Confidential

Introduction and Notes ofiPS Cell Stock
As of 2024/01/19

CiRA Foundation

Contents
About CiRA Foundation‒ Organization / Purpose / Facility

About iPS Cell Stock‒ Outline / Precautions / Achievement for Clinical Use / Paper

About Available Cell Lines‒ Recommended Cell Lines / Cell Line List

About Procedures for Request‒ Provision Fee / General Flow / Required Documents / Contact Us
CiRA Foundation / Confidential

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CiRA Foundation
April 1, 2020
Registered as a public interest incorporated
Foundation by the Cabinet Office（Located inside CiRA buildings）
Center for iPS Cell Research and Application

Kyoto University
BasicResearch
MedicalApplication
Education
Training

CiRA

iPSCs
Manufacturing,
QC and Storage

CiRA Foundation / Confidential

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Our purpose：Bridge over the valley of death

CiRA and otherresearch institutions
Basic research on
iPSCs

CiRA Foundation
Manufacturing iPSCs,
Bridge to industry

Industry
Manufacture,sale of regenerative
medical products/
Provision to medicalinstitutions
CiRA Foundation / Confidential

4Facility for iPS Cell Therapy (FiT) License
We obtained the manufacturing license based on
the PMD Act. (License#26FZ110001)*We are also recognized as the Cell Processing Center.
(the Japan Act on Securement of Safety of Regenerative Medicine)(Facility#FA5200001)

 Experience
Abundant experience in the production/testing ofclinical grade iPSCs and iPSC-derived
differentiated cells under the GMP-compliant
quality system and facilities.
CiRA Foundation / Confidential

5Our iPS Cell lines iPS Cell Stock
We have been providing off-the-shelvesclinical-grade iPSCs at low cost since 2015.

HLA-homozygous iPSCs

These iPS cells were generated from the blood of
healthy donors who are homozygous in theirexpression of the protein HLA-A, HLA-B, or HLA-DR.
We provide 27 clinical-grade cell lines from 7 donors
and some of these cell lines were used in several
Japanese clinical trials/research.

HLA-genome-edited iPSCs

These iPS cells are designed to reduce the risk ofimmune rejection. We manufacture and provide themby targeting HLA-A, -B, and -CIITA for the genomeedited knockout. Also, they are capable ofsuppressing both T and NK cell activity because theyretain HLA-C and HLA-E.

SeV-iPSCs

These iPS cells were made using Sendai Virus (SeV)
vectors, instead of Episomal Plasmids. From a patent
licensing point of view, we recommend them tocommercial users.

 Research Materials

We provide human-derived research materials. Users
can use them even for drug discovery, but we don’t
provide clinical-grade ones for regenerative medicines.

CFiS Series

These are research-grade iPS cells generated fromthe blood of a healthy donor who isn’t homozygous
in HLA. Users can use them just by agreeing with theterms and conditions.

Covid-19 iPSCs

These iPS cells were made from COVID-19
convalescent patients.
CiRA Foundation / Confidential6What is iPS Cell Stock?
“iPS Cell Stock” is a high-quality off-the-shelf iPSC forregenerative medicine.
high-quality

off-the-shelf

Already used in several Japanese clinical trials!

Able to choose iPSCs from several cell lines!
■HLA-homozygous iPSCs
27 clinical-grade lines from 7 donors■HLA-genome-edited iPSCs
2 clinical-grade lines from 1 donor■SeV-iPSCs
2 clinical-grade lines from 1 donor

CiRA Foundation / Confidential

7Precautions
1. If users want to utilize clinical-grade iPSCs, we kindly request that users first use our researchgrade iPSCs and share with us the results of differentiation, such as immunostaining figures. Dueto the limited availability of vials for our clinical-grade iPSCs, we primarily offer them to users who
have previously utilized our iPSCs. But as for these cell lines (KTRH05, KTRH26, QHJI14s04-ABⅡKO-03, and QHJI14s04-ABⅡ-KO-11), users can first use clinical-grade iPSCs.
2. We only provide our iPSCs to institutions or companies with research plans that appropriately
comply with local regulations, such as IRB approvals.
3. Users should get the appropriate license from iPS Academia Japan which controls the patents ofiPS Cells. For further details and inquiries, please directly engage with iPS Academia Japan. The
third-party patent information will be provided during the contract signing process. At their own
risk, users may need to refer to and deal with effective patents in their country.
4. We acknowledge that users shall have exclusive ownership of differentiated cells, but please notethat ownership of iPSCs doesn’t transfer to users. If users need to get ownership of iPSCs, theyhave to sign the ownership transfer agreement. After signing it, we’ll transfer the ownership with
non-transferable covenants.
CiRA Foundation / Confidential

8What is Research-grade iPSCs?

