FPT155: A first-in-class therapeutic CD80-Fc fusion ... - FPT155 oral... · FPT155: A...
Transcript of FPT155: A first-in-class therapeutic CD80-Fc fusion ... - FPT155 oral... · FPT155: A...
FPT155: A first-in-class therapeutic CD80-Fc fusion protein that augments T cell co-stimulationSusannah D Barbee, PhD
Five Prime Therapeutics, South San Francisco, CA
• I have the following financial relationships to disclose:
• I am an employee of Five Prime Therapeutics
• I am a stockholder in Five Prime Therapeutics
• I will not discuss off label use and/or investigational use in my presentation
Disclosure Information
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 2
3© 2019 Five Prime Therapeutics, Inc. All Rights Reserved
FPT155: First-In-Class CD80-Fc Fusion Protein Engineered to Activate T Cells Through Multiple Pathways
Normal T cell activation via CD80 FPT155 uses the binding interactions of CD80 to:
• Directly engage CD28 to enhance its co-stimulatory activity (without super agonism)
• Block CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T cell activation
Antigenpresenting cell
CD80 extracellular domain
T cell
(+) signal
TCRMHC
CD28CD80
Human IgG1 FcCD80 is a co-stimulatory molecule expressed on
antigen presenting cells
First in Human phase 1a/1b trial initiated in Nov 2018
• Flow cytometry-based assays indicate that FPT155 binds to cells via CD28 and CTLA-4 but not via
PD-L1
• FPT155 binds to primary T cells and in vitro-expanded T cells but not to hematopoietic subsets that
express only PD-L1 (e.g. monocytes)
FPT155 Binds to Cell-Surface CD28 and CTLA-4
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 4
CHO-CD28
Binding to cell lines that express a single ligand
CHO-CTLA-4 CHO-PD-L1
CD4+ T cells
CD8+ T cells
Monocytes
Binding to human
PBMC
1 0 -1 1 0 0 1 0 1 1 0 2
0
2 0
4 0
6 0
8 0
F P T 1 5 5 [n M ]
% b
ou
nd
by
FP
T1
55
1 0 -1 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4
0
2 0
4 0
6 0
8 0
1 0 0
F P T 1 5 5 [n M ]
% b
ou
nd
by
FP
T1
55
1 0 -1 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4
0
2 0
4 0
6 0
8 0
1 0 0
F P T 1 5 5 [n M ]
% b
ou
nd
by
FP
T1
55
1 0 2 1 0 3 1 0 4
0
2 0
4 0
6 0
8 0
1 0 0
F P T 1 5 5 [n M ]
FP
T b
ind
ing
(%
ma
x)
• 293-based “artificial APC” express an OKT3 scFv to provide TCR stimulation and/or a
truncated FcγRI to cluster FPT155 in the cellular synapse
• Activity observed with FPT155 requires TCR signal and Fc-mediated clustering
FPT155 Activity Requires Co-Presentation with TCR Stimulus
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 5
293-OKT3-CD64silent
293-OKT3
293-CD64silent
IL2 Production PD-1 expression
Naïve CD4+ T cells + 293 aAPC
CD28
293 aAPC
Human T cell
FPT155
TCR
.
CD64silentOKT3 scFv
1 0 1 1 0 2 1 0 3 1 0 4
0
2 0
4 0
6 0
8 0
1 0 0
D o n o r 7 4 - n a iv e 4 T
P D 1
F P T 1 5 5 [n M ]
% P
D-1
+
H E K 2 9 3 -O K T 3lo
-C D 6 4ta i l le s s
H E K 2 9 3 -O K T 3lo
H E K 2 9 3 -C D 6 4ta i l le s s
1 0 1 1 0 2 1 0 3 1 0 4
0
2 0
4 0
6 0
8 0
D o n o r 7 4 - n a iv e 4 T
P ro life ra t io n
F P T 1 5 5 [n M ]
% C
FS
Elo
H E K 2 9 3 -O K T 3lo
-C D 6 4ta i l le s s
H E K 2 9 3 -O K T 3lo
H E K 2 9 3 -C D 6 4ta i l le s s
• FPT155 potently co-stimulates the activation of MART-1 antigen-specific T cells in vitro
• The effect is sensitive to peptide concentration, indicating that TCR-induced signals are critical for activity
• Activity is observed at lower concentrations than are required to detect soluble binding, and lower than are
expected to saturate CTLA-4
• Absence of activity with Ipilimumab suggests that FPT155 may be efficacious when co-stimulation is limiting
FPT155 Co-Stimulates T Cells in the Context of Antigen-Specific TCR Stimulation when CD28 Ligands are Limiting
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 6
CD28
K562
Transduced human T cell
FPT155
HLA-A2
MART-1
TCR
.
