological and effector functions

#1 ∗ #2 ∗ #3

=Combinatorial diversity has the potential to generate unlimited therapeutic molecules#4∗

Signal 1: HLA + Peptide (pHLA)

Signal 2: IL-2 Variant

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CUE-100 Series:• HLA class I (A*02:01; A*11:01; A*24:02)

• Optimized framework that allows for incorporation of diverse T cell epitopes

• IL-2 variant as a co-stimulatory signal:• Maintains on-target activity on relevant T cells

• Minimizes off-target activity on irrelevant T cells

• Mitigates non-specific cytokine release

• Desirable safety profile

• Manufacturability follows standard processes for commercial mAb production

CUE-100 Series: Exploiting IL-2

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SIDE VIEW

TOP-DOWN VIEW

Fc

A*02

:01

A*02

:01

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CUE-101: Lead Clinical Candidate for HPV-Driven Malignancies

Clinical Rationale• HPV-16 E7 protein is a primary driver of

tumorigenesis

• E711-20 peptide is a highly conserved T cell epitope and is immunogenic

• Clinical trial builds upon robust patient stratification: inclusivity based on HLA-A*02:01+ and HPV-16+ tumor status

CUE-101Immuno-STAT Design

Signal 1: HLA-A*02:01 + HPV-16 E711-20 peptide

Signal 2:IL-2 variant

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Fc Backbone

Fc

A*02

:01

A*02

:01

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CUE-101 In Vitro Cellular Selectivity

Selective Binding Intact & Selective Effector Function

CUE-101 specifically targets and activates HPV-E7 T cells

Immuno-STAT (nM)

HPV-specific CD8+ T cells

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0.001 0.01 0.1 1 10 100 1000 10000

0102030405060708090

[CUE-101] (nM)

% C

UE

-101

Bou

nd C

ells HPV E711-20 CD8+ T Cells

Naive CD8+ T Cells

CMV pp65495-503 CD8+ T Cells

Immuno-STAT (nM)

CMV-specific CD8+ T cells

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CUE-101 In Vitro Expansion of E7-Specific T Cells

CUE-101 selectively expands HPV-E7 T cells with minimal effects on other immune cell lineages

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E711-20-Specific CD8+ T Cells

Vehicle-Treated CUE-101-Treated

0.01 0.1 1 10 100 1000 10000100

101

102

103

104

105

106

107

[CUE-101] (nM)

Imm

une

Cel

l Sub

sets

(abs

olut

e co

unts

)

CD4+ T cells CD4+ CD25+ Foxp3+ T cellsCD8+ T cells

NK cells

E711-20-specific CD8+ T cells

0.01 0.1 1 10 100 1000 10000100

101

102

103

104

105

106

107

[CUE-101] (nM)

Imm

une

Cel

l Sub

sets

(abs

olut

e co

unts

)

CD4+ T cells CD4+ CD25+ Foxp3+ T cellsCD8+ T cells

NK cells

E711-20-specific CD8+ T cells

0.01 0.1 1 10 100 1000 10000100

101

102

103

104

105

106

107

[CUE-101] (nM)

Imm

une

Cel

l Sub

sets

(abs

olut

e co

unts

)

CD4+ T cells CD4+ CD25+ Foxp3+ T cellsCD8+ T cells

NK cells

E711-20-specific CD8+ T cells

0 20 40 600

25

50

75

100

Days Post Engraftment

Ove

rall

Surv

ival

(%)

IsotypeCD4 depletedCD8 depletedTumor naive

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CUE-101 Surrogate Activity in an In Vivo Preclinical Model

0 10 20 30 40 50

0

300

600

900

1200

1500

Days Post Rechallenge

Tum

or v

olum

e (m

m3 )

Combo TreatedNaive

TC1 Tumor Model: Improved Survival (mono vs combo w/

anti-PD-1)Memory is dependent upon

CD8+ T cells

Prior TreatmentTreatment Naive

Induction of Long Term Memory

Re-challenge of long-term protected mice at post d80 in absence of additional treatment

