March 29, 2018
BrightPath Biotherapeutics, Co., Ltd.

Collaborative research agreement concluded with RIKENon iPS cell-derived NKT cell therapy
Tokyo, March 29, 2018 — BrightPath Biotherapeutics, Co., Ltd. (“BrightPath”) hereby
announces that it has entered into a collaborative research agreement with RIKEN
regarding a natural killer T (NKT) cell therapy. Under this agreement, BrightPath will
participate in the project pursued by the RIKEN Center for Integrative Medical Sciencesthat aims at technology development and clinical application of this novel allogeneic cancer
immunotherapy using NKT cells redifferentiated from induced pluripotent stem (iPS) cells(“iPS-NKT cell therapy”).
This is a RIKEN-led project from the “Center for development of cancer immunotherapy
technology by regenerating natural killer T-cells,” which was accepted as a Center for
Clinical Application Research on Specific Disease/Organ (Type B) of the Research Center
Network for Realization of Regenerative Medicine of the Japan Agency for Medical
Research and Development. This project is also part of the RIKEN Program for Drug
Discovery and Medical Technology Platforms. An investigator-initiated clinical trial targetinghead and neck cancers is slated to start within fiscal year 2019.
NKT cells are immune cells that are capable of directly attacking cancer cells and activatingother immune cells via an adjuvant process. Activated NKT cells produce various types ofcytokines that elicit activation of natural killer (NK) cells and maturation of dendritic cells of
the innate immune system.* Mature dendritic cells then cause killer T cells of the adaptive
immune system* to proliferate and become activated, resulting in a synergisticallyenhanced anti-tumor effect. By activating innate immune system, NKT cells are capable ofkilling major histocompatibility complex (MHC)-negative cancer cells, which T cells areincapable of killing. This is one feature that is unique to iPS-NKT cell therapy.
Despite their significant anti-cancer potential, current cell therapies using NKT cells havetheir downsides. Unlike with chimeric antigen receptor T-cell therapy (CAR-T, wherepatients’ own T cells are employed to treat cancer), they are extremely difficult to harvest
from the body and culture and grow to quantities that are adequate for clinical treatment,
since NKT cells make up only from 0.01% to 0.1% of total blood T cells. Overcoming thislimitation is what prompted RIKEN to initiate research in iPS cell technology. Dr. HaruhikoKoseki, Group Director of the Laboratory for Developmental Genetics, and associatessought to realize the timely production of NKT cells in sufficient and stable quality andquantity for treatment with iPS cell technology, in which unlimited numbers of NKT cell
derived pluripotent stem cells are grown and then induced to re-differentiate into NKT cells.
As a research partner and proprietor of the option to acquire the exclusive rights to develop,
manufacture, and market iPS-NKT cell therapy research products, BrightPath is set to fully
support the aforementioned investigator-initiated trial towards the world’s first clinicalapplication of this therapy.

1[Explanation of terms]*Innate and adaptive immune systems—The immune system is classified into two types:
innate and adaptive. The innate immune system quickly responds to and attacks foreign
substances that have entered the body (e.g., bacteria, viruses) or formed within it (e.g.,cancer cells). The adaptive immune system takes longer to respond but is more specific;
based on information gathered on the foreign invaders, B and T cells are mobilized to fighttheir specific targets. The innate system not only eliminates foreign substances but also
assumes another important role of passing on information that is specific to such
substances to the adaptive system through antigen-presenting cells, e.g., dendritic cells.

BrightPath Biotherapeutics
BrightPath is a clinical stage biopharmaceutical company focused on the development ofnovel cancer immunotherapies to transform cancer treatment for refractory or progressive
cancers that cannot be treated with conventional standard therapies. In addition to cancer
peptide vaccines currently in clinical trials in Japan and the United States, BrightPath isactively involved in developing cell therapies, immunomodulatory antibodies and new drugs
targeted at cancer specific neoantigens.
RIKEN
RIKEN is Japan’s largest and most comprehensive research organization for basic andapplied science, and a world leader in a diverse array of scientific disciplines, including
physics, engineering, chemistry, computational science, biology, and medical science. In aneffort to contribute to society by disseminating their research achievements, RIKEN isactive in joint research and contract research, supported by partnerships with universities
and businesses, and also engages in activities involving technology transfer to industry,
such as intellectual property transfer.
Contact・BrightPath Biotherapeutics Co., Ltd.
Business Administration
Phone: +81-3-5840-7697
E-mail: irpr05@brightpathbio.com
https://www.brightpathbio.com/english/index.html

2Supplementary Information
March 29, 2018

Stock Exchange Listings: Tokyo Mothers
Securities Code: 4594

Characteristics of iPS-NKT cell therapy
This is an induced pluripotent stem (iPS) cell technology-based Natural killer T(NKT) cell therapy. NKT cells are believed to possess multifaceted antitumor
effects, but have proven difficult to supply in adequate amounts for therapy. iPS
cell technology has enabled the timely provision of NKT cells in sufficient quantity
for clinical use in allogeneic immunotherapy.

NKT cells

iPS technology

Immune cells with multifaceted antitumor
ああああ effects

Enables cell banking as predifferentiatedstage andああああtherefore an as-needed
supply of cells in quantitiessufficient for clinicaltreatment• Activate innate immunity• Induce adaptive immunity• Alter immunosuppressive
environment1Antitumor effects of innate and adaptive immunity (general overview)
The innate immune system not only possesses direct antitumor activity but also induces acancer-specific adaptive immune system through cancer antigen presentation by antigenpresenting cells. Effective activation of the innate system, located upstream of multiple
immune responses, is expected to lead to synergistic antitumor effects.
Innate immune cells

Adaptive immune cellsAntigen-presenting cells

Recognize common antigens(e.g., NK cells, NKT cells)

Recognize only certain specificantigens but are highly effective atkilling cancer cells(e.g., T cells)

Bridge innate and adaptive
immune responses(e.g., dendritic cells)

Maturation

Antigen presentation ⇒Activation of adaptive immune
cells that recognize specificantigens

Antigen uptake bymature antigenpresenting cells

CrosstalkRelease ofvarious antigens
Killing

KillingSignals such as stress(Cancer cells)2Multifaceted effects of NKT cells
In addition to the above-mentioned innate-immunity activities in general, NKT cells
are equipped with several properties that allow for further potent antitumor effects
Presented below in black are general innate-immunity activities, while NKT cell specific properties are in red(NKT cell)(Dendritic cell)
Antigen uptake bymature antigenpresenting cells

Active crosstalk

Alter immunosuppressiveenvironment

Antigen presentation ⇒Activation of adaptive immune
cells that recognize specificantigens

Release ofvarious antigens(Macrophages/MDSC)

Activation
Killing

KillingSignals
such as stress
Killing(NK cell)(Cancer cells)

Killing by innate immunity

Killing by adaptive immunity
3(T cells)