PRP HO family: novel biologic immunomodulators

XVIII Encuentro de Cooperación Farma-Biotech

Madrid, 29 de octubre de 2019

PRP‐HO family: novel biologic immunomodulators

Content

1. The Institution: IDIBELL / PurPose Biotherapeutics

2. The Research Group

3. The Product: PRP-HO family of immunomodulators

a) Background

b) Target Indications

c) Differential features facing the market

d) Innovative mechanism of action

e) Current status of development

f) IPR protection

g) Pitfalls & Risks to be considered

4. Partnering Opportunities

XVIII Encuentro de Cooperación Farma-Biotech

1. The Institution

IDIBELL, biomedical and biotechnology cluster in the life and health sciences sector

http://www.biopol.cat/cat/

http://www.biopol.cat/cat/

2. The Research Group

Prof. Joan Torras

(Nephrology Unit, CSUB-IDIBELL)Prof. Santiago Rodriguez de Córdoba

(CIB, CSIC, Madrid)

Prof. Peter F. Zipfel

(Hans Knöll Institute, Germany)Prof. Anna M. Blom

(Lund University, Sweden)

COLLABORATORS AND ADVISORS:

“No one can whistle a symphony. It takes an orchestra to play it”Halford E. Luccock

PIITG Group

(Molecular Genetics Lab- IDIBELL)

Ana Luque

Inmaculada Serrano

Javier Checa

Alejandro Cuenca

Marta Guevara

Bryan Herrera

Andreja Anžič

Zhara Mohammadkarimi

3. The Product (Background)

Immunomodulation

+ undesired activation of the

immune system

3. The Product (Target Indications)

3. The Product (Differential Features Facing the Market)

- Low efficacy

- Relevant and non-specific adverse events

Present anti-inflammatory and immunosuppressive drugs

3. The Product (Differential Features Facing the Market)

PRP-HO7

Hit molecule: Immunomodulatory naturally occurring blood protein-Olivar et al. (2013) J Immunol. 190: 2857-72. -Olivar et al. (2016) J Immunol. 196: 4274-90.-Serrano et al. (2018) Front Immunol. 9: 892.-Luque et al. (2019) Semin Cell Dev Biol. 85: 143-52.-Luque et al. (2019) Kidney Int. In Press.

3. The Product (Innovative Mechanism of Action)

Pro-inflammatory

Immunogenic

Anti-inflammatory

Tolerogenic

PRP-HO7 novel mechanism of action:

Immunomodulator able to “reprogram” key cells

orchestrating the immune response


PRP-HO7 isoform induces a anti-inflammatory, tolerogenic state in dendritic cells

- Olivar et al. (2013) J Immunol. 190: 2857-72.

PRP-HO7PRP-HE8


- Surface marker expression:

- Cytokine production:

0 5 0 1 0 0

0

5 0

1 0 0

1 5 0

H ill S p e c if ic b in d in g d a ta

P R P -H O 7 (n M )

Sp

ec

ific

bin

din

g

B m a x 7 3 .4 9 4 .8 1

h 2 .4 7 1 .2 4

K d 2 .0 6 0 .3 1

- Target binding:


Pre-clinical efficacy (I)

Lupus NephritisFemale NZBW F1

Systemic Lupus Erythematosus (SLE)

Ig G

P R P -H O 7 P B S P R P -H O 7 P B S

C 3

CY

P

PR

P-H

O7

PB

S

0

1 0

2 0

3 0

4 0

5 0Ig

G (

MF

I)

******

CY

P

PR

P-H

O7

PB

S

0

2 0

4 0

6 0

8 0

C3

(M

FI)

******

-Luque et al. (2019) Kidney Int. In Press.

w20

w24

w28

w32

w36

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

P r o te in u r ia

A g e (w e e k s )

(ug

/24

h)/

g P R P -H O 7

C Y P

P B S

******

********

29 36353433323130282726252420

S ta r t

tre a tm e n t

S ta r t

fo llo w u pS a c rific eA d m in is tra t io n : s c . in je c t io n

Q u a n tity : C Y P 2 .5 m g /m o u s e e v e ry 1 0 d a y s

P R P -H O 7 5 0 g /m o u s e , o n c e /2 w e e k s

P B S v e h ic le , o n c e /2 w e e k s

W e e k

48


Comparative transcriptional profile of CYP- and PRP-HO7-treated lupus nephritis kidneys

CYP PRP-HO7 PBS

H&E(100x)

CY

P

PR

P-H

O7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

Re

lati

ve

ex

pre

ss

ion

(L

og

2F

C)


Pre-clinical efficacy (I)Systemic Lupus Erythematosus (II)

PRP-HO7 vs. CYP:

-Specificity

-Toxicity



Pre-clinical efficacy (I)Systemic Lupus Erythematosus (III)

PRP-HO7 prevents ectopiclymphoid structures

development in autoimmune lupus nephritis

w19

w21

0

1

2

3

4

5

A g e (w e e k s )

De

rm

ati

tis

Sc

ore

P B S

P R P -H O 7

C Y P

** ***

**

**

Facial rash

Female MRL/lpr

0 5 0 1 0 0 1 5 0

0

5 0

1 0 0

D a y s

Pe

rc

en

t s

urv

iva

l

C Y P

P R P -H O 7

P B S

7 0 1 4 7

*

8

S ta r t

tre a tm e n t

S ta r t

fo llo w u p

W e e k

14131210 11 17 212019181615 22

S a c rific eA d m in is tra t io n : ip . in je c t io n

Q u a n tity : C Y P 2 .5 m g /m o u s e e v e ry 1 0 d a y s

P R P -H O 7 1 0 0 g /m o u s e , o n c e /w e e k

P B S v e h ic le , o n c e /w e e k



Pre-clinical efficacy (I)Systemic Lupus Erythematosus (IV)

NZBW F1

MRL-lpr

Lupus nephritis

-prone mice

PRP-HO7

Vehicle /

PRP-HE8

CXCL13

CXCL13

Ectopic

Lymphoid

structures 1. Proteinuria

2. Anti-dsDNA Abs

3. Complement deposition

4. Renal tissue injury

5. Survivall

1. Proteinuria

2. Anti-dsDNA Abs

3. Complement deposition

4. Renal tissue injury

5. Survival


The anti-inflammatory and tolerogenic functions of PRP-HO7 restore immune homeostasis and improve autoimmune lupus pathology.

Pre-clinical efficacy (I)Systemic Lupus Erythematosus (V)

Inflammatory Bowel Disease

Pre-clinical efficacy (II)

1 2 3 4 5 6 7 8 9

-2 0

-1 0

0

1 0

D a y

B

W (

% v

s D

0)

B la nk

D S S C o n tro l

P R P -H O 7

M in o c y c lin e

* ** * * *

* * * ** * * *

* * * ** * *

* * * *

* * * *

* * * ** * * * * * * * * * * *

1 2 3 4 5 6 7 8 9

0

1

2

3

4

D a y

Dis

ea

se

Ac

tiv

ity

In

de

x (

DA

I)

B la nk

D S S C o n tro l

P R P -H O 7

M in o c y c lin e

* * * * * * * * * * * * * * * * * * *

* * * *

* * *

* * * *

* * *

* *

* *

* * * ** * * *

* * * *

3. The Product (Current Status of Development)

Control PRP-HO7 Enbrel

Hindlimbs (End of study)

Rheumatoid Arthritis

PRP-HO7

Pre-clinical efficacy (III)


PRP-HO7PRP6-HO7


H2L: PRP6-HO7 - Improved biologic

- Smaller than a MoAb (< 100 kDa)

- Same immunomodulatory activity and stability tan PRP-HO7

- Non-glycosylated

- Scalable and cost-effective recombinant protein production in E. coli

- Symmetry

- Flexibility

- a-helix vs. b-sheet


Structural features of PRP6-HO7 vs. Monoclonal antibodies


NRR

Heptamer

Monomer

kDa

191

97

64

51

39

28

14

PRP6-HO7 production (E. coli)

