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Validation of anti-ICOS antibody as a drug candidate for anti-tumor immunotherapy through neutralisation of regulatory T cell suppressive activity – VICIT

anti-ICOS mAb, an immunotherapy to neutralize the Treg suppressive function

Inhibit Treg, suppressors of antitumor immunity, represents a major goal in the field of anti-tumor immunotherapy. VICIT proposes to use a proprietary anti-ICOS mAb to neutralize the expansion and suppressive function of Treg cells in solid tumors

validate ICOS as target in other tumors and effective anti-ICOS therapy in vivo

* validate ICOS as therapeutic target in muirne models using neutralising anti-mICOS antibody and cells expressing ICOS or not. <br />* validate ICOS as therapeutic target in different human solid tumors <br />* validate the therapeutic potential of drug candidiate in a murine humanised model <br />* évaluate mechanisms of action to interst an industrial partner for the industrial development of the antibody (humanisation, toxicity) l <br /> <br />In case of success, this drug candidate will represent an adjuvant treatment to reactivate anti-tumor immunity and prevent relapse

* Develop mammary and lung tumor models implanted in mice to reproduce the human pathology and validate in vivo the impact of anti mICOS antibody
* Develop a humanised murine model to analyse the impact of anti hICOS 314,8
* Establishment of mouse models inwhich only Treg are devoided in ICOS expression
* Develop immuno-histochemistry to visualize ICOS and other immune markers and validate ICOS as target in other solid tumors

The analyses on patients tumor samples confirm that within tumors Treg highly express ICOS that increases the interest to target ICOS as adjuvant therapy in solid tumors
Murine anti-ICOS allows the elimination of Treg in murine tumor models. However, the impact on tumor growth has still to be explored in complementary experiments using humanized mouse and modified antibodies. Furthermore, a new unexpected effect on graft versus host disease has been revealed.
These results have convinced an industrial to develop anti-Icos therapeutical antibodies through a worldwide exclusive license.

Publication Faget J Cancer Rse 2012, Labidi-Galy-I OncoImmunol 2012; international extension of the patent (PCT/FR2010/00829) with addtion of new results; Contact with two Biotechs with patent interest; Validation of ICOS as a target in ovarian cancer; Filing a new patent on the use of Ac anti-hICOS 314.8 for the treatment of GVHD; oral communication G. Marodon (ECI12-1465) European Congress of Immunology Glasgow in September 2012

Faget J. et coll. Cancer Res 2012, PMID: 23026134
Labidi-Galy I. et coll. Cancer Res 2011 PMID: 21697280
Patent filed by the consortium(EP12306046 03/09/2012)
Oral communication G. Marodon (ECI12-1465) ECI 2012 Glasgow

The inhibition of regulatory T cells (Treg), suppressors of anti-tumor immunity, represents a major objective in the field of tumor immunotherapy. The teams of the consortium have accumulated original observations pointing to a critical role an interaction between Treg and a subset of dendritic cells, the plasmacytoid DC (pDC), controlling Treg expansion and suppressive function in different pathologies. Teams 1 and 4 have identified this molecular interaction between Treg and pDC and developed neutralising monoclonal antibodies directed against the co-stimulatory molecule expressed on Treg and engaged by pDC. The main assets of the present project rely on a joined patent from Team 1 and Team 4 (filled INSERM- Transfert March 2011) protecting a proprietary high affinity mouse anti-human co-stimulatory molecule neutralising mAb and its use to neutralise Treg in breast carcinoma and other tumors. Team 1 and Team 4 have developed an expertise in immune evasion mechanism in human tumors and Team 4 and 2 has pioneer the field of co-stimulatory/regulatory molecule of the CD28 family.
The objectives of the program arei), to validate this co-stimulatory molecule as a therapeutic target in several mouse tumor models in place in Teams 1 and 2 using an antagonist anti-mouse co-stimulatory molecule mAb; ii) to develop an in vivo model with selective inactivation of this co-stimulatory molecule in Treg (Team 2), which will prove that this co-stimulatory molecule expressed by Treg is a therapeutic target in cancer; iii) to use a mouse model reconstituted with a human immune system, including Treg, (Team 3) to validate the therapeutic potential of the proprietary anti-human co-stimulatory molecule drug candidate;(iv) to validate this co-stimulatory molecule as a therapeutic target in different types of human carcinoma (breast, ovarian, cervix) and lymphoma (Team 1 and 4).
This program represents a first step critical to consolidate the present intellectual property and to establish partnership to pursue the industrial development of the mAb for therapeutic purpose. In case of success, the humanized anti-human co-stimulatory molecule will represent a drug adjuvant to most carcinomas and likely other tumor types, allowing reactivation of anti-tumor immunity and prevention of relapse. This program is so far unique and should yield a highly innovative drug to neutralise Treg in cancer. Importantly, the proprietary anti-human co-stimulatory molecule antibody is expected to achieve Treg inhibition with high selectivity and with no or minor secondary effects, as compared to other Treg-targeted strategies, such as anti-CTLA4.

Project coordinator

Monsieur Christophe CAUX (Centre Régional de Lutte contre le Cancer de Lyon - Centre Léon BERARD) – christophe.caux@lyon.unicancer.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM Transfert INSERM-TRANSFERT
CRCM U891 INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE PACA ET CORSE
I3 UNIVERSITE PARIS VI [PIERRE ET MARIE CURIE]
UPMC UNIVERSITE PARIS VI [PIERRE ET MARIE CURIE]
Centre Léon Bérard (ESPIC - Etablissemen Centre Régional de Lutte contre le Cancer de Lyon - Centre Léon BERARD

Help of the ANR 400,402 euros
Beginning and duration of the scientific project: November 2011 - 24 Months

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