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***

CUE-101 surrogate shows improved survival and long-term memory that is CD8-dependent, both as a monotherapy and in combination with anti-PD-1

Days Post Rechallenge

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CUE-101 Surrogate Expands E7-Specific T Cells In Vivo

Specific T Cell Expansion in Tumors

Upregulation of PD-1 Expression

Antigen-Specific TILs are Cytolytic

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Vehicl

e

mCUE-1

01αP

D1

Combo

0

50

100

% A

gS a

mon

g C

D8+

T c

ells

***

**

Vehicl

e

mCUE-1

01PD-1

Combo

0

20

40

60

% IF

Nγ+

of C

D8+

T c

ells

Vehicl

e

mCUE-1

01PD-1

Combo

0

10

20

30

40

50

% o

f CD

107a

+, G

ranz

yme

B+

of C

D8

T ce

lls

**

*

**

***

Blood

Spleen

Tumor

0

2000

4000

6000

8000

10000

gMFI

of P

D1

AgS CD8+Non AgS CD8+

***

CUE-101 expands tumor specific T cells that functionally respond to peptide stimulation and upregulate PD-1 expression

***

***

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CUE-101 vs Wild-Type IL-2: Mitigating the Risk Associated with Systemic IL-2 Activation

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• PBMC from healthy human donors were stimulated for 18 hours with increasing amounts of CUE-101 or recombinant human IL-2

• Cytokine production was assessed in culture supernatant by MSD

2019 2020

Q1

Phase 1 RP2D

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CUE-101 Phase 1 Monotherapy Clinical Trial: Data rich design to inform clinical development plans and registration paths

Phase 1a Mono H&N Escalation

Phase 1a Mono H&N Expansion

Part A

Part B

Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Initial Phase 1a Data Readout• Safety/immunogenicity• PK/PD• Translational

Biomarkers

Phase 1a Data Readout• Safety/Immunogenicity• PK/PD• Translational Biomarkers• ORR (Clinical Response)

• Patient inclusion criteria HPV+, p16+, HLA-A*02:01 • ~50 patients 2nd line and beyond refractory/ metastatic• 12 top tier clinical centers, 3x3 dose escalation cohort enrollment• Starting dose derived from minimum anticipated biological effect level (MABEL)• Part A and Part B includes expansion option for up to 9 patients in a dose cohort to gain statistical confidence

for a recommended phase 2 dose (RP2D)

2021

Trial Initiation• Site openings ~ 10

sites by end of 2019• Patient dosing initiated• Cohort Expansion

Objectives of CUE-101 Ph I Study Design

• Establish safety of CUE-101 and the CUE-100 framework- De-risk potential for IL-2 toxicity and generalized immune response to support future

expansion of the pipeline

• Establish PK/PD relationships based on mechanistic biomarkers- Measure T cell expansion in blood via pMHC multimers- Measure T cell responses in blood against HPV E711-20 epitope (IFN-γ ELISPOT)- Immunophenotyping

• Determine recommended dose for future Ph. II study

• Assess Overall Response Rate (ORR) as monotherapy

• Evaluate totality of all data to understand paths forward as a monotherapy as well as combo w/ PD-1/PD-L antagonists

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CUE-101 Clinical Development Network and Current Status

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• Sara Pai and Lori Wirth: MGH/Harvard and Dana Farber• Bonnie Glisson: MD Anderson• Jill Gilbert and Mike Gibson: Vanderbilt• Nabil Saba: Emory• Doug Adkins: Wash U, St. Louis• Julie Bauman: University of Arizona• A. Dimitrios Colevas: Stanford• Barbara Burtness: Yale• Frank Worden: University of Michigan• Lara Dunn: MSKCC• Christine Chung: Moffitt• Christina Rodriguez: University of Washington• Elizabeth Heath and Ammar Sukari: Wayne State

✔

✔

✔

✔

✔ = Site Open

September 30, 2019 08:00 ETCue Biopharma Initiates Patient Dosing in Phase 1 Study of CUE-101 for HPV16-driven Head and Neck Squamous Cell Carcinoma (https://www.cuebiopharma.com/investors-media/news/)

