MDNA-11: An Engineered IL-2 Superkine for Cancer Immunotherapy

1. Executive Summary

MDNA-11 is an investigational, next-generation interleukin-2 (IL-2) immunotherapeutic agent developed by Medicenna Therapeutics Corp., a clinical-stage company specializing in engineered cytokines termed 'Superkines'.[1] Identified as a long-acting, 'beta-enhanced not-alpha' IL-2 super-agonist, MDNA-11 represents a rational design approach aimed at overcoming the significant limitations associated with high-dose aldesleukin (recombinant human IL-2), the first approved cytokine therapy for cancer.[2] Its engineering incorporates specific mutations to enhance binding affinity for the IL-2 receptor beta chain (CD122) while abrogating binding to the alpha chain (CD25), coupled with fusion to human albumin to extend its pharmacokinetic half-life.[6] This design intends to preferentially stimulate anti-cancer effector immune cells, such as CD8+ T cells and Natural Killer (NK) cells, while minimizing the activation of immunosuppressive regulatory T cells (Tregs) and avoiding toxicities like vascular leak syndrome (VLS) linked to aldesleukin.[7]

Clinical evaluation is primarily centered on the ongoing Phase 1/2 ABILITY-1 trial (NCT05086692), a global, multi-center study assessing MDNA-11 as both monotherapy and in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab (KEYTRUDA®) in patients with advanced solid tumors.[4] Efficacy data reported to date demonstrate promising anti-tumor activity. As monotherapy, particularly at higher doses (≥60 µg/kg) in patients resistant to prior immune checkpoint inhibitor (ICI) therapy, objective response rates (ORR) ranging from 25% to 30% have been observed, including complete responses (CRs) and durable partial responses (PRs) in challenging tumor types such as metastatic melanoma and MSI-H pancreatic cancer.[1] In combination with pembrolizumab, early results from dose escalation show encouraging activity, with reported ORRs around 31-36% in relevant patient populations, including a CR in chemo-refractory anal squamous cell carcinoma and PRs in microsatellite-stable (MSS) colorectal cancer.[18]

The safety profile of MDNA-11 observed in ABILITY-1 appears favorable and distinct from aldesleukin. Treatment-related adverse events (TRAEs) have been predominantly Grade 1-2, transient, and consistent with immune activation (e.g., infusion-related reactions, pyrexia, chills, nausea).[19] Crucially, no dose-limiting toxicities (DLTs) were reported during dose escalation up to 120 µg/kg (Q2W), and no cases of VLS have been observed, supporting the success of the engineering strategy in mitigating severe IL-2 toxicities.[14] The combination with pembrolizumab has not revealed new safety signals.[14]

Pharmacodynamic analyses confirm the intended mechanism of action, showing consistent, dose-dependent expansion of CD8+ T cells and NK cells, sustained with repeat dosing, with minimal impact on Tregs.[1] Notably, MDNA-11 promotes the expansion of key T cell subsets associated with durable anti-tumor immunity, including effector memory, central memory, and a unique population of progenitor 'stem-like' TCF1+ CD8+ T cells.[1] Significantly, greater expansion of these stem-like T cells has been correlated with clinical responses, suggesting a potential biomarker for durable benefit.[1] Evidence of immune activation within the tumor microenvironment has also been observed in paired biopsy studies.[14]

Collectively, the data position MDNA-11 as a promising next-generation IL-2 immunotherapy candidate. Its engineered selectivity appears to translate into a favorable safety profile and potent, durable immune activation in humans. The observed single-agent activity in ICI-resistant tumors and encouraging combination results suggest potential utility in addressing significant unmet needs in oncology. The correlation between stem-like T cell expansion and clinical response provides mechanistic insight and potential predictive value. Ongoing expansion cohorts in the ABILITY-1 trial, now extending into Europe, will further define its efficacy and safety across various tumor types and treatment settings.[1]

2. Introduction to MDNA-11

Medicenna Therapeutics Corp., a clinical-stage immunotherapy company with operations based in Toronto and Houston [1], is focused on the development of novel engineered versions of interleukins, termed 'Superkines'.[32] The company's platform leverages protein engineering to modify cytokines like IL-2, IL-4, and IL-13, aiming to enhance their therapeutic properties by improving specificity, function, and safety profiles compared to their native counterparts.[2] Beyond individual Superkines, Medicenna is also exploring advanced platforms like BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and T-MASK™ (Targeted Metalloprotease Activated SuperKine) designed to target immunologically challenging tumors or specific disease contexts, including autoimmune diseases.[2] This focus on cytokine engineering places MDNA-11 within a broader strategic framework aimed at modulating immune responses for therapeutic benefit across various diseases.

