TNAX Biopharma Corporation
We improve the quality of life of patients with intractable diseases by discovery of truly valuable pharmaceuticals
through innovative research on immunoreceptors.

Developing

July 17, 2024

first-in-class biologics which target immunoreceptors and their ligands discovered byProfessor Akira Shibuya, University of Tsukuba
Pipeline
Target ID/Validation& Lead Generation
TNAX101A/
IMB1001

DNAM-1/CD226

TNAX103 CD300A
Undisclosed

Undisclosed

Optimization

PreclinicalPartnered with

UC, CD, SLE

AKI, AIS,First-In-Human

IND

Unpartnered

SCI, AMI

Exclusively licensed
out to IMIDomics forworldwide territory

Undisclosed

 TNAX101A = Humanized anti-DNAM-1 (CD226) mAb
 Anti-inflammatory/fibrotic drug for immune-mediated inflammatory diseases

 TNAX103 = Humanized anti-CD300A mAb

Inflammatory
Bowel Diseases

Efferocytosis promotor for acute ischemic diseases
 An undisclosed early stage research program is underway.

 Robust IP exclusively licensed from University of Tsukuba

Acute Kidney Injury

Acute Ischemic Stroke

Exclusive license agreementwith sublicensing rights
1Acute kidney injury (AKI)
6,470,038 cases in 2021
1,272,824

Huge market!
Total market$5,208M

2,210,038
Japan

Renal replacement therapy& Off-label drugs (including
ACEIs, ARBs, Diuretics and
NSAIDs)USA

5Eur
2,986,567

Source DelveInsight Business Research(September 2022)•

Can be seen in up to 7% of hospital admissions and 30% of ICU admissions.

•

Mortality rate for hospitalized patients: 40 – 50%•

Mortality rate for ICU patients: >50%•

The most common (45%) cause of AKI in hospitalized patients:
proximal tubular epithelium injury)••

Glomerulus

ATN (renal
TubuleHigh risk of developing progressive CKD and ESRD over time
No effective means for preventing or treating AKI

ATN: Acute tubular necrosis

CKD: Chronic Kidney Disease

ESRD: Endo-Stage Renal Disease2

The mortality rate of AKI is very high.

 SA-AKI has a particularly highmortality rate and represents aclinical challenge.
 High demand for treatment andprevention of CSA-AKI
Mortality in AKI patients receiving RRT in ICU: Nationwide database in Japan
3

Pathogenesis of AKI and solution
Injury and necrosis of tubular epithelium and(vicious cycle of) Inflammation
Solution

Promotion of Efferocytosis (phagocytosis and clearance of dead cells)
 Suppression of vicious cycle of Inflammation
 Suppression of ischemia-reperfusion injury
 Recovery from kidney fibrosis

4Efferocytosis promotors block vicious circle ofinflammation induced by organ ischemia.

Expansion of tissue damage
in the surrounding area

IschemiaMΦ

Vicious circle
of inflammation
Inflammation

remove deadcells by efferocytosis.

Macrophages

Cell Death

DAMPs
Dead cells

Solutions
Released fromischemia-induced
dead cells andproduceproinflammatory
cytokines.

Preventing thetissue damage

Ischemia

from spreading
Cell Death

Vicious circle
of inflammation
Inflammation

Efferocytosis
promotor

DAMPs

DAMPs: damage-associated molecular patterns

5CD300a inhibits myeloid cell activation
via interaction with phosphatidylserine (PS) on dead cells.
Dead cells“Eat me”
signalCell death(Apoptosis)
死細胞

Living cell

PS

CD300a = a key anti-efferocytic molecule,which induces resistance to dead cell removal“Don’t eat me”
signal

CD300aCD300aCD300a

Mast
CD300a blockade enhances neutrophil-chemoattractants
such as CXCL-1 and ameliorates the pathology of cecal
ligation and puncture-induced sepsis

DC
CD300a blockade enhances Treg cell expansion via
augmenting IFN-b production and ameliorates the pathologyof barrier surface inflammation such as DSS-induced colitis,
atopic dermatitis, and allergic airway inflammation

Mφ
CD300a blockade enhances efferocytosis andischemia andreperfusion injury in the brain,ameliorates the pathology ofheart and kidney.
1) Dead cells expose PS, which displays “Eat Me” signals, and macrophages induce efferocytosis to clear dead cells.
2) However, PS bound to CD300a expressed on macrophages, which displays “Don’t Eat Me” signals, induces
resistance to efferocytosis.
6Anti-CD300a mAb promotes CD300b-mediated efferocytosis
by macrophages and enhances dead cell removal.