Research-grade iPSCs

Research-grade iPSCsCiRA Foundation / Confidential9

3 strategies to promote iPSC therapy
Allogenic iPSC
HLA-homozygous
Super donor

Patient

HLA-genome-edited
Super donor

Patient

Autologous iPSC
Patient

CRSPER-Cas9

27 cell lines / 7 donors

HLA-A, HLA-B, CⅡTA edited

my iPS®

Cover ca.40% of JapaneseWorldwide coverage

Order madeCiRA Foundation / Confidential

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Progress in our iPSC-based cell therapy
Sponsor/Investigator

iPS cell line

Masayo Takahashi(RIKEN)

QHJI01s04

Masayo Takahashi(Kobe City Eye Hospital )QHJI01s04

Yasuhiko Hirami
QHJI01s04(Kobe City Eye Hospital )Jun Takahashi
QHJI01s04(Kyoto University)
Yoshiki Sawa
QHJI14s04(Osaka University Graduate School of Medicine)
Hideyuki Okano
YZWJs513(Keio University School of Medicine )Kohji Nishida
YZWJs524(Osaka University Graduate School of Medicine)
Noriyuki Tsumaki
QHJI01s04(Kyoto University)
Keiichi Fukuda
QHJI14s04(Keio University School of Medicine)

Cell type
Retinal pigment epithelium(cell suspension)
Photoreceptor cells(Neural retinal sheet )Retinal pigment epithelium(cell suspension)
Retinal pigment epithelium(cell strips)
retinal sheets
Dopaminergic progenitor cells(cell aggregate)
Cardiomyocytes(Cell patch)neural stem/progenitor cells(cell suspension)
Corneal epithelium(allogeneic, cell sheet)
Chondrocytes(Cartilage tissue)
Ventricular cardiomyocytes(Spheres)
Ventricular cardiomyocytes(Spheres)
Innate lymphoid cells(Natural Killer Cells)

Heartseed Inc.

QHJI14s04

Shin Kaneko(Kyoto University)

QHJI01s04

Megakaryon Co.

YZWJs513

Platelets

Shigeto Shimmura(Keio University School of Medicine)

QHJI01s04

Corneal endothelial cell(cell suspension)

Disease indications

Current stage

Clinical Research：
Completed
Clinical Research：
Retinitis pigmentosa
Completed
Clinical Research:
RPE impaired disease
TerminatedClinical Research：
RPE impaired disease
Recruiting
Clinical Research：
Retinitis pigmentosa
Active, not recruiting
Clinical Trial：
Parkinson's disease
Active, not recruiting
Clinical Trial：
Ischemic Cardiomyopathy
Recruiting
Spinal cord injury at subacute
Clinical Research：
Recruiting
stage
Corneal opacity due to limbal stem Clinical Research：
Completedcell deficiency
Clinical Research：
Knee articular cartilage damage
Active, not recruiting
Heart failure
Clinical Research：
Recruiting(Dilated cardiomyopathy)
Heart failure
Clinical Trial：(Ischemich heart disease)
Recruiting
Clinical Trial：
Ovarian cancer
Recruiting
Clinical Trial：
Thrombocytopenia
Recruiting
Clinical Research：
Bullous keratopathy
Recruiting
Age-related macular degeneration

Modified Table.3 in a paper by Yoshida et al., Med (2022) DOI：10.1016/j.medj.2022.10.003

CiRA Foundation / Confidential11Paper on iPSC Stock

Yoshida et al., Med (2022)
DOI：10.1016/j.medj.2022.10.003
CiRA Foundation / Confidential

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Available cell lines: KTRH series1）US donor-derived iPS Cells with Sendai virus vector
GradeClinical-gradeResearch-grade

Cell lines

KTRH05
KTRH26*Users can use clinical-grade celllines for research use.
KTRH26

SourceHuman peripheral blood, derived from healthy US donor

VectorSendai Virus vectors（CytoTune®）

Feature Conformable to the donor eligibility regulations of Japan, the U.S., and Europe.
 We used the Sendai virus vector instead of episomal plasmids.
（No residuals of the Sendai virus confirmed.） Users can use clinical-graded cell lines even if it is the first provision.