CD64silent
0.3 ng/mL
1.1 ng/mL
3.3 ng/mL
10 ng/mL
MART-1 peptide titration 10 ng/mL MART-1 peptide
MART-1 TCR+ panT cells + K562 aAPC
Fc control
Fc control +10 μg/mL
Ipilimumab
FPT155
1 0 - 1 1 0 0 1 0 1 1 0 2
0 .0
0 .2
0 .4
0 .6
0 .8
1 0 n g /m L p e p tid e
F P T 1 5 5 o r F c c o n tro l [n M ]
IL2
[n
g/m
L]
F c c o n tro l + 1 0 u g /m L Ip i
F P T 1 5 5 + 1 0 u g /m L Ig G 1 c o n tro l
0
F c c o n tro l + 1 0 u g /m L Ig G 1 c o n tro l
IL2 production
1 0 - 1 1 0 0 1 0 1 1 0 2
0 .0
0 .2
0 .4
0 .6
IL2
F P T 1 5 5 [n M ]
IL2
[n
g/m
L]
1 0 n g /m L
3 .3 n g /m L
1 .1 n g /m L
0 .3 n g /m L
M A R T -1 p e p tid e
0
• The CD28 superagonist antibody TGN1412 induces spontaneous cytokine release by PBMC when
immobilized on plastic
• The cytokine profile matches that of clinical cytokine release syndrome
• FPT155 alone does not induce spontaneous cytokine release in this format
• Cytokines are produced when FPT155 is co-immobilized with anti-CD3, indicating that FPT155 is functionally
active in this assay format, but requires co-engagement with the TCR for T cell activation
FPT155 is Not a T Cell Superagonist
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 7
FPT155 alone
FPT155
+ anti-CD3
TGN1412 alone
n = 5
Each line represents an
individual donor
IL2IFNγ IL6 TNFα
0 0 .1 0 .3 1 3 1 0 3 0
0
2 0 0
4 0 0
6 0 0
8 0 0
P ro te in [g /w e ll]
IFN
[p
g/m
l]
0 0 .1 0 .3 1 3 1 0 3 0
0
4
8
1 2
P ro te in [g /w e ll]
IL2
[n
g/m
l]
0 0 .1 0 .3 1 3 1 0 3 0
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
P ro te in [g /w e ll]
IL6
[n
g/m
L]
0 0 .1 0 .3 1 3 1 0 3 0
0
1 0
2 0
3 0
4 0
P ro te in [g /w e ll]
TN
F
[n
g/m
l]
Spontaneous PBMC cytokine release in vitro
• mFPT155 exerts monotherapy anti-tumor activity in multiple tumor models including CT26, MC38,
EMT6, A20, and WEHI164‡
• Mice that reject tumors in response to mFPT155 are protected from subsequent re-challenge
• mFPT155 exhibits synergistic activity in combination with anti-PD-1 in the CT26 model
The Murine Surrogate mFPT155 Can Induce Complete Tumor Regression After a Single Dose at 0.2 mg/kg
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 8
0 5 1 0 1 5 2 0 2 5 3 0
0
4 0 0
8 0 0
1 2 0 0
1 6 0 0
2 0 0 0
2 4 0 0
T u m o r G ro w th
D a y s p o s t- in o c u la t io n
Tu
mo
r V
olu
me
(Me
an
mm
3
SD
)
0 0 2 1 0 1 3
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
D a y 2 1
Tu
mo
r V
olu
me
(Me
an
mm
3
SD
)
**
N u m b e r o f tu m o r re g re s s io n s (o f 1 5 )
mIgG2a
mFPT155 0.1 mg/kg
mFPT155 0.2 mg/kg
mFPT155 0.6 mg/kg
mFPT155 0.9 mg/kg
CT26 tumor growth Day 21 tumor volume
Number of tumor regressions (of n = 15)
‡Data on file
• mFPT155 also has significant activity in other refractory
tumor models, including Renca and 4T1‡
• Activity in such tumor models suggests that FPT155
could have clinical activity in tumor types that respond
poorly to IO therapies
mFPT155 is Efficacious in Tumor Models Typically Refractory to IO Treatment
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 9
0 5 1 0 1 5 2 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
D a y s p o s t- in o c u la tio n
0 5 1 0 1 5 2 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
D a y s p o s t- in o c u la tio n
0 5 1 0 1 5 2 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
D a y s p o s t- in o c u la tio n
Tu
mo
r V
olu
me
(m
m3)
0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
D a y s p o s t- in o c u la tio n
Pe
rce
nt
su
rviv
al
B16-F10
tumor
growth
B16-F10
survival
mIgG2b control
mFPT155 (mIgG2a)
3 mg/kg
anti-CTLA4 (mIgG2b)
10 mg/kg
‡Data on file
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
D a y 2 1
* * * *n s
* * * *
* * * *n s
0 5 1 0 1 5 2 0 2 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
T u m o r G ro w th
D a y s p o s t- in o c u la t io n
Tu
mo
r V
olu
me
(Me
an
mm
3
SD
)
• CTLA-4 blockade via a Fc-silent antibody has minimal monotherapy activity against CT26
• Slight but non-significant loss of activity in combination suggests that mFPT155 has CTLA-4-
mediated function independent of neutralization
mFPT155 Retains the Majority of Its Activity in vivo Independent of Its Interactions with CTLA-4
