Abstract 190P
Background
CD39 is an extracellular ectonucleotidase highly expressed in the tumor microenvironment (TME) that, sequentially with CD73, contributes to the production of adenosine (Ado), via hydrolysis of adenosine triphosphate (ATP). IPH5201 is a blocking anti-CD39 monoclonal antibody (mAb) that may promote antitumor immunity by accumulating immunostimulatory ATP released by necrotic cells and reducing immunosuppressive Ado levels in the TME. Targeting the Ado pathway has recently been reported to improve Durvalumab (D) efficacy in early-stage NSCLC patients, through the use of Oleclumab, an anti-CD73 mAb. In a first-in-human study (NCT04261075), IPH5201 was well tolerated alone or in combination with D. Here we explored preclinical efficacy of IPH5201 in combination with anti-PD-L1 and chemotherapies (CT).
Methods
CD39 expression was assessed in early and late stage NSCLC biopsies. In vitro, CT were assessed for their ability to induce ATP release by dying tumor cells and IPH5201 was evaluated for its ability to accumulate the released ATP. In vivo, human (hu) CD39 Knock-In (KI) mice were used to engraft syngeneic tumors and evaluate the efficacy of a mouse (mo) version of IPH5201 (moIPH5201) alone or in combination with CT and anti-PD-L1.
Results
CD39 was expressed in both squamous and adenocarcinoma subtypes of NSCLC with no difference according to the stage of the disease. In a mouse tumor model engrafted in huCD39KI mice, moIPH5201 was able to decrease the human CD39 enzymatic activity and to lower the Ado level in situ. In vitro, CT induced ATP release by tumor cells and IPH5201 was able to accumulate the released ATP. Finally, in vivo, in a mouse tumor model engrafted in huCD39KI mice, moIPH5201 improved the anti-tumor efficacy of gemcitabine and anti-PD-L1 combination.
Conclusions
IPH5201 was shown to block CD39 enzymatic activity, to lower Ado and increase ATP levels in the TME and finally to improve anti-tumor efficacy in preclinical models. Altogether, the expression profile of CD39 in early stage NSCLC and preclinical combination data support the clinical evaluation of IPH5201 in combination with D and CT in early stage NSCLC patients.
Legal entity responsible for the study
Innate Pharma, AstraZeneca.
Funding
Innate Pharma, AstraZeneca.
Disclosure
C.L. Paturel: Financial Interests, Personal, Project Lead: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. N. Anceriz: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. J. Eyles: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Lapointe: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Denis: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. V. Breso: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. R. Courtois: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. S. Augier: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. L. Brown: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Luheshi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Watkins: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z.A. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Tu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Vivier: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma; Financial Interests, Personal, Leadership Role: Innate Pharma. P.G. Fraenkel: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Leadership Role: AstraZeneca.