The development of MDNA-11 is rooted in the history of IL-2 therapy in oncology. Recombinant human IL-2 (rhIL-2, aldesleukin, marketed as Proleukin®) was one of the earliest immunotherapies approved by the US Food and Drug Administration (FDA) for metastatic renal cell carcinoma and metastatic melanoma, capable of inducing durable complete responses in a small subset of patients.[27] However, the broad clinical application of high-dose aldesleukin has been severely hampered by several critical limitations. Its mechanism involves binding to IL-2 receptors expressed on various immune cells. While activation of effector T cells (Teff) and NK cells via the intermediate-affinity IL-2 receptor (composed of β and γ chains, CD122/CD132) mediates anti-tumor effects, aldesleukin also potently stimulates immunosuppressive regulatory T cells (Tregs) via the high-affinity trimeric receptor (α, β, and γ chains; CD25/CD122/CD132).[8] This Treg activation can counteract the desired anti-tumor immunity. Furthermore, aldesleukin possesses a very short pharmacokinetic half-life (minutes), necessitating frequent, high-dose administration to achieve therapeutic levels.[8] These high doses are associated with severe, often life-threatening toxicities, most notably vascular leak syndrome (VLS), which involves fluid extravasation into tissues and can lead to hypotension, edema, and organ dysfunction, often requiring intensive care management.[4]

MDNA-11 was specifically engineered by Medicenna as a next-generation, long-acting IL-2 Superkine to directly address and overcome these fundamental limitations of aldesleukin.[4] It is the company's lead IL-2 candidate, designed with the explicit goal of improving both the efficacy and safety profile of IL-2 based therapy.[2] This deliberate engineering effort aims to fundamentally redesign IL-2 therapy, setting a high benchmark for its clinical performance and potential differentiation from both aldesleukin and other IL-2 variants in development. Its classification encompasses roles as an antineoplastic agent, an immunotherapy, an interleukin (specifically an IL-2 replacement/agonist), a lymphokine, and a recombinant fusion protein.[35] The success of MDNA-11 hinges on demonstrating clinically meaningful improvements in the therapeutic index compared to its predecessor.

3. Mechanism of Action: Engineering Selective IL-2 Pathway Activation

The therapeutic rationale and molecular design of MDNA-11 are centered on precisely modulating the IL-2 signaling pathway to enhance anti-tumor immunity while mitigating the drawbacks associated with native IL-2.

3.1. Limitations of Native IL-2 (Aldesleukin)

As outlined previously, native IL-2 (aldesleukin) exhibits pleiotropic effects due to its interaction with different forms of the IL-2 receptor (IL-2R) complex.[36] The high-affinity trimeric IL-2R (αβγ; CD25/CD122/CD132), predominantly expressed on Tregs, binds IL-2 avidly even at low concentrations, leading to the expansion and activation of these immunosuppressive cells.[8] While higher concentrations of IL-2 can activate the intermediate-affinity dimeric IL-2R (βγ; CD122/CD132) found on effector CD8+ T cells and NK cells, promoting anti-tumor responses, this requires doses that inevitably also stimulate Tregs and trigger severe toxicities via off-target effects, including activation of endothelial cells expressing IL-2R components, contributing to VLS.[7] Furthermore, the short in vivo half-life of aldesleukin necessitates frequent high-dose administration, exacerbating toxicity issues.[8]

3.2. MDNA-11 Design: 'Beta-Enhanced Not-Alpha' Selectivity

MDNA-11 incorporates specific protein engineering features to overcome these limitations by altering its receptor binding profile.[8] The core IL-2 component of MDNA-11 (termed MDNA109FEAA) contains seven amino acid mutations relative to wild-type human IL-2.[6] Five mutations (L80F, R81D, L85V, I86V, I92F), derived from the previously developed IL-2 superkine H9, are designed to significantly enhance binding affinity to the IL-2Rβ chain (CD122).[8] Two additional mutations (F42A, E62A) were introduced specifically to eliminate binding to the IL-2Rα chain (CD25).[6]

