Patent grant for anti-RAMP2 antibodies
January 10, 2023

Kidswell Bio Corporation

Outline
Application No./ Filingdate2022-136364(2022-8-29)

Name of invention
Anti-RAMP2 antibodies

Patent No.

Patentee
Kidswell BioCorporation7202011• RAMP2（Receptor Activity-Modifying Protein 2):
Form RAMP2/CRLR with Calcitonin Receptor-Like Receptor (CRLR) in a cell surface andcombine with Adrenomedullin (AM) and have variety of bioactivities such as formation of
new blood vessels and vascular protection by transmitting angiogenesis signals into cells.
(e.g., growth of tumor by activating formation of new blood vessels, etc.)• Anti-RAMP2 antibodies:
Combine with RAMP2・CRLR and inhibit the formation of new blood vessels⇒ Expect a high possibility of inhibition of abnormal angiogenesis.

AMRAMP2・CRLR

Anti-RAMP2
antibody

Cell surface

Formation of blood vessels

Formation blood vessels

2Application possibility for retinopathy of prematurity (1)• Adrenomedullin (AM), which selectively binds to
RAMP2, is known to stimulate formation of bloodvessels in ischemic diseases.
• ⇒ Expect an inhibitory effect for the formation ofblood vessels in ischemic diseases.

Diseases caused by the formation ofblood vessels by ischemia⇒ Application possibility forretinopathy of prematurity

Inhibition effect in a prematurity retinopathy model mouse model※: w/o change of oxygen
partial pressure: w/ decrease of oxygen partialpressure

出生後日数 (Postnatal day)Increased AM expression was observed due
to decrease of oxygen partial pressure(ischemic state).
（＝stimulate the formation of blood vessels）

Inhibition of the formation of blood vessels
was observed with blocking the binding of
RAMP 2 and AM.

Confirmed inhibition of the formation of blood vessels in retinopathy of prematurity
mouse model by blocking RAMP2 effect⇒ Expected for clinical application for retinopathy of prematurity.
※Shindo et al.Am J Pathol.2013 Jun;182(6):2380-90

3Application possibility for retinopathy of prematurity (2)• Comparative investigation of drug effect between anti-VEGF drugs (angiogenesisinhibitors) and anti-RAMP2 antibodies in the abnormal formation of blood vessels⇒ Confirmed equivalent inhibition effect.

Enlarged view ofneovascular tuft(NVT)

Anti-RAMP2
Aflibercept antibody
Abnormal proliferation ofblood vessels

Fluorescent staining
image of retinal vessel

Comparison of areas (%) where abnormal
proliferation of blood vessels (Neovascular tuft)
was observed

4Unmet Medical needs for retinopathy of prematurity
Retinopathy of prematurity (ROP):• Disease in premature infants that makes retinal blood vessels
abnormally proliferated when the sudden environment changes
from a stable mother’s body.
• As a baby is born with immature retinal blood vessels, retina
ischemia is developed, and abnormal formation of blood vessels isstimulated.
• While ROP progresses, potential for retinal detachment becomes
higher and some eyes with ROP progress to severe visual disorderand permanent vision loss.
(The top cause of childhood blindness, about 40% of all)Angiogenic
sprouting

Proliferation progression andbeginning of retinal
detachment (blue color)

Severe retinal
detachment (blue color)

Progression of retinopathy of prematurity（Source：National Center for Child Health and Development HP）

Current treatments have a high probability of relapse, and no effective treatment has been established yet.
Treatment
methodPhotocoagulation

Treatment results• First option of standard therapy• Photocoagulate avascular areas where blood vessels
have not yet grown and inhibit the release ofangiogenesis factors.
• Many disease complications such as severe
cicatrization and narrowing of visual fieldAnti-VEGF
Drug• Bevacizumab, ranibizumab and aflibercept are current
medicines.
• It is said that 20.8 to 83.0% of patients administrated
ranibizumab have relapse of retinopathy.

