Corporate Presentation

May 21, 2024
Copyright © BrightPath Biotherapeutics Co., Ltd.

Copyright © BrightPath Biotherapeutics Co., Ltd.

Disclaimer
The material that follows is a presentation of general background information about BrightPath Biotherapeutics Co., Ltd. (“BrightPath”) as of the date of this presentation. This material prepared solely for
information purpose and is not to be construed as a solicitation or an offer to buy or sell any securities and should not be treated as giving investment advice to recipient.
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BrightPath will operate in the future. The important factors that could cause our actual results, performance or achievements to differ materially from those in the forward- looking statements include, among
others, risks associated with product discovery and development, uncertainties related to the outcome of clinical trials, slower than expected rates of patient recruitment, unforeseen safety issues resulting
from the administration of our products in patients, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment
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should prevail.

1

BrightPath Bio (Tokyo Stock Exchange Growth 4594)
 BrightPath Bio is a clinical-stage biopharmaceutical company focused on developing immuno-oncology products
 Three focused modalities: cell therapy, immune modulatory antibody, and cancer vaccine
 BP2202 is a novel platform of allogeneic CAR-T cell therapy using iPS cell-derived NKT cell
Developed productMechanism/target

Cancer typeBP2201

iPS cell-derived NKT cells

HNSCC

BP2202

CAR-iPSNKT (Undisclosed)

BP2301

HER2 CAR-T

Discovery

Preclinical

PI

PII

Cell Therapy
Hematologic
Malignancy
Sarcoma,
GynecologicalTumorsAntibody
BP1200CD73

BP1202

CD39

BP1210

TIM-3

BP1212

CD39×TIM-3

Cancer Vaccine
BP1209Personalized neoantigen

Solid Tumor
2

01
Cell
Therapy3

BP2201 (Unmodified iPS-NKT Cell)
FY2023 Highlights
 The first-in-human Phase I study of the iPS cell-derived NKT cells was conducted in patients with r/r HNSCC under
the primary endpoint of tolerability and safety
 Some patients at high-dose experienced some level of tendency of tumor shrinkage, which has demonstrated
encouraging early clinical activity of the iPS cell-derived NKT cells
 These initial safety and efficacy results of the first-in-human study are encouraging and provide preliminary
evidence that using iPS-NKT as effector cells for a novel allogeneic CAR-T platform might be an effective cancer
treatment strategy
 In this study, iPS-NKT cells were administered at a low-dose (3x107cells/m2) and high-dose (1x108cells/ m2) in multiple
dosing, through the tumor artery as monotherapy without prior lymphodepletion to exert its most distinct feature ofpriming endogenous anti-tumor T cells.
 Low-dose (n=3) : 1 SD, 2 PD
High-dose (n=6): 4 SD, 1 PD, 1 NE

DCR 33.3%
DCR 80% (4 of 5 evaluable patients)

 The most frequently observed trAEs were Grade 1 or 2 fever (1 patient at low-dose, 4 patients at high-dose)
Source: Professor Shinichiro Motohashi MD, Ph.D, of Chiba University, at CD1-MR1 2024 Conference4BP2202 (CAR-iPSNKT)A Novel Allogenic CAR-T Platform Invariant natural killer T (iNKT) cell is a rare subset of T lymphocytesthat has not only direct but indirect anti-tumor activity by priming CD8+
T cells and other immune cells
 Allogeneic CAR-transduced iPSC-derived iNKT cells retain the naïve
iNKT’s function of inducing host CD8+ T cells• The enhanced fitness and the spread antigens of the induced
host CD8+ T cell are expected to prolong the durability of clinicalresponse Induced pluripotent stem (iPS) cell technology enables clinical-scale
manufacturing of iNKT cells that preserve those functions
 Fully IP protected and worldwide license assigned in US/EP/JP until 2031
• Exclusive right to use iPS-NKT / CAR iPS-NKT cells; the mostdesirable methodology for clinical-scale manufacturing offunctional NKT cells from a rare subset of lymphocytes

CD40L→DC cross-talking

HLA independentVα24β11TCR

NK Receptor(NKG2D etc.)→Tumor Killing5BP2202 (CAR-iPSNKT) (cont’d)iNKT cells induce host endogenous CD8+T with memory phenotype, which is expected to provide
durability of clinical responses
allo NKT

Innate - adaptive immunity bridging
DC cross-talking
CD8+ T cross-priming
Myeloid cell (TAM, MDSC) reprogram1
Innate anti-tumor response
HLA independency
No need to TCR gene editing2
Low GvHD risk
Proliferating capacity

allo γδTallo NK

✓

✓

✓

✓

✓

n.a.

✓
✓

alo αβT

Possible source of
durability

✓

✓
✓

✓
•

✓

✓

✓

1
2

iNKT cells kill tumor-associated macrophage /myeloid-derived suppressive cell thorough
TCR/CD1d.
TCR gene editing is not necessary to avoid therisk of GvHD. Thus, proliferative capacity is not
dampened

NKT cell is a rare subset of innate lymphocytes representing less than 1% of the total
lymphocyte
 Rationale to use iPSC as cell source for clinical scale manufacturing offunctional iNKT cells•

Express a semi-invariant TCR recognizing glycolipids presented by the monomorphic
MHC like molecule CD1d
 HLA independency provides low GvHD risk
6

BP2202 (CAR-iPSNKT) (cont’d)Prototype HER2-CAR iNKT cells showed target-specific anti tumor effects
 Cytotoxic activity (A) and Cytokine secretion (B)(HER-2 expressing tumor cell line SK-OV-3)

BrightPath SITC2022

 Tumor burden of SK-OV-3-luc bearing mice (A), Spider plotof total flux and body weight ratio (B) and Survival rate (C)BrightPath SITC2023

7

BP2202 (CAR-iPSNKT) (cont’d)Landscape of iPS-NK/NKT platform company
Target (IND filing year)
Company
iPS-T

unmodified
unmodified

Blood Cancer CAR
Lymphoma

Leukemia

Multiple
MyelomaSolid Tumor
CAR

HER2 (2023)

2018

Collaborations(Platform type licensee)
2018 (2 Targets)

CD19 (2023)
CD19/CD20(－)
CD5 (－)

iPS-NK

CD19 (2022)

Not disclosed

TACI/BCMA(－)

Not disclosed

Not disclosed(－)(2024)

2021
2019 (3 Target)
2021 (4 Target)(2024)

CD38 (2025)

iPS-NKT

2021(Multiple Target)

EGFR (2025)
GPC3 (2024)

2020(RIKEN)-: IND schedule undisclosed at the research stage

Source: Company

8

BP2301 (HER2 CAR-T)
Autologous, non-virally CAR transduced, HER2-targeting CAR-T cells• T cell differentiation and phenotypes

 Stem cell memory-like T (TSCM) phenotype-rich CAR-T cells, mediated by the non-viral
piggyBac transposon system for CAR transduction
 TSCM effector exhibiting continuous proliferation capacity and self-renewal ability, andlong-lived in vivo
 Able to overcome T cell exhaustion in an immunosuppressive solid tumor
microenvironment, leading to durable clinical responses• BP2301 exhibited memory-like phenotype• Persistence of memory-rich CAR-T cells

HER2 CAR+ CD4+
CD45RA

CD8α

TEFF

TSCM

TEM

TCM

CD4

CCR7

HER2 CAR+ CD8+CCR7CD45RA

HER2 CARHER2 CAR+

TEFF

TSCM

TEM

TCM

CCR7

9

BP2301 (HER2 CAR-T) (cont’d) PiggyBac-mediated, TSCM-rich BP2301 demonstrated potent and sustained killing activity
 BP2301 showed persistent cytotoxicity against
HER2+ sarcoma in a serial killing assay Data
Target Cells: U2-OS (Osteosarcoma)
E:T =1:1

Target Cells: SK-OV-3 (Ovarian)

Tumor alone

1st round

Tumor cell survival index

 BP2301 eradicated inoculated tumor in an ovariancancer xenograft model+HER2 CAR-T
2nd round

Tumor alone+HER2 CAR-T
3rd round

Tumor alone+HER2 CAR-T
0

9

18

27

36
45
Time (hrs)

54

63

72

 Phase 1 clinical trial ongoing 3 + 3 Dose-escalation Design (n=12)
8.3 x 105
cells/kg

