Cue Biopharma/Merck Collaboration

Nasdaq: CUE | February 2020

Cue Biopharma/Merck CollaborationImmune Responses, On Cue™

Antigen-Specific Immune Tolerance Drug Development Summit | February 26, 2020

2 © 2020 CUE BIOPHARMA

Emulating Nature’s Cues to Selectively Modulate T Cells

FC

Immuno-STAT

Fc

Signal 1

Signal 2

Co-Stimulatory/Co-Regulatory

Signal

MajorHistocompatibility Complex (MHC)

T Cell Receptor (TCR)

Co-Stimulatory/Co-Regulatory

Receptor

Selectivity/Specificity

Induction/Control

T Cell

Antigen-Presenting Cell

Signal 1Signal 2

Rationally engineered Immuno-STAT biologics selectively targetand modulate the activity of disease-relevant T cells


Immuno-STAT Modularity

Co-stim/Co-reg

MHC

Fc Backbone

Peptide

Peptide epitopes to target different diseases

Different HLA alleles (class Iand II) to address global

patient populations

Distinct biological signals, including cytokines; cell-surface receptors; and/or other targeting

modalities (e.g. scFv etc)

Fc engineering to dial in or dial out biological and effector functions

Combinatorial diversity presents potential to generate therapeutic molecules for a broad set of diseases and patient populations


Proins76-90, K88S/DR4-PDL1 Immuno-STAT (IST) Selectively Inhibits Antigen-Specific CD4+ T Cell Expansion from PBMCs of T1D Donors

Class II DRB1*04

Proinsulin76-90

Fc (effector-less)

PD-L1

Suppression of pathogenic antigen-specific CD4 T cell

expansion

D0PBMC + pathogenic peptide

D10Tetramer readout

CognatePDL1-IST

Non-cognatePDL1-IST

Expansion of pathogenic antigen-specific CD4 T cells

Pathogenic T cell (orange)


Early Intervention with Immuno-STAT Selectively Reduces the Number of Proinsulin (PI) Responsive CD4+ T Cells in Transgenic Mice

0 8 10 12 14 16 18 200

100

200

300

600

1000

1400

Days Post Immunization

SFC

per

e6

cells

PIHA

0 8 10 12 14 16 18 200

100

200

300

600

1000

1400


SFC

per

e6

cells

PI

HA

Untreated MiceIFN𝛄 ELISpot

IST Treated MiceIFN𝛄 ELISpot

Treatment with Proins-DR4-PDL1 IST starting on Day 1 post immunization selectively suppresses expansion of PI-reactive cells without inhibiting expansion of HA-reactive cells

Peptide CFAImmunization

Proins76-90, K88SHA307-319


Proins76-90, K88SHA307-319

Veh dose IST dose


Day 12 Day 190

200

400

600

800

SFC

per

e6

cells

Day 9 and 12 - IFNy - SPL

PI/HA Immunized + PI Stim

PI/HA Immunized/IST Treated + PI Stim

* ns

Day 12 Day 19

SpleenBlood

mu

IL-2

mu

IFN𝜸

Day 12 Day 190

200

400

600

800

SFC

per

e6

cells

Day 9 and 12 - IL-2 - BLD



** *

SFC

per

106

cells

Day 12 Day 19

n = 3-5 SEMUnpaired t-testDay 12 Day 19

0

200

400

600

800

1000

SFC

per

e6

cells

Day 9 and 12 - IFNy - BLD



* ns

SFC

per

106

cells

Day 12 Day 19

SFC

per

106

cells

Day 12 Day 190

100

200

300

400

500

SFC

per

e6

cells

Day 9 and 12 - IL-2 - SPL



** *

SFC

per

106

cells

Day 12 Day 19

** * ** *

* ns * ns

PI/HA Immunized DR4 Tg MicePI76-90 K88S Peptide Stimulated

Untreated IST Treated

Significant Reduction in Proinsulin-Specific IL-2 & IFN𝛾 Producing CD4+ T Cells in Blood and Spleen after Immuno-STAT Treatment


In Vivo Treatment with Proins76-90, K88S/DR4-PDL1 Immuno-STAT Suppresses Cytokine Production by Proins (PI)-Specific CD4+ T Cells

IFN𝛄

IL-2

PI PI/HA PI/HA + ISTImmunization:

IFN𝛄

PI PI/HA PI/HA + ISTImmunization:

* * ns ns

IL-2

PI PI/HA PI/HA+

IST-3005-2639

0.0

0.5

1.0

% IF

Ng+

am

ong

CD

4+ T

cel

ls

PI PI/HA PI/HA+

IST-3005-2639

0.0

0.5

1.0

1.5

% IL

-2+

amon

g C

D4+

T c

ells

PI PI/HA PI/HA+

IST-3005-2639

0.0

0.5

1.0

% IF

Ng+

am

ong

CD

4+ T

cel

ls

PI PI/HA PI/HA+

IST-3005-2639

0.0

0.5

1.0

1.5

% IL

-2+

amon

g C

D4+

T c

ells

Restimulation: Restimulation:PI HA

IFN𝛄 IL-2 IFN𝛄 IL-2

Treatment with ProIns-DR4-PDL1 IST suppresses cytokine production of PI-specific CD4+ T cells (IL2, IFNg, TNFa, IL-17) without affecting HA-reactive cells

PI/HA+ IST

PI/HAPI PI/HA+ IST

PI/HAPI PI/HA+ IST

PI/HAPI PI/HA+ IST

PI/HAPI


Proins (PI)-Specific CD4+ T Cells Produce Lower Levels of Cytokine Following Proins76-90, K88S/DR4-PDL1 Immuno-STAT Treatment

IFN𝛄+ Cells IL-2+ Cells IL-17+ CellsTNFα+ Cells

PI/HA immunized

PI restimulation HA restimulation

IFN𝛄

Nor

mal

ized

to M

ode

***** ** **

PI/HA PI/HA+

IST-3005-2639

0

5000

10000

15000

IFN

g gM

FI

PI/HA PI/HA+

IST-3005-2639

0

5000

10000

15000

IL-2

gM

FI

PI/HA PI/HA+

IST-3005-2639

0

5000

10000

15000

20000

IL-1

7 gM

FI

PI/HA PI/HA+

IST-3005-2639

0

5000

10000

15000

TNFa

gM

FI

PI/HA immunized + IST

Treatment with ProIns-DR4-PDL1 IST reduces the gMFI of cytokines produced by PI-specific cytokine+ CD4+ T cells without affecting HA-reactive cells

PI/HA+ IST

PI/HA PI/HA+ IST

PI/HA PI/HA+ IST

PI/HA PI/HA+ IST

PI/HA


Late Intervention with Immuno-STAT Selectively Reduces the Number of Proins (PI) Responsive CD4+ T Cells In Vivo

ProinsResponse

(IL-2)

Day 11 Day 12 Day 13

HA Response

(IL-2)

Day 12 Day 13Day 11

Veh

IST

Veh

IST


Proins76-90, K88SHA307-319

Day 0

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells

PI Response_Blood IFNg0.01

0.06

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells

HA Response_Blood IFNg

Immunized + no IST/Vehicle

Immunized+IST

0.510.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells

PI Response_Blood IL2

0.002

0.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells

HA Response_Blood IL2


Immunized+IST

0.05

0.05

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.06

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.510.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.002

0.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.05

0.05

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.06

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.510.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.002

0.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.05

0.05

VehicleIST Treated

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.06

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.510.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells


0.002

0.04

D11 D12 D130

250

500

750

1000

150020002500


SFC

per

e6

cells



Immunized+IST

0.05

0.05

VehicleIST Treated


Summary

• Successful generation of Immuno-STAT molecules comprised of Class II HLA molecules (DRB1*04) along with PD-L1 inhibitory ligand to selectively dampen autoreactive CD4+ T cells

• Treatment with Proins76-90, K88S/DR4-PDL1 Immuno-STAT significantly suppressed expansion of Proins-specific CD4+ T cells both in vitro and in vivo

• The effect of Proins76-90, K88S/DR4-PDL1 Immuno-STAT treatment was antigen specific as treatment did not result in a reduction of HA-specific CD4+ T cells

• A single in vivo administration of Proins76-90, K88S/DR4-PDL1 Immuno-STAT at the peak of immunization response significantly reduced the frequency of Proins-responsive T cells

Cue Biopharma/Merck Collaboration

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