COMMUNIQUE DE PRESSE



INNATE PHARMA A PRESENTE UN POSTER
“DE LA RECHERCHE A LA PHASE II, DONNEES DE
PHARMACOLOGIE DE IPH 1101” AU CONGRES 2007
DE L’ASCO (“AMERICAN SOCIETY OF CLINICAL ONCOLOGY”)

Marseille le 4 juin 2007

À l’occasion du 43ème congrès de l’ASCO (« American Society of Clinical Oncology »), Innate
Pharma S.A. a présenté une série de données pharmacologiques couvrant de la recherche aux
essais cliniques de Phase II pour son candidat-médicament IPH 1101, un agoniste des
lymphocytes non-conventionnels T γδ.
Cette présentation résume l’ensemble des connaissances pharmacologiques sur l’approche
immunothérapeutique ciblant les lymphocytes T γδ.
Le poster présenté à l’ASCO est joint en page suivante en format A3.




070604_IPH_ASCO_2007_vf Page 1/3
COMMUNIQUE DE PRESSE




A propos d’Innate Pharma :
Fondée en 1999 et financée par des investisseurs en capital de premier plan jusqu’à son
introduction en bourse sur Euronext Paris en 2006, Innate Pharma S.A. (Euronext Paris:
FR0010331421 – IPH) est une société biopharmaceutique qui développe des médicaments à
mécanismes d’actions nouveaux et ciblant le système immunitaire inné.
Le travail pionnier des scientifiques fondateurs et des équipes d’Innate Pharma a permis la
création de trois plateformes de produits (cellules T gamma delta, cellules NK et TLR),
bénéficiant chacune d’éléments de validation clinique directs ou indirects en cancérologie.
En dehors du cancer, les candidat-médicaments d’Innate Pharma présentent un potentiel de
développement dans le traitement des maladies infectieuses et des pathologies inflammatoires
chroniques. La molécule la plus avancée de la Société est en Phase II en cancérologie.
Fort de son positionnement scientifique dans la pharmacologie de l’immunité innée, de sa
propriété intellectuelle et de son savoir-faire en matière de R&D, Innate Pharma entend
devenir un acteur majeur sur le marché en forte croissance de l’immunothérapie.
Basée à Marseille, France, Innate Pharma comptait 74 collaborateurs au 31 mars 2007.
Retrouvez Innate-Pharma sur www.innate-pharma.com


Informations pratiques :
Code ISIN FR0010331421
Code mnémonique IPH


Disclaimer :
Le présent communiqué, et les informations qu’il contient, ne constitue ni une offre de vente
ou de souscription, ni la sollicitation d’un ordre d’achat ou de souscription, des actions Innate
Pharma dans un quelconque pays.


Pour tout renseignement complémentaire, merci de contacter :
Innate Pharma Alize Public Relations
Stéphane Boissel, Directeur Général Adjoint Caroline Carmagnol
Tél. : +33 (0)4 96 19 05 58 Tél. : +33 (0)6 64 18 99 59
stephane.boissel@innate-pharma.fr caroline.carmagnol@wanadoo.fr




070604_IPH_ASCO_2007_vf Page 2/3
Other immune cells


γδ T cell targeted immunotherapy
Vγ9Vδ2 T (γδ) lymphocytes:
stimulation
Cytokines and
chemokines


a promising approach for immunotherapy of solid tumors “Phosphoantigens” like IPH 1101 activate γδ T cells via T Cell Receptor
•
IPH 1101 induces early up-regulation of CD25 at the surface of γδ T cells
•
+++
Low doses of IL-2 promote γδ T cell expansion in vivo after activation of IPH 1101
•
IL-2
Activated γδ T cells rapidly produce cytokines and chemokines that, in turn, stimulate other cells of the immune system (conventional T, NK, DC)
•
AUTHORS: H. SICARD*, E. BOMPAS** , J. BENNOUNA** , V. LEVY*** , P.SQUIBAN* , S. LAFAYE DE MICHEAUX* , E VIEY* , IL-2
γδ TcR
IPH 1101 receptor
γδ T cell effectors with potent cytotoxic activity spontaneously recognize and kill tumor cells
•
S. SALOT* , J.TIOLLIER* , F. CALVO***; * Innate Pharma, Marseille, France γδ T cell
** Oncologie Médicale, Centre René Gauducheau, Saint Herblain, France *** C.I.C., Hôpital Saint Louis, Paris, France expansion



Research and Pre-Clinical phases Clinical phases
Clinical applications as cell therapy (Innacell γδ TM) or injectable compound
Non human primate (cynomolgus) model Selection of therapeutic indications
Safety and preliminary correlation between dose/pharmacological activity in humans
for pharmacology and safety assessment of IPH 1101 for future clinical trials with specific efficacy assays