2.7 x 106
cells/kg

 Primary objective:
Safety and tolerability
 Secondary objective: Expansion and persistence of BP2301, efficacy
 Lymphodepletion:

3-day regimen
FLU 25 mg/m2 + Cy 250 mg/m2

10

01
Antibody
Pipelines11BP1202 (anti-CD39 Antibody) A Novel Strategy on Targeting CD39
Rediscovery of CD39 as a target for depleting cancer cells and Tregs, while avoiding adenosine generation in thetumor microenvironment
 The conventional strategy to inhibit adenosine generation hasn't yielded promising results thus far
 We revisited CD39 expression by cancer cells themselves and Tregs within TME and proposed the CD39 targetingstrategy that emphasizes the depletion of these cells rather than the inhibition of its enzyme activities
MOA (1)
Direct killing

CancerCell

ADCC
Direct Killing

MOA (2)Treg depletion

MOA (3)
Enzyme Inhibition• BP1202-NF2, a glycoengineered anti-CD39 antibody,
depletes CD39 expressing cancer cells and promotes
immune response by CD39high Treg depletion andCD39 enzymatic activity blockade• CD39 catalyzes the production of immunosuppressive
and CD39 expression is elevated on tumor-infiltrating
Tregs, whereas it is expressed broadly but
moderately or slightly expressed by other tumorassociated immune cells• BP1202-NF2 selectively depletes CD39high T cells andblockades CD39 enzymatic activity of CD39int/low
Conventional anti-CD39 antibodies rely
immune cells in tumor
solely on prevention of enzymatic activity

12BP1202 (anti-CD39 Antibody)(cont’d)Direct Killing

Treg depletion

100.00010.01

Ab (ug/mL)

1100

EC50 = 12.3 ng/mL

BP1202(unmodified IgG1)

30

BP1202-NF2(altered glycosylation)

20

Control IgG1

Treg

Fr. I
CD4+FOXP3CD8+ PD-1+Tim-3+
CD8+ PD-1+
CD8+PD-1-Tim-3-

1000.000001

HD PBMC0.0001

0.01

1

100

Ab (μg/mL)

NSCLC TIL

NSCLC PBMC
NSCLC TIL

0
00
0
00
0
15 0
00
0
20 0
00
00

20

40

ADCC against activated Treg

NSCLC PBMC

Fr. II

50

50

30

0
0.000001

HD PBMCADCC against OAW42 (E/T=10)
EC50 ==9.5EC
9.5ng/mLng/mL50

 CD39 expression was elevated on tumor-infiltrating Tregs
and exhausted CD8+T cells in NSCLC patientsFr. IIIADCC (fold change)

ADCC (%)

40

 BP1202-NF2 demonstrated high ADCC activity
against Treg

10

 BP1202-NF2, of which glycosylation is optimized by CD39 density, affinity to CD39, andaffinity against FcγRIIIa, showed potent killingof CD39+ cancer cell line in ADCC assay

CD39 expression(binding sites/cell)

Ecto-enzyme inhibition
 BP1202 (unmodified IgG1) andBP1202-NF2 (altered glycosylation)
show high affinity for recombinanthuman CD39 (KD(M) x10-10) andTregs( x10-9)

 Maximum blockade of membraneassociated CD39 is 80% at 10μg/mL,
which is compar-able to IPH5201’s 70%(industry high) BP1202-NF2 released the adenosine-inducing
immunosuppression of CD8+ T cells BP1202-NF2 selectively depleted
CD39hi population of CD4+ T cells andCD8+ T cells in ex vivo cultured
human PBMCs

ATP

-

+

+

+

*ATP is catalyzed theconversion toadenosine by CD39
ecto-enzyme

13

BP1212 (anti-CD39 x anti-TIM3 Bispecific Antibody)First-in-class Dual Blockade of CD39 and TIM-3
Blockade of redefined immune checkpoints where it’s meant to function by targeting two pathways
 CD39 is well known as an intervening enzyme for adenosine generation and Tim-3 is recognized as a T-cell exhaustion marker.
However, the strategy to inhibit those functions hasn't been performing as well as expected.
 We redefined CD39 and Tim-3 as a new immune checkpoint different from conventional understanding by combinatory targeting
two pathways.
 TIM-3 and CD39 are co-expressed by not only exhausted T cells but DC/myeloid cells that we shed light on.
 The co-expression of TIM-3 and CD39 on dendritic cells induces tolerization through distinct pathways, working synergistically tosuppress the activation of innate immunity and disturbing the bridge to adaptive immunity.
Dual expression of TIM-3 and CD39