This dual modification results in what Medicenna terms a 'beta-enhanced not-alpha' profile.[3] Preclinical bio-layer interferometry studies confirmed this altered selectivity. MDNA-11 demonstrated approximately a 30-fold higher binding affinity for human CD122 (KD​ ≈ 6.6 nM) compared to rhIL-2 (KD​ ≈ 210 nM).[8] Concurrently, while rhIL-2 bound strongly to human CD25 (KD​ ≈ 24 nM), MDNA-11 showed no detectable binding to CD25 even at concentrations up to 2000 nM, an effect attributed directly to the F42A and E62A mutations.[8] Similar selectivity (high CD122 affinity, no CD25 binding) was observed for cynomolgus monkey receptors, validating this species as a relevant model for non-human primate (NHP) studies.[8]

3.3. Albumin Fusion for Extended Half-Life

To address the short half-life of IL-2, the engineered MDNA109FEAA moiety is genetically fused to a recombinant human albumin scaffold.[4] Albumin fusion is a well-established strategy to increase the hydrodynamic radius and in vivo persistence of therapeutic proteins, thereby reducing renal clearance and extending the pharmacokinetic half-life.[9] This allows for less frequent administration; clinical studies employ a once-every-two-weeks (Q2W) dosing schedule for MDNA-11, a significant improvement over the multiple daily or hourly infusions required for aldesleukin.[38] Additionally, albumin's natural propensity to accumulate in tumors and inflamed tissues might potentially enhance the delivery or retention of MDNA-11 within the tumor microenvironment.[4]

3.4. Preferential Stimulation of Effector Immune Cells

The engineered receptor selectivity ('beta-enhanced not-alpha') combined with the extended half-life is designed to translate into a specific pattern of immune cell activation.[10] By preferentially binding to the intermediate-affinity IL-2Rβγ complex (CD122/CD132) and avoiding the high-affinity IL-2Rαβγ complex (CD25/CD122/CD132), MDNA-11 aims to selectively stimulate immune cell populations crucial for anti-cancer immunity, namely CD8+ T cells and NK cells, which express IL-2Rβγ.[2]

Conversely, the abrogation of CD25 binding is intended to minimize the stimulation of Tregs, which heavily rely on CD25 for high-affinity IL-2 binding and subsequent expansion and suppressive function.[5] Preclinical studies measuring downstream signaling (pSTAT5) supported this: MDNA-11 showed enhanced potency on naïve CD8+ T cells and NK cells compared to rhIL-2, while exhibiting significantly reduced potency on Tregs.[8] This preferential activation of effector cells over suppressive cells is hypothesized to shift the immune balance towards a more effective anti-tumor response. The design also aims to avoid activating endothelial cells, potentially reducing the risk of VLS.[7]

The combination of these two core engineering strategies – altered receptor selectivity and albumin fusion – represents an integrated approach. It targets both the biological profile (favoring effector over regulatory cells, reducing toxicity risk) and the pharmacokinetic profile (enabling convenient dosing, sustained exposure) simultaneously. This holistic design is fundamental to the goal of creating an IL-2 therapy with a significantly improved therapeutic window, potentially enabling safer administration at doses sufficient to achieve durable anti-tumor immunity, both alone and in combination regimens where managing overlapping toxicities is critical.

4. Clinical Development Program: The ABILITY-1 Study (NCT05086692)

The primary clinical evaluation of MDNA-11 is conducted through the ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) study, registered under ClinicalTrials.gov identifier NCT05086692.[5]

4.1. Study Overview

ABILITY-1 is a Phase 1/2, global, multi-center, open-label clinical trial designed to evaluate MDNA-11 in patients with advanced solid tumors.[4] The study commenced in August 2021, with primary completion anticipated around June 2026 and final study completion expected by December 2026.[40] It aims to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of MDNA-11 administered intravenously (IV).[4]

4.2. Study Design and Cohorts

The trial employs a multi-part, adaptive design involving sequential cohorts [44]:

• Part 1: Monotherapy Dose Escalation: Utilized a modified 3+3 design to determine the safety and tolerability of ascending doses of MDNA-11 monotherapy. Doses ranged from 3 µg/kg up to 120 µg/kg IV, administered once every two weeks (Q2W).[5] Step-up or priming doses (e.g., two doses of 30 µg/kg before escalating to 60 µg/kg or 90 µg/kg) were implemented at higher dose levels to potentially improve tolerability.[26] This part is complete.
• Part 2: Monotherapy Dose Evaluation: Additional patients were enrolled at selected higher doses (e.g., 90 µg/kg, 120 µg/kg) to further characterize safety, PK, and PD.[25] This part is complete.
• Part 3: Monotherapy Dose Expansion: Currently enrolling patients at the determined monotherapy Recommended Dose for Expansion (mRDE), which was established as 90 µg/kg IV Q2W (preceded by priming doses of 30 and 60 µg/kg).[26] This part focuses on specific tumor types likely to benefit from MDNA-11 monotherapy.[1]
• Part 4: Combination Dose Escalation: Evaluating ascending doses of MDNA-11 (e.g., 60, 90, 120 µg/kg Q2W or Q3W) administered in combination with a fixed dose of pembrolizumab (400 mg IV Q6W).[1] This part aimed to determine the safety and tolerability of the combination and establish the combination Recommended Dose for Expansion (cRDE). Enrollment in this part was anticipated to complete mid-calendar 2025.[1]
• Part 5: Combination Dose Expansion: Planned to initiate mid-calendar 2025 [1], enrolling patients with specific tumor types at the cRDE, which was established as MDNA-11 90 µg/kg IV Q2W plus pembrolizumab 400 mg IV Q6W.[19]

4.3. Patient Population

Key eligibility criteria include [28]:

• Age ≥ 18 years.
• Histologically or cytologically confirmed locally advanced or metastatic solid tumor that is relapsed or refractory to standard therapies.
• Measurable disease per RECIST v1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ function (hematologic, renal, hepatic).
• Life expectancy of at least 12 weeks.
• Willingness to use effective contraception (for patients of childbearing potential).

The dose escalation phases enrolled patients with a wide range of advanced solid tumors ("all-comers"), including melanoma, renal cell carcinoma (RCC), pancreatic ductal adenocarcinoma (PDAC), various sarcomas, non-small cell lung cancer (NSCLC), ovarian cancer, tonsillar squamous cell carcinoma, and gastro-esophageal adenocarcinoma.[24]

The dose expansion cohorts are more focused, targeting specific tumor types based on potential immunologic sensitivity or signals from earlier phases [1]:

• Monotherapy Expansion: MSI-H/dMMR tumors, TMB-H tumors, cutaneous melanoma, virally associated tumors, potentially others like RCC.[1]
• Combination Expansion: MSI-H/dMMR tumors (including colorectal), TMB-H tumors, cutaneous melanoma, gynecological tumors (e.g., ovarian, endometrial, cervical), potentially others like bladder, HNSCC, esophageal, gastric/GEJ, NSCLC, Merkel cell, BCC, cSCC.[1]

Key exclusion criteria aim to ensure patient safety and minimize confounding factors, including [28]:

• Recent prior systemic anti-cancer therapy (typically within 4 weeks) or radiotherapy (typically within 2 weeks, with specific rules for palliative or lung radiation).
• Known active or untreated central nervous system (CNS) metastases (patients with stable, treated brain metastases may be eligible).
• Another active malignancy within the previous 3 years (exceptions for curable cancers).
• Clinically significant autoimmune disease or conditions exacerbated by immunotherapy.
• Requirement for ongoing systemic corticosteroids (>10 mg prednisone equivalent daily) or other immunosuppressive therapy.
• Severe pulmonary, cardiac, or other systemic disease.
• Known active hepatitis B or C infection.
• Prior allogeneic tissue/solid organ transplant.
• Pregnancy or lactation.