✔

✔

2019 2020 2021 2022

Q1

Phase 1 RP2DSafety ±Immunologic Effect

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CUE-101 Clinical Development Plan: Opportunities in Distinct Patient Populations

Phase Ib/II Neoadjuvant H&N Combo

Phase Ib/II PD1 Combination1st line Recurrent/Metastatic HNSCC

Phase 1a Mono H&N Escalation

Phase 1a Mono H&N Expansion

Phase 1b Potential other studies

PD1 + CUE-101Safety & Activity

Part C Combo Dose Escalation

Part A

Part B

Part DCombo Expansion

TBD - Strategy for addressing additional HPV16 driven cancers

Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

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Pipeline

Program Discovery Optimization IND-Enabling Phase I Development Partner

CUE-100 Series – MHC Class I / IL-2

CUE-101 (HPV E7 / A02)

CUE-102 (WT1 / A02)

CUE-102 (WT1 / A24)

CUE-103 (Undisclosed)

CUE-200 Series – MHC Class I / CD80 and 4-1BBL

CUE-201 (Undisclosed)

CUE-300 Series – MHC Class II / Undisclosed

CUE-301 (Undisclosed)

Immuno-Oncology (IO) Chronic Infectious Disease (CID) Autoimmune (AI)

Asia Rights

Asia Rights

Asia Rights

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Cue-102 (WT-1) Program Update

• WT-1 epitopes selected for HLA-A02 and HLA-A24 alleles - based on published preclinical, clinical data and competitive landscape

• Successful generation of Immuno-STATs with both HLA-A02 and HLA-A24:- validation of platform modularity

• Successful demonstration of Immuno-STAT-driven expansion of WT-1-specific primary human T cells:- direct evidence for biological PoC in support of future clinical applications

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Early Data with WT1 Immuno-STATs Demonstrates Activity in Primary Human Samples

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WT1 IST expanded

WT1

-tetra

mer

-PE

WT1-tetramer-APC

WT1

-tetra

mer

-PE

WT1-tetramer-APC

Pre-Treatment

10 days

A.

WT1-specific Immuno-STATs stimulate expansion of WT1-specific T cells from both an unprimed (A) and primed (B) T cell repertoire

WT1 peptide expanded

WT1-tetramer-APC

WT1

-tetra

mer

-PE

WT1

-tetra

mer

-PE

WT1-tetramer-APC

WT1 IST expanded

WT1

-tetra

mer

-PE

WT1-tetramer-APC

10 days 8 days

B. Pre-Treatment

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KRAS: Opportunity for Targeting Via Immuno-STATs

90%

45%

35%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pancreatic Colorectal Lung

% C

ance

r Pat

ient

s w

ith K

RA

Sm

ut

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Distribution of KRAS Mutations Variants2

Sources: 1: Wang et. al, Journal of Medicinal Chemistry 20132: Vasan et. al, Clinical Cancer Research 2014

Frequency of KRAS Mutation by Indication1

While there has been recent progress in addressing G12C through irreversible cysteine binding (i.e., Amgen, Mirati), G12V and G12D are considered particularly challenging targets for traditional (i.e., small molecule, antibody) approaches

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Expanding CUE-100 Series: G12V/D KRAS Hot-Spot Mutations

Targetpopulation:

e.g., HLA-A02, HLA-A11

KRAS mutant peptide: G12V/D

Development of G12V and G12D KRAS Immuno-STATs on the CUE-100 framework

• Harness the learnings from CUE-101 program and the established precedence for manufacturing of the CUE-100 series framework

• G12V/D KRAS Immuno-STATs to be developed for multiple alleles (e.g., HLA-A02, HLA-A11)

Fc

Objective: Development of Immuno-STAT biologics that selectively expand G12V and/or G12D KRAS epitope-specific CD8+ T cells capable of eradicating mutant KRAS-positive tumor cells

Signal 1: KRAS G12V/D T cell epitope

Signal 2:IL-2 variant

Fc Backbone

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Immune Responses, On Cue™

Thank You

Copyright © 2019 Cue Biopharma, Inc.