• 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.

5 10 15 20 25 30 35 40 450

500

1000

1500

2000

Days Post-Implant

Mean

Tu

mo

r V

olu

me (

mm

3)

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.)