4.4. Study Endpoints

The primary objectives of the Phase 1 portions (escalation/evaluation) are to assess the safety and tolerability profile of MDNA-11 (alone and in combination), identify any DLTs, and determine the mRDE and cRDE for the Phase 2 expansion phases.[4]

Secondary objectives include characterizing the PK profile of MDNA-11, evaluating its PD effects on peripheral immune cell populations (e.g., CD8+ T cells, NK cells, Tregs, activation markers, stem-like cells), and assessing preliminary anti-tumor activity.[4] Anti-tumor activity is measured by ORR, Disease Control Rate (DCR = CR+PR+Stable Disease), Progression-Free Survival (PFS), and Duration of Response (DoR), assessed using RECIST v1.1 and potentially immune-related criteria (iRECIST) via CT/MRI scans performed every 8 weeks.[24]

4.5. Trial Sites

The ABILITY-1 study is being conducted globally. Confirmed or planned site locations include centers in the United States (Florida, Georgia, California, Michigan), Australia (Queensland, New South Wales), Canada (Ontario), South Korea, and multiple centers within the European Union following EMA approval of the CTA in June 2024.[24] The expansion into Europe is intended to accelerate patient enrollment across the various study cohorts.[30]

The adaptive and integrated nature of the ABILITY-1 trial design, encompassing both monotherapy and combination therapy from early dose finding through to focused expansion, represents an efficient approach. It allows for data-driven decision-making, such as the selection of specific tumor types for expansion based on emerging activity signals (e.g., ICI-resistant melanoma, MSI-H tumors). Furthermore, evaluating both treatment modalities within a single protocol facilitates direct comparisons of safety, PK/PD, and efficacy using consistent methodologies, accelerating the understanding of MDNA-11's distinct contribution versus its synergistic potential with checkpoint inhibitors. This comprehensive dataset will be crucial for optimizing future development, including the design of potential Phase 3 registration trials.

5. Clinical Efficacy Results

Data presented from the ABILITY-1 trial indicate that MDNA-11 demonstrates anti-tumor activity both as a single agent and in combination with pembrolizumab, particularly in heavily pre-treated patient populations, including those resistant to prior immunotherapy.

5.1. Monotherapy Efficacy

In the initial monotherapy dose escalation cohorts, early signs of tumor control were observed even at lower doses. One report cited tumor control (defined as CR, PR, or SD) in 4 out of 10 evaluable patients at doses ≤ 30 µg/kg, including patients with sarcoma, melanoma, and pancreatic cancer.[45] Another analysis reported tumor control in 37% (7/19) of evaluable patients across the dose-escalation phase.[28]

More compelling activity has emerged from analyses focusing on patients receiving higher doses (≥ 60 µg/kg), particularly those eligible for Phase 2 expansion and often resistant to prior ICI therapy. Several reports converge on an ORR in the range of 25% to 30% in these specific subgroups:

• An ORR of 25% (5 responses out of 20 patients: 1 CR, 4 PRs) was reported among ICI-resistant, high-dose (≥60 µg/kg), Phase 2-eligible patients pooled from monotherapy escalation and expansion cohorts.[14]
• In the monotherapy dose expansion cohort alone (N=10, all ICI-failed), the ORR was 30% (3 PRs).[1]
• Another analysis pooling Ph2-eligible patients from expansion and escalation (≥60 µg/kg) reported an ORR of 29.4% (5/17).[22]
• Focusing specifically on the tumor types selected for the Phase 2 monotherapy expansion, an ORR of 40% (4/10) was noted in one report.[22]
• Earlier data from dose escalation (N=26 evaluable) showed an ORR of 7.7% (2 confirmed PRs) with 8 patients achieving SD (30.7%), including 3 with durable SD (>6 months).[26]

Specific durable and deep responses have been highlighted:

• Melanoma: A confirmed CR was achieved in a patient who had failed dual checkpoint inhibitors; this response was ongoing at week 63 [16], having evolved from a PR observed at week 52.[31] Overall, in 11 evaluable cutaneous melanoma patients, 1 CR and 2 PRs were observed (ORR 27.3%).[14] Durable stable disease lasting over 1.5 years has also been reported in a melanoma patient.[24] Reports mention 100% regression of target lesions in responding melanoma patients.[17]
• Pancreatic Cancer (PDAC): Significant activity was observed in patients with MSI-H PDAC. Among 3 evaluable MSI-H patients, 2 achieved PRs (ORR 66.7%).[14] One of these responders experienced complete regression of target and non-target lesions, achieved a durable response lasting 20 months during the study, and remained off all anti-cancer therapy for 11 months after completing the study.[16] This patient was initially treated in the 60 µg/kg cohort.[26] Another PDAC patient showed a PR lasting over a year.[24]
• Other Tumors: Stable disease has been noted in patients with sarcoma [24] and Basal Cell Carcinoma (BCC).[25] A PR was also reported in a patient with MSI-H small bowel cancer with metastases in the pancreas (initially misclassified as PDAC).[14]