Phase I Clinical Trial Innacell γδ™ (mRCC)
Selection of Oncology Indications Clinical Pharmacodynamy
Pre-Clinical Pharmacology
Autologous γδ T Cell Therapy
Non human primate: pharmacological In vivo pharmaco follow-up of solid tumor patients
Renal Cell Carcinoma (RCC): a relevant target DAY 15 DAY 1

property study of γδ T cell agonists for γδ T cell immunotherapy IPH 1101-101 trial
in mRCC patients
Cell washing Leukapheresis

• IPH 1101-expanded γδ T cells lyse efficiently
• γδ T cells are widely represented in Dose-ranging PD in IPH 1101-101 trial
• Cell Therapy Product (CTP) is produced from autologous PBMC
• Dose-range effect of IPH 1101 (with a fixed dose of IL-2) Biological activity in humans:
1000
stimulated by IPH 1101 and cultivated during 15 days in RPMI
and specifically autologous primary renal cell
RCC tumor-infiltrating lymphocytes
is established in the relevant non human primate species




as compared to pre-dose
medium supplemented with FCS and IL-2
tumors (short-term 51Cr-release cytotoxicity
(TILs) in two untreated patients • Activation (cytokine release) but no specific
Cell Storage
Cell Expansion




γδ fold-increase
γδ T cell expansion without IL-2
assay)
(stained with anti-Vδ2 antibody) 100
IPH 1101 Dose range effect
Absolute γδ amplification rates




• Study design: CTP was administered in a dose-escalating Unique Cell
300 80
Stimulation
schedule: three patients per dose-level, from 1 to 8 billion, 1st cycle • Specific, reproducible IPH 1101-dose related
• Scheme of




% specific lysis
10
250 ∗P<.0003
60
with CTP alone (safety assessment), subsequent ones with low pharmacodynamy with cytokine release and
administration and Daudi (positive control)
Tumor evaluation (mRCC)
∗P<.004
200
doses of IL-2 s.c. (2 x 2 M IU total dose) to sustain γδ T cell γδ T cell blood expansion when combined with
Raji (negative control)
safety profile for ∗P<.017
40 Patients Dose Stabilization None
expansion
Primary normal cells a fixed low dose of IL-2 (2 M IU total dose)
the therapeutic 150
In billion of cells in weeks
Primary tumor cells
regimen are 20 01 (II) 1 9
100
• Safety: Transient flu-like symptoms (cytokine release) with mild • Some patients (4/24) showed no γδ T cell 0.1
assessed in this 02 (III) 5
50 200 600 1200 1500 1500/IL-2C1 1800
0
fever, chills, fatigue, nausea during treatment for most patients. expansion at all, probably due to sub-optimal
model 03 (I) 111
30:1 (n=11)
7.5:1 15:1
IPH 1101 Dose (mg/m2)
Two DLTs: one patient at 6 billion cells with hypotension (CTC G3), IL-2 exposure
Patient #1 effector:target ratio
Patient #2
0
04 (II) 27
IL-2 0.12 2.4 12 48 72 96
one patient at 8 billion cells with biological DIC (CTC G3) 4
only
05* (II) 50
IPH 1101 dose (mg/kg) IFN-γ TNF-α MIP1-α
Cytokine IL-4, IL-5, IL-7, IL-10, IL-12
IL-8 IL-6
Efficacy Model 06 (II) 24
• Clinical Efficacy: Interesting data of disease control with two
IPH 1101 alone +/- + ++ ++ +++
07 (II) 11
patients showing tumor shrinkage - Disease stabilization > 24 weeks
D0 before dosing D7 after 96 mg/kg Not Detected
hPBMC reconstituted NOD-SCID mouse: 08 (I) 12
for 50% of patients and case reports of clinical benefit IPH 1101 + IL-2 ++ + ++ ++ +++
• Survey of blood cell
4.3% 79.5% 8
09** (I) 28
an animal model for efficacy studies
populations,
10 (I) Stable > 30
• Biological Activity: Circulating blood γδ T cells double at day 10 • Pro-inflammatory cytokines are released within hours after IPH 1101 administration, with or
including γδ T cells
without IL-2 co-administration (dosage with the CBA Flex® (BD Pharmingen) technology)
after 4 and 8 billion cell infusion Tumor shrinkage: * -22% and ** -48%
(number and • NOD-SCID mice are s.c. engrafted with human tumor (RCC 786-O cell line),
phenotype) is human PBMC are injected i.p.
CD3




performed by flow
IL-2 Dose range effect
Phase I Clinical Trial injectable drug
cytometry • γδ T cell expansion is achieved with i.p. administration of IPH 1101 and low dose IL-2
Vgamma9
IPH 1101: 1 hour i.v. day 1
Tumor
IL-2 dose-effect comparison in vivo in Phase IIa in mRCC
Phase I clinical in solid tumor patients, assessment
IL-2: Fixed dose s.c. (2 M IU) from day 1 to day 7
• Anti-tumoral efficacy of γδ T cells was assessed through measurement of tumor growth
IL-2 dose range effect including mRCC (IPH 1101-101 trial) IPH 1101-201 trial
at a fixed dose of IPH 1101 1500
50
• Ongoing randomized open labeled phase II clinical trial in mRCC testing two therapeutic regimen:
IL-2
ii
Tumor volume (mm3)




Control: no PBMC IPH 1101 (750 mg/m2, 50 ml infusion in 30 min ) with two doses of IL-2: 2M IU total dose and
• Study design: IPH 1101 was administered in a dose-escalating
40
IPH 1101 + IL-2 Cycle 1 Cycle 2 Cycle 3
• Dose range effect of IL-2 8M IU total dose
90
PBMC + IL-2 alone
%Vδ2+ cells




schedule : three patients per dose-level, from 200 to 1800 mg/m2 Sensitivity
1000
% of γδ cells at Day 6




80
exposition has been (100 ml infusion 60 min) corresponding to 5 to 45 mg/kg, 1st cycle test
PBMC + IPH 1101 + IL-2
30
70
established after a fixed with IPH 1101 alone (safety assessment of the drug alone),
60 *** p<0.0001
Tumor evaluation (mRCC only)
dose of IPH 1101 20
subsequent ones with low doses of IL-2 s.c. (2 M IU total dose)
500
50
(50mg/kg) combined with 35
Patients Dose Stabilization
to sustain γδ T cell proliferation
40
in mg/m2 in weeks
10
increasing doses of s.c.




Fold increase in NK or T cells
30
01 (II) 54 30
• Safety: Transient signs of cytokine release (fever,




as compared to pre-dose
as compared to pre-dose
γδ fold increase at C1D6
IL-2 (daily for 5 days 20
0 200
06 (I) 72
0
hypotension, nausea) during IPH 1101 treatment for most
A:0.075; B:0.3; C:1.2; 0 7 14 21 28 35 42 49 56 63
d0 d7 d14 d21 d28 d0 d7 d14 d21 d28 d0 d7 d14 d21 d28
10 25 25
07 (II) 14
Days
spleen tumor
IP
patients. Most AE were observed only at the 1st administration of
D:2.4 M IU) 0
• In vivo expanded γδ T cells migrate • In vivo expanded γδ T cells (IPH 1101/IL-2
A B C D 13 (I) 600 17
IPH 1101 alone and did not increase with co-treatment with IL-2. 20 20
to the tumor site (flow analysis of co-treatment) are significantly more efficient 14 (III) 9
• Co-administration of 1.2 M IU/animal IL-2 per day Two patients experienced DLT at 1800 mg/m2 : one patient with
γδ T cell content of various organs) than IL-2 alone in impairing tumor growth 1200
15 (I) 82
(corresponding to human 8 M IU total dose) induces 15 15
fever and hypotension (both CTC G3) and one patient with
50 17 (II) 39
optimal expansion of γδ T cells n.s. * p<0.05
hypotension (CTC G3) 10 10
40 (I) 59
40
41 (I) 8
NH Primate IL-2 dose A B C D
%Vδ2+ cells




• Biological activity: Maximum tolerated dose with significant 5 5
42 (I) 12
• γδ T cell expansion through IPH 1101/IL-2 co-treatment
0.075 0.3 1.2 2.4
(total M IU) 1500
γδ T cell expansion has been established at 1500 mg/m²
30
43 (I) 11
is not impaired by co-administration of oral TKIs 0 0
of IPH 1101
Equivalent Human dose 0.5 2 8 16 44 (II) 17
20 NK 2M IU NK 8M IU T 2M IU T 8M IU
2M IU (n = 18) 8M IU (n = 21)
48 (I) 35
(total M IU)
A: 150 mg/kg imatinib for 4 days
Equivalent dose by BSA* 0.25 1 4 8 18 (I) 72
• Clinical Efficacy: Encouraging signals of anti-tumoral efficacy • NK and total T cells are not expanded with
• Specific pharmacological expansion of
10
1800
B: 90 mg/kg sorafenib for 3 days 19 (I) 51
(M IU/m2) γδ T cell with IPH 1101 is significantly
in mRCC with more than half of patients (8/15) showing more these doses of IL-2
C: 80 mg/kg sunitinib for 3 days
0
related to dose of IL-2 administered
than 35 weeks of stabilization MOTZER Risk Group: (I) Favorable , (II) Intermediate, (III) Poor
* Body Surface Area no TKI A B C