Binding of CD300a expressed on macrophages to PS exposed on the surface of dead cells
 Induction of resistance to efferocytosis (dead cell removal)
Dead Cell

Anti-CD300a mAb

Efferocytosis promotor

macrophages

Anti-CD300a mAb  Recovery of defects in efferocytosis  Normalization of diseased tissue clearance
7

Natural history of AKI
Renal function is expected to be completely recovered by TNAX103.
Complete recovery of renal function

Development of progressive CKD

Many AKI patients are

irreversible.
Irreversible loss of kidney
function (and evolve into

Exacerbation of the rate ofprogression of pre-existing

CKD

ESRD)
Clin J Am Soc Nephrol. 2008 May;3(3):881-6

8

Cell death of vascular endothelium and renal tubular epithelium plays animportant role in the pathological progression from AKI to AKD to CKD.

Fibrosis

Dead cell

Ischemia
Vicious cycle of inflammation,
fibrosis and tissue injury
Acute inflammation

DAMPs

Tissue injury

9Inflammation after AKI causes renal dysfunction and fibrosis.

10Efferocytosis promotor is indicated to restore normal kidneys
from AKI and AKD and prevent progression to CKD.

Efferocytosis promotor
Increased phagocytosis of dead cells by macrophages
reduces DAMPs release, suppresses acute inflammationand prevents the vicious cycle of induction of further deadcells and tissue injury.
11Macrophage-specific CD300a KO mice
attenuate AKI induced by bilateral IRI.
Suppression of renal tissue injury

Suppression of tubular damage

Suppression of renal dysfunction

12Macrophage-specific CD300a KO mice attenuate
progression from AKI to CKD (kidney fibrosis).
Ischemia-reperfusion injury (IRI) model in micevv

Reperfusion

Bilateral kidney ischemia
for around 15 min

Suppression of kidney fibrosis (Masson Trichrome)

Acute kidney injury
1~2 days after IRI

Chronic kidney injury
with fibrosis
28 days after IRI

Suppression of kidney fibrosis (Sirius Red)

13

Anti-CD300a mAb promotes efferocytosis
and attenuates AKI and kidney fibrosis.
Enhancement of efferocytosis

Suppression of renal dysfunction

Suppression of renal tissue injury

Suppression of kidney fibrosis (Masson Trichrome)14

Patients with CDK express higher levels of CD300A than healthy controls, andCD300A expression is positively correlated with impaired renal function.

CD300A expression may be a good marker for patient selection.

Nephroseq v5 online database（http://v5.nephroseq.org）
DN: diabetic nephrosis
FSGS: focal segmental glomerulosclerosis

15

Target Product Labels of TNAX103 in AKI
Prevention of ischemic-AKI (due to cardiac surgery) in an “at risk” population








≧ 65 years of age
Suffering from a kidney problem (such as CKD)
Suffering from a chronic disease (such as heart failure, liver disease, diabetes, etc.)
Dehydrated or unable to maintain fluid intake independently
Having a blockage in urinary tract or being at risk of thisHaving a severe infection or sepsis
Taking nephrotoxic medicines (NSAIDs, ACEIs, ARBs, diuretics, aminoglycosides,
contrast media, etc.)

Treatment of diagnosed ischemic-AKI in patients following cardiac surgery

16Anti-CD300a mAb is expected to improve the prognosis of

AKI associated with ischemic heart disease.
Improvement of
myocardial damage

Increase in cardiac
function

Improvement of fibrosis

ICM: ischemic cardiomyopathy

Over-expression of CD00A
in ICM patients

CD300A expression is negatively correlated withcardiac function in patients with ICM.
17

Anti-CD300a mAb is expected to improve the prognosis of

AKI associated with sepsis.