Source：Nippon Ganka Gakkai Zasshi 2020 issued by Japanese Ophthalmological Society 124(12) 1013-1019

VI Observation method
On the first day, third to fourth day after injection, adverseevents such as endophthalmitis were checked to see if
the activity of retinopathy is reduced. Since relapse
occurs at a high rate after intravitreal injection ofranibizumab, regular fundus examination is required
even when retinopathy is relieved.
For AP-ROP*, anti-VEGF therapy alone is difficult to treat
and requires additional treatment in 75.0 to 87.5% ofcases. There are cases of early recurrence within 1 to 3
weeks after administration, and frequent fundus
examination is required.
（*AP-ROP: Aggressive Posterior Retinopathy of Prematurity “Fulminant ROP”）
Source: Excerpt from the guidance of anti-VEGF treatment for retinopathy of prematurity(Ganka Gakkai Zasshi 124 (12)) 5

Novel mechanism different from anti-VEGF drug
Different pathways of the formation of blood vessels（AM and VEGF pathway）
AM pathway

VEGF pathway

VEGF

AM
Anti-RAMP2 antibody

Anti-VEGF

Endothelial cell growth
Inhibition effect of HUVEC proliferation in AM pathway

Inhibition effect of HUVEC proliferation in VEGF pathway
0 .4 00 .3 5

E Y L E A

Anti-RAMP2antibody

0 .3 08 5 H 70 .2 5

G r o w t h (O D 4 5 0 )G r o w t h (O D 4 5 0 )0 .4 00 .3 5A v a s t in
0 .3 0Anti-RAMP2antibody

8 5 H 70 .2 50 .2 0
0 .2 0
1 0- 1 2

1 0- 1 0

A n t ib o d y

1 0- 8c o n c

1 0- 6(M )Anti-RAMP2 antibodies inhibit vascular endothelial cell growth(Anti-VEGF drug has less inhibition effect of cell growth)

1 0- 1 2

1 0- 1 0

A n t ib o d y

1 0- 81 0- 6c o n c .( M )Anti-VEFG drug inhibits vascular endothelial cell growth（Anti-RAMP2 antibodies have less inhibition effect of cell growth）

Anti-RAMP2 antibodies inhibit HUVEC proliferation in AM pathway.
（Anti-VEGF drugs can’t inhibit it.）※HUVEC: ヒト臍帯静脈内皮細胞

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Licensing activities• Confirmed equivalent inhibition effect between anti-RAMP2 antibodies and anti-VEGF drug
(aflibercept).
• Anti-RAMP2 antibodies inhibit the formation of blood vessels in different pathway from antiVEGF drug.
• In combination with anti-VEGF drug, expect better treatment effect and inhibition of relapse.

⇒ Expect positive therapeutic effects for both patients who have not been treated wellwith currently available anti-VEGF drugs and have relapsed after using anti-VEGF drugs.

KWB accelerates licensing activities for anti-RAMP2 antibodies while
differentiating current medical treatments.
Market potential of retinopathy of prematurity

Number of patients
Estimate in FY 2021 (drug pricestandard)
RanibizumabJapanGlobal

5,000 patients/ year

23,800～45,600人／年（2009）※1（2010）※2

７00 million yen

4 to 7.5 billion yen ※3Source ※1: Japan Intractable Diseases Information Center_ retinopathy of prematurity,※2: Pediatr Res. 74 Suppl 1:35-49. 2013., ※3: 1USD=JPY135

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All for Kids, Kids for All

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Corporation (“KWB”), not for soliciting investment in KWB shares.
Information provided in this material may contain so-called “forward-lookingstatements.” These statements are based on current expectations, forecasts
and assumptions that are subject to risks and uncertainties, which could cause
actual outcomes and results to differ materially from these statements. Risks
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This material includes information on pharmaceutical products andregenerative medicine (or related products), etc., which is being developed orlaunched. However, this is not intended to promote our products or provide
medical advices.
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