Provision Fee To non-profit: Free To profit: JPY100,000 /one vial (~USD690, 1USD=145JPY)
NoticeHomozygous only in HLA-A
CiRA Foundation / Confidential

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Available cell lines: QHJI series2）Most used HLA-homozygous iPS Cells derived from PBMC
GradeClinical-gradeResearch-grade

Cell lines

QHJI01s04
QHJI14s03
QHJI14s04

Ff-I01s04
Ff-I14s03
Ff-I14s04

QHJI01s04

SourceHuman peripheral blood, derived from healthy Asian donor

VectorEpisomal PlasmidsFeature The underlined cell lines were used in several Japanese clinical trials/research.
(Please refer to our paper ”Yoshida et al., Med (2022)DOI：10.1016/j.medj.2022.10.003”.)

Provision Fee To non-profit: Free To profit: JPY100,000 /one vial (~USD690, 1USD=145JPY)
NoticeHomozygous in HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ and HLA-DP

CiRA Foundation / Confidential

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Available cell lines: YZWJ series3）Most used HLA-homozygous iPS Cells derived from Cord Blood
GradeClinical-gradeResearch-gradeCell lines

YZWJs513
YZWJs516
YZWJs524
YZWJs527
YZWJs531

Ff-WJs513
Ff-WJs516
Ff-WJs524
Ff-WJs527
Ff-WJs531

YZWJs513

SourceHuman umbilical cord blood, derived from healthy Asian donor

VectorEpisomal Plasmids

Feature The underlined cell lines were used in several Japanese clinical trials/research.
(Please refer to our paper ”Yoshida et al., Med (2022)DOI：10.1016/j.medj.2022.10.003”.)

Provision Fee To non-profit: Free To profit: JPY100,000 /one vial (~USD690, 1USD=145JPY)
NoticeHomozygous in HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ and HLA-DP
CiRA Foundation / Confidential

15List of available cell lines
Derived from PBMC
HLA: Homozygous(HLA-A-B-DRB1)
Vector: Episomal Plasmid

Donor: QHJI
(24:02-52:01-15:02)

Donor: RWMH
(33:03–44:03–13:02)

Donor: DRXT
(24:02–07:02–01:01)
Donor: RJWI
(24:02–54:01–04:05)

Clinical-gradeResearch-grade

QHJI01s01

Ff-I01s01

QHJI01s04

Ff-I01s04

QHJI14s03

Ff-I14s03

QHJI14s04

Ff-I14s04

RWMH09s01

Ff-MH09s01

RWMH15s01

Ff-MH15s01RWMH15s02

Ff-MH15s02

RWMH23s01

Ff-MH23s01

DRXT18s02

Ff-XT18s02

DRXT18s03

Ff-XT18s03

DRXT28s04

Ff-XT28s04

DRXT28s05

Ff-XT28s05

DRXT28s17

Ff-XT28s17*Genomic mutations in BCOR and BRD3 genes were detected in this clone.

RJWIs03

Ff-WIs03

CiRA Foundation / Confidential

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List of available cell lines
Derived from Cord Blood
HLA: Homozygous(HLA-A-B-DRB1)
Vector: Episomal Plasmid

Donor: YZWJ
(24:02–52:01–15:02)

Donor: ILCL
(24:02–52:01–15:02)

Donor: GLKV
(33:03–44:03–13:02)

Clinical-gradeResearch-grade

YZWJs513

Ff-WJs513

YZWJs516

Ff-WJs516

YZWJs524

Ff-WJs524

YZWJs527

Ff-WJs527

YZWJs531

Ff-WJs531

ILCLs14

Ff-CLs14

ILCLs21

Ff-CLs21

ILCLs23

Ff-CLs23

ILCLs31

Ff-CLs31

GLKVs09

Ff-KVs09

GLKVs13

Ff-KVs13

GLKVs16

Ff-KVs16

GLKVs31

Ff-KVs31
CiRA Foundation / Confidential17

List of available cell lines
Derived from PBMC
Vector: Sendai Virus

Donor: KTRH

Clinical-gradeResearch-grade

KTRH05*Users can use clinical-graded celllines for research use.

KTRH26

CiRA Foundation / Confidential

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List of available cell lines
HLA: Genome-editedwith CRISPR-Cas9
Vector: Episomal Plasmid

Clinical-gradeResearch-grade

QHJI14s04/ABⅡ-KO-03

Derived from QHJI14s04
HLA: Genome-editedwith CRISPR-Cas9
Vector: Episomal Plasmid

QHJI14s04/ABⅡ-KO-11
QHJI14s04/ABⅡ-KO-12*Users can use clinical-graded cell lines forresearch use.