Disease control rates (DCR) and clinical benefit rates (CBR, typically CR+PR+SD > 6 months or 24 weeks) provide further context. In the cohort of 20 ICI-resistant, high-dose, Ph2-eligible patients, the DCR was 55% and the CBR was 40%.[14] Another analysis in 14 similar patients reported a CBR of 50%.[17]

The observation of durable responses, including CRs and long-lasting PRs persisting even off-treatment, is particularly noteworthy. This suggests that MDNA-11 monotherapy can induce profound and potentially sustained anti-tumor immune responses, aligning with the mechanistic goal of activating long-term immune memory, possibly mediated by the observed expansion of stem-like T cells.

5.2. Combination Therapy Efficacy (MDNA11 + Pembrolizumab)

Early data from the combination dose escalation cohorts (MDNA-11 at 60 µg/kg and 90 µg/kg Q2W plus pembrolizumab 400 mg Q6W) indicate encouraging anti-tumor activity in heavily pre-treated patients.[14]

Objective response rates reported from these initial combination cohorts include:

• An ORR of 36% (5 responses: 1 CR, 4 PRs) among 14 patients with tumor types being enrolled in the Phase 2 expansion cohorts.[19]
• An ORR of 31% (4 responses out of 13 patients) when restricted to cancers planned for the Phase 2 combination expansion (cutaneous melanoma, MSI-H/dMMR, TMB-H tumors).[19]
• An earlier report noted an ORR of 22% (2 responses: 1 CR, 1 PR) among 9 evaluable patients.[16]

Specific responses in the combination setting highlight activity in tumor types often considered challenging for immunotherapy:

• Anal Squamous Cell Carcinoma (SCC): A CR was achieved at the first 8-week scan in a 70-year-old male patient who had progressed on two prior lines of chemotherapy. The patient remained on combination treatment with a confirmed CR.[16]
• Colorectal Cancer (CRC): A confirmed PR was observed in a 52-year-old female patient with MSS (microsatellite-stable) / TMB-H CRC who had progressed on two prior chemotherapy lines. This response was ongoing at week 32, with further deepening of response noted even after stopping study treatment for 4 months.[16] Another PR in MSS colon cancer was also mentioned.[15]
• Endometrial Cancer: A high ORR of 50% (2 responses in 4 patients) was reported in this subgroup receiving combination therapy.[22]

Disease control rates in the combination arm were reported as 78% (7/9 patients with CR, PR, or SD) in an earlier analysis [16] and 57% (8/14 patients) in a later analysis.[19]

The activity seen in MSS CRC and chemo-refractory anal SCC with the combination therapy is particularly interesting. These tumor types generally exhibit lower response rates to single-agent PD-1 blockade compared to melanoma or MSI-H tumors. This suggests that MDNA-11 might enhance the efficacy of pembrolizumab in these less immunologically responsive settings, potentially by increasing immune cell infiltration or activation within the tumor microenvironment, thereby sensitizing the tumors to checkpoint inhibition. This "immune sensitizer" role could significantly broaden the applicability of immunotherapy combinations.

5.3. Preclinical Efficacy Data

The clinical findings are supported by preclinical studies demonstrating MDNA-11's activity:

