mdna109: an il-2 superkinetm agonist for cancer …

• IL-2 signals through binding to either high affinity or intermediate affinity receptor complexes on lymphocytes. • High affinity receptor – a ternary complex of CD25, IL- 2Rβ and IL-2Rγ – expressed on T reg cells. • Intermediate affinity receptor – binary complex of IL-2Rβ and IL-2Rγ – expressed on naïve T cells. • Binding of IL-2 to either receptor triggers downstream signalling through the JAK-STAT, MAP kinase, and PI3K pathways, leading to proliferative responses. • Naïve T cells express only IL-2Rβ and IL-2Rγ and at low levels compared to activated and T reg cells, which express the high affinity receptor at higher levels, leading to relative insensitivity of this desired T cell population to expansion by exogenous IL-2. • Additionally, CD25 expression on endothelial cells is implicated in the toxicity and vascular leak seen with treatment by Proleukin. • MDNA109 was designed by the lab of Chris Garcia at Stanford University to bind the intermediate affinity receptor with higher affinity than WT IL-2. Nature 2012 PMID 22446627 • Yeast display, selecting for muteins with enhanced IL-2Rβ binding affinity, followed by biophysical and functional characterization. • MDNA109 selectively expands CD8+ T cells in vivo, has superior anti-tumor activity and does so with less evidence of adverse effects in mouse models. • Combination therapy with anti PD-1 in mouse model produces robust curative response in a dose-dependent manner. • IL-2 plays a central role in the immune system, stimulating both the proliferation of effector T cells and regulatory T cells. • Proleukin, a bacterially expressed wild-type IL-2 was approved by the FDA for the treatment of metastatic renal cell carcinoma and metastatic melanoma in 1992 and 1998 respectively. • While yielding robust, durable responses in some patients, Proleukin’s utility was limited by i) a minority of patients demonstrating clinical response and ii) a significant toxicity profile that required in-patient administration in specialist centers. MDNA109’s engineered receptor binding properties is intended to overcome both these limitations PROGRAM OVERVIEW IL-2 Receptor Biology Selective Targeting of Effector T cells IL-2 - A PROVEN CANCER IMMUNOTHERAPY MDNA109: An IL-2 Superkine TM Agonist For Cancer Immunotherapy • Medicenna is developing a pipeline of engineered cytokine products (Superkines and Empowered Cytokines), with pharmacologically-optimized receptor-binding properties. • MDNA109 is an IL-2 cytokine variant with 200X greater affinity for the IL-2Rβ than native IL-2, that leads to preferential expansion of effector cells over regulatory T cells. • MDNA109’s receptor binding properties were engineered to maximize the anti-tumor effects mediated by IL-2, while reducing the mitigating immune effects and the potential for the severe side effects observed with Proleukin® (aldesleukin). MDNA109 is currently in preclinical development, with clinical development targeted for late 2018. 5 10 15 20 25 30 35 40 45 0 500 1000 1500 2000 Days Post-Implant Mean Tumor Volume (mm 3 ) PBS anti-PD-1 MDNA109 (5 ug q.d.) MDNA109 (25 ug q.d.) anti-PD-1 + MDNA109 (5 ug q.d.) anti-PD-1 + MDNA109 (25 ug q.d.)

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Page 1: MDNA109: An IL-2 SuperkineTM Agonist For Cancer …

• IL-2signalsthroughbindingtoeitherhighaffinity orintermediateaffinityreceptorcomplexesonlymphocytes.

• Highaffinityreceptor– aternarycomplexofCD25,IL-2RβandIL-2Rγ– expressedonTreg cells.

• Intermediateaffinityreceptor– binarycomplexofIL-2RβandIL-2Rγ– expressedonnaïveTcells.

• BindingofIL-2toeitherreceptortriggersdownstreamsignallingthroughtheJAK-STAT,MAPkinase,andPI3Kpathways,leadingtoproliferativeresponses.

• NaïveTcellsexpressonlyIL-2RβandIL-2RγandatlowlevelscomparedtoactivatedandTreg cells,whichexpressthehighaffinityreceptorathigherlevels,leadingtorelativeinsensitivityofthisdesiredTcellpopulationtoexpansionbyexogenousIL-2.

• Additionally,CD25expressiononendothelialcellsisimplicatedinthetoxicityandvascularleakseenwithtreatmentbyProleukin.

• MDNA109wasdesignedbythelabofChrisGarciaatStanfordUniversitytobindtheintermediateaffinityreceptorwithhigheraffinitythanWTIL-2.Nature2012PMID22446627

• Yeastdisplay,selectingformuteins withenhancedIL-2Rβbindingaffinity,followedbybiophysicalandfunctionalcharacterization.

• MDNA109selectivelyexpandsCD8+Tcellsinvivo,hassuperioranti-tumoractivityanddoessowithlessevidenceofadverseeffectsinmousemodels.

• CombinationtherapywithantiPD-1inmousemodelproducesrobustcurativeresponseinadose-dependentmanner.

• IL-2playsacentralroleintheimmunesystem,stimulatingboththeproliferationofeffectorTcellsandregulatoryTcells.

• Proleukin,abacteriallyexpressedwild-typeIL-2wasapprovedbytheFDAforthetreatmentofmetastaticrenalcellcarcinomaandmetastaticmelanomain1992and1998respectively.

• Whileyieldingrobust,durableresponsesinsomepatients,Proleukin’s utilitywaslimitedbyi)aminorityofpatientsdemonstratingclinicalresponseandii)asignificanttoxicityprofilethatrequiredin-patientadministrationinspecialistcenters.

MDNA109’sengineeredreceptorbindingpropertiesisintendedtoovercomeboththeselimitations

PROGRAMOVERVIEW

IL-2ReceptorBiology

SelectiveTargetingofEffectorTcells

IL-2- APROVENCANCERIMMUNOTHERAPY

MDNA109:AnIL-2SuperkineTMAgonistForCancerImmunotherapy

• Medicenna isdevelopingapipelineofengineeredcytokineproducts(Superkines andEmpoweredCytokines),withpharmacologically-optimizedreceptor-bindingproperties.

• MDNA109isanIL-2cytokinevariantwith200XgreateraffinityfortheIL-2RβthannativeIL-2,thatleadstopreferentialexpansionofeffectorcellsoverregulatoryTcells.

• MDNA109’sreceptorbindingpropertieswereengineeredtomaximizetheanti-tumoreffectsmediatedbyIL-2,whilereducingthemitigatingimmuneeffectsandthepotentialfortheseveresideeffectsobservedwithProleukin®(aldesleukin).

MDNA109iscurrentlyinpreclinicaldevelopment,withclinicaldevelopmenttargetedforlate2018.

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PBSanti-PD-1MDNA109 (5 ug q.d.)MDNA109 (25 ug q.d.)anti-PD-1 + MDNA109 (5 ug q.d.)anti-PD-1 + MDNA109 (25 ug q.d.)