Research-grade
Ff-I01s04-AB II-KO-16

Derived from Ff-I01s04

Ff-I01s04-AB II-KO-50
Ff-I01s04-AB II-KO-54
Ff-I14s04-AB II-KO-7

Derived from Ff-I14s04
Derived from
Ff-XT28s05*Not established by CiRA_F

Ff-I14s04-AB II-KO-13
Ff-I14s04-AB II-KO-24
Ff-XT28s05-cont*This cell line is not genome-edited because it’s for control use.

Ff-XT28s05-ABo_To

Kitano et al., Molecular Therapy - Methods & Clinical Development 26 15-25 (2022): https://doi.org/10.1016/j.omtm.2022.05.010

CiRA Foundation / Confidential

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Provision Fee(Up-front Payment per vial)
To Non-Profit

iPS Cell Stock(ex. university,research institution)

To Profit(ex. private company,start-up)

HLA homozygous-Research-grade

:

Free

JPY 50,000/one(1) vial

-Clinical-grade

:

Free

JPY 100,000/one(1) vial

:

Free

JPY 100,000/one(1) vial

-Research-grade

:

Free

JPY 100,000/one(1) vial

-Clinical-grade

:

Free

JPY 200,000/one(1) vial

SeV iPS /”KTRH”-Only Clinical-grade

HLA genome-edited

In addition to the provision fee above, an applicant of iPSC stock, whether profit or non-profit, is required to arrange for shipping fromCiRA Foundation to its research location by its cost.
After obtaining market authorization for the product, the applicant will owe iPS Stock System Maintenance Fee (Please see the nextslide).
We provide only research-grade iPS Cell stock to new users who first use our iPS Cell Stock in principle. But as for HLA genome-editedlines and KTRH lines, users can use clinical-grade iPS Cell Stock for their non-clinical research.

CiRA Foundation / Confidential

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Procedure for using the iPSC stock
1

User Registration
 New users only

A few days

2

Application
 Per each research plan

1 month3

Examination of Application
by iPS Cell Stock Review Committee

4Agreement

1 month Collaborative research agreement with CiRA foundation License agreement with iPS Academia Japan: commercial organizations only

A few weeks

5

Shipping iPS Cells and Payment

Please see our website for details.
https://www.cira-foundation.or.jp/e/project/stock.html

CiRA Foundation / Confidential

21Required documents for a new application
Required documents
Before you
apply

When you
apply

Notes

(Form0) iPS Cell Stock New Application
Confirmation Request Form

We upload the blank form of this document.
Please refer to the website below.
https://www.cira-foundation.or.jp/e/research-institution/ips-stock-project/stock.html

New application / Change application

You can submit them by our application system.

Research Plan ※Please prepare a research protocol that has been or will be submitted to an ethics review committee, etc.
(For research conducted outside of Japan)
If a review by an Ethics Review Committee is not required, please prepare a sheet of A4-sized research
outline that includes the following information at a minimum, with 300-500 words.
・Target Disease(s)・Type of differentiated cells
・Milestones or Aims of the research plan

Letter of ethical approval ※Please prepare the ethical approval letter for your research proposal.
(For research conducted outside of Japan)
If a review by an Ethics Review Committee is not required, please prepare a notification or an email from theEthics Review Committee that shows it’s not required.

Documentation on how to store each gradeof cell obtained ※（Only if you first use our iPS Cell Stock）※
・Biography of the principal researcher
・Overview of the institution
・Materials on the research performance

Please prepare a file that describes the management system in your organization for the iPS cell stock youplan to be provided by us.
Please refer to this template.
(ReferenceHow to store provi

Please attach papers or other materials(posters or data in differentiation such as flow cytometry) that include
the following information. If the material is divided into multiple documents, please also upload them in the“Other references" section.
・Experience in culturing human iPS cells
・Experience in inducing differentiation into target cells from human iPS Cells※ If you have partner institutions which use our iPSCs together, please prepare their documents too.
CiRA Foundation / Confidential22Contact us About iPS Cell Stockips-stock-shinsa*cira-foundation.or.jp
Please change * to @

 About Research Materials
minnano-saibou*cira-foundation.or.jp
Please change * to @CiRA Foundation / Confidential23

www.cira-foundation.or.jp

Public Interest Incorporated Foundation
606-8397 京 都 市左京区聖護院川原町5 3番地

53 Shogoin kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan.