Michelle Morrow, PhD VP, Preclinical Translational Pharmacology - PowerPoint Presentation

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Michelle Morrow, PhD

VP, Preclinical Translational Pharmacology

F-star Therapeutics

FS118, a Tetravalent PD-L1 and LAG-3 mAb2 Bispecific to Overcome and Prevent Checkpoint Resistance

CONFIDENTIAL

The Evolution of Cancer Therapy

Modulating the thresholds for immune cell activation

CTLA-4

TIGIT

PD-1

PD-1

LAG-3

LAG-3

TCR

CD28

OX40

4-1BB

CD27

CD80/CD86

CD155

PD-L1

PD-L2

FGL-1

MHC

CD80/CD86

OX40L

4-1BBL

CD70

Combinatorial approaches, including bispecific antibodies, aim to build on the success of PD-1 monotherapy

CONFIDENTIALLAG-3 Biology is Important in Cancer Progression and Response to Checkpoint Therapy

T cell

Tumor

cell

PD-1

Tumor

cell death

MHC II

PD-L1

LAG-3

Combination of PD-(L)1 and LAG-3 blockade modulates T cell responses and drives anti-

tumor

activity preclinically

1,2

and has shown promise in clinical trials

3

1 Woo et al, 2012 Cancer Research

DOI: 10.1158/0008-5472.CAN-11-1620

2

Tawbi

et al, 2022 New England Journal of Medicine

doi

: 10.1056/NEJMoa2109970

3 Koyama et al, 2016 Nature Communications

DOI: 10.1038/ncomms10501

4:

Kraman et al, 2020 Clinical Cancer Research

DOI: 10.1158/1078-0432.CCR-19-3548

5 Andrews et al 2020 Science Immunology

https://doi.org/10.1126/sciimmunol.abc2728

APC

LAG-3:MHC Class II blockade

TCR

MHC II

MHC I

APC

PD-1:PD-L1 blockade

FGL-1

Anti-PD-1

Anti-LAG-3

CONFIDENTIALLAG-3 Biology is Important in Cancer Progression and Response to Checkpoint Therapy

T cell

APC

Tumor

cell

PD-1

TCR

MHC II

MHC I

Tumor

cell death

PD-L1

LAG-3

Combination of PD-(L)1 and LAG-3 blockade modulates T cell responses and drives anti-

tumor

activity preclinically

1,2

and has shown promise

in

clinical trials

3

Adaptive resistance may occur following compensatory upregulation of LAG-3 and PD-L1, limiting activity of a combination approach

3,4

1 Woo et al, 2012 Cancer Research

DOI: 10.1158/0008-5472.CAN-11-1620

2

Tawbi

et al, 2022 New England Journal of Medicine

doi

: 10.1056/NEJMoa2109970

3 Koyama et al, 2016 Nature Communications

DOI: 10.1038/ncomms10501

4:

Kraman et al, 2020 Clinical Cancer Research

DOI: 10.1158/1078-0432.CCR-19-3548

5 Andrews et al 2020 Science Immunology

https://doi.org/10.1126/sciimmunol.abc2728

LAG-3:MHC Class II blockade

Upregulation of LAG-3

Upregulation of PD-L1

PD-1:PD-L1 blockade

FGL-1

MHC II

LAG-3 Biology is Important in Cancer Progression and Response to Checkpoint Therapy

T cell

APC

Tumor

cell

PD-1

TCR

MHC II

MHC I

Tumor

cell death

PD-L1

LAG-3

Combination of PD-(L)1 and LAG-3 blockade modulates T cell responses and drives anti-

tumor

activity preclinically

1,2

and has shown promise in clinical trials

3

Adaptive resistance may occur following compensatory upregulation of LAG-3 and PD-L1, limiting activity of a combination approach

3,4

Cleavage of LAG-3 has been an important mechanism in overcoming PD-1 resistance

5

FS118 is a potent blocker of the PD-L1 and LAG-3 pathways, and induces LAG-3 shedding to overcome and avoid resistance to PD-1 blockade