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 10
anti-CTLA4-silent
mFPT155
mIgG2a 50 mg/kg
mFPT155 0.9 mg/kg
anti-CTLA-4-silent 50 mg/kg
Combination
CT26 tumor growth Day 21 tumor volume
• mFPT155 treatment promotes recruitment and subsequent infiltration of T cells
• The response is specific to effector T cells and is not observed for Treg
mFPT155 Promotes Effector T Cell Recruitment into Tumors
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CD3 staining in CT26 tumors CD4 and CD8 staining in MC38 tumors
Control
mFPT155
skin
tumor
Adjacent normal
Tumor margin
Tumor core
n = 5 per group
CD4 CD8
Days post-treatment
0
2 5 0 0
5 0 0 0
7 5 0 0
IgG
2a
mF
PT
155
IgG
2a
mF
PT
155
11 15
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
De
ns
ity
(#
/mm
2)
IgG
2a
mF
PT
155
IgG
2a
mF
PT
155
11 15
• mFPT155 preferentially induces effector T cell activation in the tumor as detectable by
transcriptomics and flow cytometry
• Effect is observed in peripheral blood only in tumor-bearing animals, indicating that mFPT155 does
not induce non-specific T cell activation at projected clinical dose levels
mFPT155 Induces T Cell Activation in Tumor-Bearing Animals at Projected Clinical Dose Levels
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 12
mIgG2a
mFPT155 0.1 mg/kg
mFPT155 0.3 mg/kg
mFPT155 0.9 mg/kg
mFPT155 10 mg/kg
mFPT155 50 mg/kg
Norm
aliz
ed m
RN
A
Tumor Whole blood Whole blood
CT26 tumor-bearing mice Naïve mice
Gzmb expression 11 days after mFPT155 administration
0 .1
1
1 0
1 0 0
* * *
0 .1
1
1 0
1 0 0
* *
0 .1
1
1 0
1 0 0
* ** **
• Trial initiated in Australia; expansion to other countries in Phase 1b
• A conservative MABEL approach was used to select starting dose for dose escalation
• We are currently evaluating combination strategies
Phase 1a/1b Clinical Trial to Evaluate FPT155 Monotherapy Activity
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PHASE 1aDose Escalation
PHASE 1bExpansion at Chosen Dose
Any Solid Tumor
Basket of Solid Tumors
Exploratory Cohorts
Select Solid Tumor Cohorts
Initiated
November 2018
Study Objectives
• Safety
• Objective response
rate and duration
• Survival
• Baseline and
on-treatment
biopsies
Real-Time Safety Assessments
• Local lab tests labs include complete blood count, full chemistry panel, and CRP on D2 and weekly
in C1
Retrospective Analyses
• Tumor at baseline (archival)
• Evidence of tumor immunogenicity (IHC, RNA, DNA)
• Tumor pre-/on-treatment biopsies mandated in 1a exploratory cohorts
• Optional biopsy collection at progression
• Immune infiltration and activation (IHC, RNA)
• Peripheral blood pre-/on-treatment
• T cell phenotype (flow cytometry)
• Peripheral cytokines, including CRS signature
• Tumor mutation burden (ctDNA)
Biomarker Analyses to Monitor Safety, Efficacy, and MOA Endpoints
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 14
• FPT155 is a first-in-class CD80-Fc fusion protein engineered to activate T cells via
engagement of CD28 and CTLA-4
• FPT155 does not have TCR-independent superagonist activity in nonclinical studies
• The murine surrogate (mFPT155) has potent anti-tumor activity in multiple murine tumor
models, including models typically refractory to IO agents
• mFPT155 has synergistic combination activity with anti-PD1
• mFPT155 promotes a favorable tumor immune contexture characterized by effector T cell
infiltration and activation
• mFPT155 preferentially activates T cells in the tumor microenvironment vs periphery
• Five Prime initiated a Phase 1a/1b clinical trial in November 2018
Summary
© 2019 Five Prime Therapeutics, Inc. All Rights Reserved 15
16© 2019 Five Prime Therapeutics, Inc. All Rights Reserved
Acknowledgements
FPT155 Core Team
Jim Adair
Ago Ahene
Leslie Fok
Sharon Horton
Sandeep Inamdar
Marc Lopez
Monica Macal
Siddhartha Mitra
Danielle Pasqualone
Renuka Sivendran
Maike Schmidt
Hong Xiang
Shelly York
Five Prime Therapeutics Senior Management
Aron Knickerbocker
Bryan Irving
Helen Collins
Nallakkan Arvindan
Francis Sarena
David Smith
External
MART-1 TCR system: Steven Rosenberg, NCI
Patients and clinicians participating in the FPT155-001 trial