18

Acute Ischemic Stroke (AIS)>795K Americans have strokes (610K new cases each year)*1.
～142K deaths a year in the US in 2019: 5th leading cause of mortality
40% of bedridden patients and 30% of dementia are caused by AIS.
Total annual stroke-related costs in the US*2 = $56.6B*1: The CDC statistics published in April 2022

・ 880K AIS cases in Europe
・ 3.3M deaths from ischemic stroke WW*2: including the costs of health care services,
stroke medications and days away from work 325K ischemic strokes are caused by large vessel occlusion annually in the US.
 Only 20% are treated with recanalization therapy

Recanalization therapies
Thrombolytic therapy

Endovascular thrombectomy

rtPA/Alteplase: The only thrombolytic

Stent Retriever and/or Aspiration

medication approved by the US FDA

 Apoptotic and inflammatory pathways begin beyond several
hours to days, and the penumbra zone survives for hours to days.
 Leading to neuronal cell death

The penumbra zone may be salvaged
with proper reperfusion and drug treatment.

Penumbra
Thrombus
Ischemic Core

Penumbra = Tissue at-risk of cell death around the ischemic core19

Rescue of penumbra by efferocytosis promotor
Efferocytosis promotors are believed to be safe and effective neuroprotectants.

Problems of Recanalization Therapy
rtPA

Endovascular thrombectomy (EVT) Short therapeutic window (≦4.5 h)
 Impossible to treat large clots

 Few medical facilities can perform EVT.

 Increase in risk of hemorrhagic transformation

 Induction of ischemia-reperfusion injury (IRI)

Sudden restoration of blood flow may bring further damage.

 Induction of ischemia-reperfusion injury (IRI)

IRI = Tissue injury with inflammatory responses(cerebral edema, hemorrhage, neuronal death, etc.)

With recent advancement in recanalization therapy, IRI has become an increasingly critical challenge in stroke treatment.

Over 50% of patients cannot attain good outcomes

Solutionsdespite timely and complete recanalization.

Efferocytosis promotors
PenumbraAttenuate IRI after recanalization
Rescue penumbra tissue
 Have no effect on hemorrhagic transformation

Ischemic Core
Cerebral Artery May be added on to recanalization therapy
 May be used alone20

CD300a KO mice improved neuronal damage andneurological scores in acute ischemic stroke model.

decreased neuronaldamage and ameliorated neurological scores afterMice deficient in CD300a on macrophages

MCAO and reperfusion.
Cd300afl/fl

Cd300afl/fl
Cd300afl/fl
Lyz2-Cre
Lyz2-Cre-Cd300afl/fl

Anti-MAP2 Ab

MCAO(60 min)

MCAO: Middle Cerebral Artery Occlusion

21

Anti-CD300a mAb improved neuronal damage andneurological scores in acute ischemic stroke model.

decreased neuronal damage andameliorates neurological scores after MCAO and reperfusion.
Anti-CD300a mAb

Given just after reperfusion
MCAO(60 min)Anti-CD300a Ab or Control Ab(20 mg/kg, i.v.)

Given 3 h after reperfusion
MCAO(60 min)Anti-CD300a Ab or Control Ab(20 mg/kg, i.v.)

MCAO: Middle Cerebral Artery Occlusion

22

Comparison with drugs in clinical trials--- TNAX103 is the only anti-inflammatory neuroprotectant
that fundamentally inhibits ischemia-reperfusion injury. --Glenzocimab (anti-GPVI on platelets)

Sovateltide （ETbR agonist)
Glunozumab (anti-GluN1)

Arterial thrombosis

TMS-007 (plasminogen activator)

IschemicstressDead glia cells

DM199 (KLK1)

Dead neuron

Elezanumab (anti-RGMa)

TNAX103
Anti-inflammatory mAb(in broad range)

ApTollNerinetide (PSD-95 inhibitor)

DAMPs

TLR4 on Myeloid cells

Other PRR on myeloid cells

Anti-inflammatory aptamer(targeting only TLR4)

Inflammatory cytokines
inflammatorystressDead glia cells

Dead neuron
23Pre-Hospital Recognition (FAST)
 Face dropping Arm weakness
 Speech difficulty Time to get help

Emergency Department

Post-launch product image

TNAX103

Immediate Diagnosis
MRI, CT, NIHSS

Bolus Injection

Evaluation for Alteplase ≦4.5 hours from symptoms onset?
 Indicated for alteplase?

No

Is Patient Suitable forEndovascular Thrombectomy?