1 Woo et al, 2012 Cancer Research

DOI: 10.1158/0008-5472.CAN-11-1620

2

Tawbi

et al, 2022 New England Journal of Medicine

doi

: 10.1056/NEJMoa2109970

3 Koyama et al, 2016 Nature Communications

DOI: 10.1038/ncomms10501

4:

Kraman et al, 2020 Clinical Cancer Research

DOI: 10.1158/1078-0432.CCR-19-3548

5 Andrews et al 2020 Science Immunology

https://doi.org/10.1126/sciimmunol.abc2728

Bispecific Activity:

PD-L1 driven

LAG-3 shedding

LAG-3:MHC Class II blockade

PD-1:PD-L1 blockade

Bispecific Activity:

Decrease in LAG-3 expression

FGL-1

MHC II

CONFIDENTIAL

FS118 has the Potential to Overcome Resistance to PD-1 Blockade by Inducing LAG-3 Shedding

Adapted from

Seldel

and

Bengsch

, 2020 Science Immunology

DOI: 10.1126/sciimmunol.abc8644

, a focus article reviewing

Andrews et al, 2020 Science Immunology

DOI: 10.1126/sciimmunol.abc2728

Surface LAG-3

ADAM10 Protease

Response to

anti-PD-1 therapy

Melanoma

SCCHN

CD4+ T cell

Anti-PD-1

FS118

Melanoma

SCCHN

CD4+ T cell

ADAM10

ADAM10

FS118: A Tetravalent Dual Checkpoint BispecificCONFIDENTIAL

F-star’s Bispecific Platform

2 natural

binding sites

2 new Fc antigen binding (

Fca

b) sites

Fc

R

 null for improved safety potential

Tetravalency Drives Potent Biology

Crosslinking

: Potent tetravalent binding (avidity) bringing cells together

Clustering:

Fcabs

drive potent immune cell activation

Conditionality:

Strong localized antitumor effect

Unique Bispecific Structure

2 + 2 Binding in a Natural

human antibody format with only ~15 amino acid

substitutions

Bispecific Antibodies Can Unlock New Biology

FS118: Dual Checkpoint Inhibitor Targeting LAG-3 and PD-L1

LAG-3

PD-L1

Key Properties:

Tetravalent “2+2” Format

Dual antagonist of PD-L1 and LAG-3

Natural IgG format for ease of manufacture and l

ow immunogenicity

Fc

g

R

null for safety

Fc

γ

R null

FS118 Activity is Superior to a

mAb

Combination

in vitro and

in vivo

Human blood cell assay

Kraman et al, 2020 Clinical Cancer Research

DOI: 10.1158/1078-0432.CCR-19-3548

FS118 overcomes PD-L1 and LAG-3 mediated inhibition to drive anti-

tumor

immunity

Mouse MC38 Colon Carcinoma Tumor Model

FS118 Surrogate Reduces LAG-3 Surface Expression by Mouse TILs

LAG-3

+

CD4

+

T cells

LAG-3

+

CD8

+

T cells

Total LAG-3 expression on

tumor

infiltrating lymphocytes

Reduced expression of LAG-3 on T cells surface

following surrogate FS118 administration

Increased expression of LAG-3 on CD4+ T cells surface following mLAG-3 + mPD-L1 combo administration

Morrow et al, SITC 2020 #715

doi

: 10.1136/jitc-2020-SITC2020.0715

FS118 Surrogate mAb

2

Increases LAG-3 Shedding

Soluble LAG-3 in the serum of

tumor

-bearing mice

Dose-dependent increase in soluble LAG-3

following a single dose of FS118

in vivo

Morrow et al, SITC 2020 #715

doi

: 10.1136/jitc-2020-SITC2020.0715

CONFIDENTIALBispecific Activity of FS118 Drives LAG-3 Shedding via Metalloproteases

Morrow et al, SITC 2020 #715

doi: 10.1136/jitc-2020-SITC2020.0715

SEB PBMC assay

SEB PBMC assay with ADAM inhibitors

Bispecificity

of FS118 is required for maximal LAG-3 shedding and is dependent upon the metalloproteinases ADAM10 and ADAM17

First-in-Human Phase 1 Clinical Trial in Heavily Pre-treated PD-1 resistant patients

Study design and objectives

FS118 duration of treatment by prior

checkpoint resistance status (*)