iDC

mD

C

PR

P-H

E8

PR

P-H

O7

PR

P6-H

O7_5n

M

PR

P6-H

O7_11n

M

PR

P6-H

O7_32n

M

0

1 0 0 0

2 0 0 0

3 0 0 0

4 0 0 0

C D 8 3

MF

I

**

*

** ****

L P S

Dose-response relationship in human MoDCs


Predictive efficacy end-point functional assay for clinical trials

Towards “personalized” medicine:

iDC

mD

C

PR

P-H

E8

PR

P-H

O7

PR

P6-H

O7

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

C D 8 3

MF

I**

G a rd iq u im o d

* *

iDC

mD

C

PR

P-H

E8

PR

P-H

O7

PR

P6-H

O7

0

5 0 0 0

1 0 0 0 0

1 5 0 0 0

2 0 0 0 0

C D 8 6

MF

I

G a rd iq u im o d

**

** *

SLE patient blood samples:

mDC

IL-4 + GM-CSF

iDC +Monocytes +

DAY 0 DAY 5 DAY 7

Differentiation Maturation

LPS / GardiquimodPRP6-HO7

In vitro assay:

PATENTS:

1- "Compositions and methods for immunomodulation"INVENTORS: (by order of signature): Aran, J.M., Olivar, R. REQUEST No.: EP11382240PRIORITY COUNTRY: European UnionPRIORITY DATE: 15/07/11PCT APPLICATION: PCT/EP2012/063932 (16/07/12)ENTITY: IDIBELL

2- "C4BP-based compounds for treating immunological diseases"INVENTORS: (by order of signature): Aran, J.M., Ruiz L.A., Ortiz, J., Lluch, N. REQUEST No.: EP17382187PRIORITY COUNTRY: European UnionPRIORITY DATE: 06/04/17PCT APPLICATION: PCT/EP2018/058773 (06/07/18)ENTITY: IDIBELL

3- “Compounds for immunomodulation"INVENTORS: (by order of signature): Aran, J.M., Luque, A., Serrano, I. REQUEST No.: EP19382910PRIORITY COUNTRY: European UnionPRIORITY DATE: 17/10/19PCT APPLICATION: ENTITY: IDIBELL

3. The Product (IPR Protection)

3. The Product (Pitfalls & Risks to be Considered)

Technology.-

Lower efficacy than expected:

- Predictive efficacy endpoint assay for clinical trials developed.

- In vivo safety and efficacy have been successfully demonstrated in systemic lupus erythematosus, colitis and

rheumatoid arthritis mouse models.

- Administration in combination with other treatments (drugs, biologics,…) in patients who do not respond to a

single therapy.

- Possibility to perform pharmacological therapy (direct PRP6-HO7 administration), or cell therapy using ex vivo

PRP6-HO7-conditioned DCs.

GMP Scaling up.-

We have already designed a candidate to be produced in E. coli bioreactors, being fully scalable.

Market.-

Although big pharma companies are controlling the market, PurPose Biotherapeutics' pipeline products have

a new and distinctive MoA that is of interest for big pharma (licensing) to consolidate its market share.

4. Partnering Oportunities

Precision medicine: First-in-class immunomodulatory biologic for autoimmune diseases

2019 2020 2021 2022

In vitro

stability

In vivo PK

(mice and rats)

In vitro

cell assay In vivo

efficacy in

SLE (mice)

Subchronic

TOX (rats)

Spin off CreationValidation of

production

GMP lot production

Preclinical

study for

IND

FTO

In vivo model

for first indication

Subchronic

TOX (monkeys)

In vivo PK (monkeys)

3 PATENTS issued

1 PATENT pending PRE GMP/GMP SCALE UP 500K€

PRECLINICAL REGULATORY 2,5M€

4. Partnering Oportunities

From the opportunity to the market: PRP-HO family - optimal cost/benefit)

- Market application: Biotechnology / Pharmaceuticals.

- Cooperation type: -License agreement.

- Joint further development (adaptation to specific needs):

Pre-clinical and clinical co-development

Regulatory compliance

Future scaling up

- Testing new applications.

- Joint venture agreement.

- Pre-seed and seed funding opportunities.

ACCELERATOR MEETING POINT

Idibell.cat

Josep M. Aran

[email protected]

[email protected]

Immunomodulation for autoimmunity

Thank you

Documents

PRP HO family: novel biologic immunomodulators