Yes
If thrombolysis fails,

Alteplase

Yes
Endovascular
Thrombectomy≦24 hours from KLN

No
Non-invasive Therapy
・Anti-cerebral edema: Glycerol・Anti-thrombin: Argatroban
・Anti-platelet: Aspirin
・Anti-coagulant: LMWHz

Stroke Sequalae↓, QOL↑ (Prevent Complications and Recurrence)24

Spinal cord injury (SCI)
•
•
•
•
•

Incidence: Approx. 17,730 new cases (US) and approx. 5,000 new cases (Jpn) each year
Prevalence: Approx. 291K cases (US) and approx.100K cases (Jpn)
Resulting from motor vehicle collisions, fall from height, etc.
No effective treatment
SCI total market = $6,784 million in 2021 Huge market!
–

Corticosteroids (epidural injections), NSAIDs, Anti-depressants, Anti-convulsants, etc.

• Data source: Economic Impact of SCI published in the journal Topics in Spinal Cord Injury Rehabilitation, Vol. 16, No. 4 in 2011
• ASIA Impairment Scale (AIS) is used to grade the severity of a person’s neurological impairment following SCI.
• These estimates do not include any indirect costs (losses in wages, fringe benefits or productivity).

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Pathology of SCI
Primary injury
Axonal rupture and contusion due to direct external force
Secondary injury
Surrounding cells undergo apoptosis or necrosis, causing further
damage. Beatie M, J Neurotrauma, 2000
Popovich PG, J Neuropathol Exp Neurol ,2002

・Demyelination (oligodendrocyte death)・Apoptosis and necrosis (Breakdown in BCSFB)→ Migration of myelocytes including neutrophils and macrophages
・Interaction of reactive astrocytes with type 1 collagen→ Scarring astrocyte formation, glial scar and cavity formation

26

Anti-CD300a mAb ameliorated locomotor performanceand histological findings in a mouse SCI model.
Possibility of expanding indication into SCI

In a mouse SCI model, anti-CD300a mAb ameliorated locomotor ability and decreased areasof SCI (H&E staining) and demyelination (LFB staining).

Waling performance (BMS score)******** ****

****

***

Possible to walk*
Impossible to walk*p<0.05, ***p<0.001
Anti-CD300a Ab
Control

3 Points: Borderline between “walkable” and “unwalkable”.

Anti-CD300a mAb facilitates locomotion in SCI model mice.

27

CD300A IP
As of May 27, 2024•

PCT/JP2018/043862

Activity modulator (Anti-CD300a antibody for treating ischemic diseases)– Japan, Canada, China, Hong Kong, South Korea, Taiwa, New Zealand, Russia  Granted– US, EP  Pending•

New patent application filed in April 2023
Humanized anti-CD300A monoclonal antibody, and its antigen-binding fragments••

JP6124261/US10519233/EP2808028  Granted
JP6226333/US9850309  Granted

Activity modulator, medicinal agent comprising same,use of CD300A gene-deficient mouse, and antiCD300A antibody

Medicament comprising activity modulator for CD300a-expressing
cell associated with allergic disease, CD300a gene-deficient mouse,
and use of activity modulator for CD300a-expressing cell28

Major publications on CD300a
1.

Koizumi H, Nakahashi-Oda C, Fujiyama S, Li J, Lee H, Lyu W, Bao TTW, Abe F, Tabuchi K Kazuko Shibuya S, Shibuya A.
Enhanced efferocytosis by CD300a blockade ameliorates acute kidney injury and subsequent fibrosis. Submitted underreview.

2.

Nakazawa Y, Nishiyama N, Koizumi H, Kanemaru K, Nakahashi-Oda C, Shibuya A. Tumor-derived extracellular vesicles
regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a. Elife. 10:e61999, 2021

3.

*Nakahashi-Oda C, Fujiyama S, Nakazawa Y, Kanemaru K, Wang Y, Lyu W, Shichita T, Kitaura J, Abe F, Shibuya A.
CD300a blockade enhances efferocytosis by infiltrating myeloid cells and ameliorates neuronal deficit after ischemic stroke.
Science Immunol, 6(64):eabe7915, 2021 DOI: 10.1126/sciimmunol.abe7915

4.

Wang Y, Nakahashi-Oda C, Okayama Y, Shibuya A. Autonomous regulation of immunoglobulin E-mediated mast cell
degranulation and immediate hypersensitivity reaction by an inhibitory receptor CD300a. J. Allergy Clin. Immun,
144(1):323-327, 20195.