FS118 was well tolerated with no treatment related serious adverse events and no dose limiting toxicity

Acquired resistance patients benefit from

longer treatment duration

Primary objectives: Safety, MTD,PK

Secondary objectives: Response, immunogenicity

Exploratory objectives: characterise PD profile

ClinicalTrials.gov identifier: NCT03440437

(*) Only patients receiving ≥ 1mg/kg FS118 are included

Data cut off 18

th

Sept 2020

FS118 Increases Soluble LAG-3 in Patient Serum

Soluble LAG-3 serum

concentration at week

1 of cycle 1

FS118 mediated a dose-dependent increase of soluble LAG-3 in patient serum

Cycle 1 Week 1

Disease Control Observed in Patients Expressing LAG-3 and PD-L1 in the TME

Immunohistochemistry: Baseline LAG-3 and PD-L1 in

tumor

All patients treated with FS118 and that remained on treatment for more than 20 weeks were classified as

Acquired Resistant

and were expressing either both (LAG-3 and PD-L1) or at least one of the two FS118 targets in the TME

Data cut off 18

th

Sept 2020

CONFIDENTIAL

Clinical Benefit with FS118 : The ATC case

“

Within a month the patient had rapid improvement in the

tumor

size and was able to swallow

”

Continued Clinical benefit as of Nov 2021

For 2 Years and 9 months

Perithyroid

metastasis

Patient Characteristics

Age

62 years

Concurrent Chemo-XRT

PD after

5 months

Nivolumab (PD-L1

+

)

PR and DOR

10 months

Braf/Mek inh (V600E mut)

Nivolumab continued 

Severe tox with PD after

4 monthsFS118 dosingFeb 2019 – ongoing for 33 months

FS118: Profound Co-Inhibition through LAG-3 Shedding

FS118 is a potent dual antagonist of PD-L1 and LAG-3 and induces LAG-3 shedding as a novel bispecific MOA, which may overcome resistance to PD-(L)1 blockade

FS118 Differentiated Mechanism

Activated

T cell

APC

Tumor

cell

PD-1

TCR

MHC II

MHC I

PD-L1 driven

LAG-3 shedding

Tumor

cell death

PD-L1 driven

LAG-3 shedding

PD-L1 driven

LAG-3 shedding

& removal of LAG-3 from cell surface

Activated

T cell

Tumor

cell

MHC II

FS118

LAG-3

PD-L1

CONFIDENTIALFS118 Clinical Development Plan

Ph 2: PD-1 Resistant SCCHN

(Biomarker enriched)

Proof of concept

On-going

n

= ~35

Patient population with unmet medical need with potential to enable a rapid registration pathway

Disease Control Rate,

Overall Response Rate

Ph 2: NSCLC & DLBCL

(Biomarker enriched)

Dose expansion

Initiating

n

= 60+

Preventing resistance in

PD-1 sensitive patients

Overall Response Rate, Duration of Response

CPI resistant

Rationale

Benefits

Trial

Superior to PD-1 alone

CPI-naïve, PD-1 sensitive

tumors

Rescuing PD-1 treatment failures

Acquired resistance

Avoiding PD-1 resistance by preventing LAG-3 upregulation while inhibiting PD-L1

Overcoming PD-1 resistance by inducing LAG-3 shedding while inhibiting PD-L1

CPI naïve

FS118 is a potent blocker of the PD-L1 and LAG-3 pathways, and induces LAG-3 shedding to overcome and avoid resistance to PD-(L)1 blockade

Unique bispecific format with potential for focussed, potent and safe immune activation

Novel anti-LAG-3 shedding mechanism, observed in preclinical studies and clinic

Well tolerated up to the highest dose of 20 mg/kg

Recommended dose of 10 mg/kg based upon PK/PD data analysis

Clinical benefit observed in

tumors

co-expressing LAG-3/PD-L1

Patient with >2 years’ survival ongoing

Ongoing studies to address the hypothesis that FS118 can overcome and avoid resistance to PD-1 blockade in Acquired Resistant Head and Neck cancer and Checkpoint Inhibitor (CPI) Naïve NSCLC & DLBCL respectivel

y

CONFIDENTIAL

Key Messages and Conclusions