MDNA11 is a Long-Acting ‘Beta-Only’ IL-2 Agonist that Demonstrates Safe and Durable Anti-Tumor Immune Response

Minh D. To, Fahar Merchant, Ma’an Muhsin, Carole Galligan, L. Bruce Pearce, Peter Lloyd, and Rosemina Merchant

Medicenna Therapeutics Inc,Toronto, Ontario, Canada

Minh D. To, PhD

I have the following financial relationships to disclose:Consultant for: N/ASpeaker’s Bureau for: N/AGrant/Research support from: N/AStockholder in: Medicenna Therapeutics Inc.Employee of: Medicenna Therapeutics Inc.

Overview of MDNA11A long-acting ‘beta-only’ IL-2 superkine with superior receptor selectivity: increases activation of effector immune cells, reduces Treg stimulation and reduces toxicities

! Mutations to enhance affinity for CD122 and abrogate binding to CD25

BLI / Octet

Human Non-Human Primate

CD122 KD (nM)

CD25 KD (nM)

CD122 KD (nM)

CD25 KD (nM)

rhIL-2 210 24 170 12

MDNA11 6.6 No binding 8.2 No

binding

! Fusion to human albumino Increases molecular weight to overcome

renal filtration, extending in vivo half-lifeo Facilitates FcRn recycling, leading to

further increase in half-lifeo Potential for enhanced therapeutic

efficacy by accumulating in highly vascularized tissues (i.e. tumors, lymph nodes)

MDNA11

MDNA11 +/- Anti-PD1: Inhibit Tumor Growth & Induce Memory and Antigen Specific CD8+ T-Cells

Vehicle MDNA11 (2 mg/kg) MDNA11 (5 mg/kg)

Anti-PD1 MDNA11 (2 mg/kg) + Anti-PD1

MDNA11 (5 mg/kg) + Anti-PD1

7/10 CR(1 premature death)

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Primary MC38 Tumors

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MC38 Re-challenge

MDNA11: IP QWx2Anti-PD1 (RMP1-14; 10 mg/kg): IP BIWx3, IPAverage size at initiation of dosing ~ 75 mm3

Study in C57Bl/6 mice.Antigen-specific CD8 T-cells by flow cytometry using H-2K MuLV p15E tetramerAll mice boosted with MC38 5 days prior to flow cytometry analysis

Control

MDNA11 (2

mg/kg

)

MDNA11 (2

mg/kg

) + A

nti-PD1

MDNA11 (5

mg/kg

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MDNA11 (5

mg/kg

) + A

nti-PD1

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peci

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P = 0.016

P = 0.008 P = 0.016

P = 0.06

Antigen-Specific Effector CD8+ T-CellsControl

MDNA11 (2 mg/kg)MDNA11 (2 mg/kg)+ Anti-PD1

MDNA11 (5 mg/kg)MDNA11 (5 mg/kg)+ Anti-PD1

P- value vs Control

MDNA11 Exhibits a Favorable Safety Profile in NHP Summary of GLP Toxicology Study in NHP

Male and female cynomolgus monkeys received 3 doses of MDNA11 (0.15, 0.3 and 0.6 mg/kg) by IV infusion 14-days apart

Key Findings: ! Main observations in cynomolgus monkeys were transient loss of appetite, reduced activity and

diarrheao More common in the high dose group (0.6 mg/kg); all animals recoveredo Mostly observed after the 1st dose; lower incidence rate or not observed after 2nd and 3rd dose

! No cytokine release syndrome in cynomolgus monkeys! No ADA in cynomolgus monkeys! No histological evidence of pulmonary edema or VLS in cynomolgus monkeys

!MDNA11 shows initial slow loss of exposure followed by a more rapid decline, suggestive of a saturable clearance process often referred to as target-mediated drug disposition (TMDD)

!Dose proportional increase in Cmax and AUC!Evidence of increase clearance following the second dose, possibly

due to immune cell expansion

1st Dose (Day 1)

2nd Dose (Day 15)

MDNA11 PK Profile in NHP

Dose(mg/kg)

StudyDay Cmax (ng/mL) AUClast (h.ng/mL)

0.151 3,430 48,800

15 3,380 40,200

0.31 7,400 135,000

15 6,220 90,300

0.61 16,000 310,000

15 12,700 193,000

MDNA11 Induces Effector Immune Cell Proliferation with Limited Effect on Tregs

Peak Fold-change in Ki67 Expression

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Control 0.15 mg/kg 0.3 mg/kg 0.6 mg/kgCD8+ T-Cell Proliferation (Ki67 Expression)

Dose Dose Dose

PD response response significantly more durable than exposure = Extended PD Effect

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Ki67 expression by immune cell quantified by flow cytometry analysis of blood samples

MDNA11 Induces Preferential Expansion of Effector Immune Cells Over Tregs

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Dose Dose Dose Dose Dose Dose

Dose Dose Dose

MDNA11 – 0.15 mg/kgVehicle Control

MDNA11 – 0.6 mg/kgMDNA11 – 0.3 mg/kgDose Dose Dose

Preferential Expansion of CD8+ T-Cells over Tregs

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MDNA11 Induces NK Cell Expansion

MDNA11 Induces Expansion of Naïve & Activated CD8+ T-Cells

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Summary

! MDNA11 is a long-acting ‘Beta-Only’ IL-2 agonist with enhanced CD122 binding that potentiates activation of effector immune cells (CD8+ T-cells and NK cells) with reduced activity on Tregs

! MDNA11 demonstrates potent efficacy as monotherapy and in combination with immune check-point inhibitors in multiple mouse syngeneic tumor models including tumor clearance, protection against re-challenges, and promotion of durable antigen specific CD8+ T-cells

! In NHP, MDNA11 induces durable proliferation and expansion of effector immune cells (CD4+ T-cells, CD8+ T-cells and NK cells) with limited effect on Tregs

! MDNA11 exhibits a favorable safety profile in cynomolgus monkeys: no ADA, no cytokine release syndrome and no pulmonary edema and VLS

Contact: Minh D. To, PhD (minh.to@medicenna.com)