CD39+
NK
DC/Mφ

CD8+ T

TIM3+CD39+

Monocyte
B cells
TIM-3+

CD4+ T
PBMC from healthy donor

14

BP1212 (anti-CD39 x anti-TIM3 Bispecific Antibody) (cont’d)
CD39 inhibition

Affinity

15,000100
TIM-3
TIM3+Binding
CD39+ tocells

10,000

MFI

TIM3+ cells
Binding to TI
CD39+ cells
Binding to CD

5,000

0
0.001 0.01

Inhibition of CD39 is enhanced on
TIM3+ CD39+ cells



1

10

100

1000

50

120x

50,000

0

✱✱✱✱

✱✱

4

✱✱

3
2
1
0

50

0
0.1

1

10

0.01 0.1

100 1000

Antibody (nM)
Antibody (nM)isotypeaCD39 aTim-3 BP1212
ctrl
aTIM-3
aCD39
combo



1
10 100 1000
Ab (nM)(nM)
Antibody

BP1212 strongly suppresses the proliferation ofsyngeneic tumor cells in combination with PD-L1
1500

Tumor Volume (cm3)100,000

w/o ATP or Ab
isotype ctl
a-TIM-3
a-CD39
BP1212-

isotype ctl
anti-TIM-3
BP1212

Robust preclinical antitumor potential

BP1212 Enhances the expansion of
IFNg-producing T cells

IFNγ+ CD8+ T cells(fold change)

Number of CD3+ Tcells

150,000+

Inhibition of PtdSr binding

100

CD39 /TIM3 cells

Effects on T cell profanation and activation+CD39 /TIM-3 cells

0.01

Antibody (nM)

Proliferation of activated-T cells
exposed to ATP

+

0
0.1

BP1212 antibody [nM ]Binding (%)

BP1212 preferentially binds
to TIM3+ CD39+ cells by thehigher affinity and avidity% inhibition of
CD39 activity

Inhibition of TIM-3

αPD-L1
αPD-L1+ BP1212

1000

500

0

0

7

14

21

28

35

Days after cell transplantation
15

BP1210 (anti-TIM3 Antibody)
A Novel TIM-3 Targeting Strategy: Blocking the Binding of All Ligands
 Increasing expression of Tim-3 and Galectin-9, one of the four
known ligands of Tim-3, are reported to relevant to poor
prognosis cancers such as pancreatic carcinoma, glioma,
cervical carcinoma, lymphoma and leukemia.
 We hypothesize that Gal-9 plays a pivotal role in facilitating
immune suppression within tumors by binding to Tim-3 on thesurface of dendritic cells. This binding inhibits dendritic cellmaturation, thereby impeding the mediation of T cell immunity.
 Conventional anti-Tim-3 antibodies are not able to inhibit Gal-9
binding effectively, which impede Tim-3 antagonist to exert fullpotential of T cell anti-tumor activities.

TIM-3 restrains antitumor immunity by
regulating inflammasome activation in DC(Dixonet al. 2021)

 The limitation is derived from two distinct epitope bins of Tim-3,
one of Gal-9 and the other of other three ligands such as PtdSr.
 BrightPath overcome the hurdle by bringing a biparatopic
antibody that inhibits both epitope bin bindings.

TIM-3 expression canserve as a marker for
terminally differentiatedeffector and exhausted
cells (Wolf, et al. 2020)

Robust Anti-tumor effect

PtdSr
PtdSr

BP1210 (anti-TIM3 Antibody) (cont’d)
A novel humanized, IgG1-Fc silent biparatopic antibody
 BP1210 binds to two distinct TIM-3 epitopes: one is the same
domain as sabatolimab (Novartis) and all other Abs advanced inclinical development, and the other is the one that enables fullinterference with Gal-9 binding and that those monoclonal Abs
do not reach

Binging Affinity Enhancement
 Biparatopic antibody
BP1210’s affinity isenhanced to KD(M) of x1010 in a combination ofClone A of x10-9 and Clone
B of x10-7