Nakahashi-Oda C, Udayanga KGS, Nakamura Y, Nakazawa Y, Miki H, Iino S, Tahara-Hanaoka S, Shibuya K, Shibuya A.
Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces. Nature Immunol, 17(4):441-450, 2016

6.

Nakahashi-Oda C, Tahara-Hanaoka S, Shoji M, Okoshi Y, Nakano-Yokomizo T, Ohkohchi N, Yasui T, Kikutani H, Honda S,
Shibuya K, Nagata S, Shibuya A. Apoptotic cells suppress mast cell inflammatory responses via the CD300a
immunoreceptor. J Exp Med, 209(8):1493-1503, 2012

7.

Nakahashi-Oda C, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A.
Identification of phosphatidylserine as a ligand for the CD300a immunoreceptor.
Biochem Biophys Res Commun, 417:646-650, 20128.

Yotsumoto K, Okoshi Y, Shibuya K, Yamazaki S, Tahara-Hanaoka S, Honda S, Osawa M, Kuroiwa A., Matsuda Y, Tennen D.
G, Iwama A, Nakauchi H, Shibuya A. Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II,
regulate mast cell and macrophage activation. J. Exp. Med. 198:223-233, 2003
29

CD226 (DNAM-1) is a promotor of immune responses and produces
inflammatory cytokines from immune cells including effector T cells.
Anti-CD226 mAb, which has a low risk of serious infections, is expected to be usedin patients who do not respond to or cannot tolerate the SoC.

TCR
Steadystate
Expression of the immunoreceptor CD226 andits ligand CD155 is negligible in healthy tissues.

CD226

MHC

CD155

Inflammation

Inflammatory
Condition
CD4+T cells(Th1, Th2, Th17, Treg)
CD155
CD226
CD8+T, NK, ILC1, 2, 3
In inflamed tissues, the expression of both
CD226 and CD155 is significantly upregulated,
Inflammatory
and the binding of CD226 and CD155 causes
cytokines
severe inflammation.
CD226 is an activating immunoreceptor expressedon both adaptive and innate immunocytes.
Upon binding to CD155, CD226 mediates an activating signal forcytokine production and/or cytotoxic activity in effector
lymphocytes (T cells, NK cells, etc.)

normaltissues
Anti-CD226 mAb normalizes inflammation
without excessive immunosuppression.

anti-CD226 mAb therapy
Inflamedtissues
Anti-CD226 mAb suppresses pro-inflammatory cytokines,
activates Treg cells and potently reverses inflammatory
conditions by targeting multiple immune responses.

Anti-CD226 mAb also maintains Treg cell function.
CD226 is also expressed on the surface of Treg cells
and attenuates effector T cell function.
30

Senior Management (CxO)•

Takahiro (Tak) Mukohira: Co-founder, CEO & Representative Director– Business development, corporate planning, international business, etc. in the pharma/healthcare
industry• Mitsubishi Tanabe Pharma, Life Science Institute, APIC, MHCS
– Licensing fingolimod, joint research labs with Scottish universities, M&A, Regenerative medicine, Digital health, etc.

– Boston-based CVC• MP Healthcare Venture Management, Inc.

– MIT Sloan School of Management, SM in MOT– Kyoto University, Pharmaceutical Sciences, R.Ph.

•

Akira Shibuya, M.D. Ph.D.: Co-founder, CSO & Board Director
Director, R&D Center for Innovative Drug Discovery
Professor, Immunology, University of Tsukuba
Academic staff/researcher in Riken, Okayama University & DNAX
Physician (hematologist) at University of Tsukuba, Tokyo Metropolitan Bokutoh Hospital and
Mitsui Memorial Hospital– University of Tsukuba, Ph.D.
– Hokkaido University, M.D.
–
–
–
–

–

Awards 1996 Hajime Memorial Award (Nobel Prize Laureate Arthur Kornberg & Paul Berg)2005 Japan Medical Association Research Encouragement Award
2009 Princess Takamatsu Cancer Research Fund Encouragement Award
2015 Tsukuba Award (Nobel Prize Laureate Leo Esaki)
2020 Education, Culture, Sports, Science & Technology Minister Science &Technology Awardetc.

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