BP1210hTIM-3 IgV domain
Inhibition of the ligand-binding Inhibition of Gal-9
bindingEnhanced IFNγ-producing T cells

Robust Anti-tumor effect Head-to-head monotherapy comparison(MC-38 mouse model)

 Inhibition of PtdSrbinding

Binding (%)

Binding (%)

50

100

50

0

0

0.01 0.1 1 10 100
Ab (nM)

0.01 0.1

Isotype
BP1210MGB453

1 10 1001000
Ab (nM)

Tumor Volume (cm3)

2000

100

isotype Ctl
BP12101500

MGB453

1000

500

0
0

7

14

21

Days after cell transplantation

28

BP1200 (anti-CD73 Antibody) Novel anti-CD73 antibody taking standard strategy of adenosine generation blockade with a bestin-class profile Attenuates the activity of CD73 as a non-competitive inhibitor without hook effect Enhances the proliferation, cytotoxicity, and cytokine production of T cells under the TME
condition The combination with immune checkpoint antibodies significantly suppressed tumor
growth and lead long term immunotherapeutic efficacy
 Good PK/TK profiles without remarkable organ toxicity in mice and monkeys
BP1200 Internalization

CD73 enzyme activity inhibition
Combination therapy of BP1200 with ICB

Enzyme inhibition

BP1202-NF2, of which glycosylation is
optimized by CD39 density, affinity to CD39
and affinity against FcγRIIIa, showed high
ADCC activity for Treg and potent killing of
CD39+ cancer cell line in ADCC assay

Tumor-Rechallenge model

Pharmacokinetics and Toxicokinetics

Cured mice treatedwith BP1200 and
aPD1 combo were
rechallenged with
the MC-38
expressing hCD73

18

01
CancerVaccine Pipeline

19BP1209 (Fully Personalized Neoantigen Vaccine)
A new platform of personalized neoantigen cancer vaccines directed by checkpoint inhibitor antibodies
 The BP1209 vaccine is delivered as a molecular complex of patient-specific neoantigen
peptides and immune-checkpoint inhibitor antibody such as anti-PD-L1 and anti-CD40
antibodies.
 The neoantigen peptides consists of three modules: HLA-class I and -class II neoantigen
epitopes, and an IgG-binding motif. The peptides non-covalently bind Fc domain of IgG, andself-assemble the antibody-vaccine complex without any chemical reaction which enables
individual synthesis and manufacturing fully personalized neoantigen vaccine

 BrightPath has developed in-house bioinformaticalgorithms to identify highly immunogenic neoantigens
from cancer patients and analyzed clinical samples fromover 100 patients
 The new vaccine platform of BP1209 in combination
with BrightPath’s algorism to identify high quality
neoantigens provides an ideal option to improve
neoantigen vaccine therapy

20BP1209 (Fully Personalized Neoantigen Vaccine) (cont’d) BP1209 exerted robust anti-tumor effect intherapeutic setting•

Atezolizumab conjugated BP1209 vaccine maintainedcomplete tumor regression in all the mice until studyend (n=9).

 BP1209 strongly enhances stem-like Tex infiltration
into tumor•

Mice treated with the BP1209 vaccine marked increasein neoantigen specific TIL•

The BP1209 vaccine increased TCF1+/ Granzyme Bstem-like Tex(s.c.)(s.c.)*Adpgk: mouse neoantigen

21

01
Company
Profile22Company Profile
BrightPath Biotherapeutics Co., Ltd. (Tokyo Stock Exchange Growth: 4594)
Business

Development of novel cancer immunotherapy

Foundation

May 2003

ListingNovember 2015

Employees

24 (as of March 2024)

Location

Headquarters:

2-2-4 Kojimachi, Chiyoda-ku, Tokyo

Research Laboratories:

3-25-22 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa

Board Member
Kenichi Nagai

CEONorihiro Nakamura

CSO

Yoichi Takeshita

CFO

Akira Yamada

Director (part-time)

Hirotaka Takeuchi

Director (outside, independent)

Tsutomu Kishino

Auditor (outside)

Taketoshi Abe

Auditor (outside, independent)

Yoshiyasu Yamaguchi

Auditor (outside)(Present)

23

Copyright © BrightPath Biotherapeutics Co., Ltd.