• In syngeneic mouse tumor models, MDNA-11 monotherapy controlled tumor growth, and combination with anti-PD1 or anti-CTLA4 antibodies induced durable tumor clearance and immunologic memory, protecting against tumor rechallenge.[7] MDNA-11 showed synergy with checkpoint inhibitors in these models.[12]
• In an aggressive orthotopic mouse model of triple-negative breast cancer (TNBC), a single dose of MDNA-11 administered prior to surgery (neoadjuvant setting) significantly prevented metastasis, extended survival, and induced a potent memory response against tumor rechallenge. Notably, single-agent MDNA-11 was more effective than a combination of anti-mPD1 and anti-mCTLA4 in this model.[6]
• In preclinical glioblastoma (GBM) models, including aggressive orthotopic mouse models and primary patient-derived GBM explants, MDNA-11 (and related constructs) significantly extended survival compared to controls, native IL-2, or anti-PD1 alone. This was associated with increased infiltration of CD8+ T cells and NK cells into the tumor.[43] Combination therapy with MDNA-11 and bizaxofusp (Medicenna's IL-4 targeting agent) showed synergistic tumor killing in human GBM tumoroids.[43]

Summary Table of Clinical Efficacy in ABILITY-1

The following table summarizes key efficacy results reported from the ABILITY-1 trial, focusing on objective response rates in relevant patient subgroups. Note that patient numbers and results may vary slightly between reports due to different data cut-off dates and analysis populations.

Treatment Arm	Patient Subgroup	N (Evaluable)	ORR (%)	CR (n)	PR (n)	DCR (%)	CBR (%)	Durability Notes / Source
Monotherapy (≥60µg/kg, ICI-R)	Overall Ph2-Eligible (Escalation + Expansion)	20	25	1	4	55	40	Includes data up to Nov 2024; CBR=CR+PR+SD>24wk 14
Monotherapy (≥60µg/kg, ICI-R)	Cutaneous Melanoma	11	27.3	1	2	--	--	CR confirmed, ongoing wk 63 14
Monotherapy (≥60µg/kg, ICI-R)	PDAC (MSI-H only)	3	66.7	0	2	--	--	1 responder durable (20mo on study, 11mo off tx post-study) 14
Monotherapy (Expansion only, ICI-R)	Overall Expansion Cohort	10	30	0	3	--	--	Data as of Nov/Dec 2024 1
Combination (Escalation)	Overall (Tumor Types in Ph2 Expansion)	14	36	1	4	57	--	Data cut-off Apr 2025 19
Combination (Escalation)	Cancers Planned for Ph2 Combo Expansion (Mel, MSI-H, TMB-H)	13	31	--	4	--	--	Data cut-off Apr 2025 19
Combination (Escalation)	Anal SCC (Chemo-Refractory)	--	--	1	--	--	--	CR at Wk 8, ongoing 16
Combination (Escalation)	CRC (MSS/TMB-H, Chemo-Refractory)	--	--	0	1	--	--	Confirmed PR, ongoing Wk 32+, deepening response off-tx 16
Combination (Escalation)	Endometrial Cancer	4	50	--	2	--	--	Data cut-off Apr 2025 22
Combination (Escalation)	Overall (Earlier report)	9	22	1	1	78	--	Data cut-off Nov 2024 16

Abbreviations: ICI-R = Immune Checkpoint Inhibitor Resistant; Ph2 = Phase 2; N = Number of evaluable patients; ORR = Objective Response Rate; CR = Complete Response; PR = Partial Response; DCR = Disease Control Rate; CBR = Clinical Benefit Rate; PDAC = Pancreatic Ductal Adenocarcinoma; MSI-H = Microsatellite Instability-High; SCC = Squamous Cell Carcinoma; CRC = Colorectal Cancer; MSS = Microsatellite Stable; TMB-H = Tumor Mutational Burden-High; Wk = Week; tx = treatment; -- = Data not specified in sources.

6. Safety and Tolerability Profile

A critical aspect of MDNA-11's development is its safety profile, particularly in comparison to the significant toxicities associated with high-dose aldesleukin. Data from the ABILITY-1 trial suggest that MDNA-11 possesses a manageable and favorable safety profile at the doses evaluated.

6.1. Overall Safety Summary

Across both monotherapy and combination therapy arms, MDNA-11 has been generally well-tolerated.[5] An acceptable safety profile has been consistently reported at doses up to 120 µg/kg IV Q2W.[14]

6.2. Treatment-Related Adverse Events (TRAEs)

The majority of TRAEs observed have been mild to moderate in severity and transient in nature. Reports indicate that over 90-95% of TRAEs were Grade 1 or Grade 2.[14] These events typically resolved within 48 to 72 hours of onset.[17]

The most frequently reported TRAEs are consistent with cytokine-mediated immune activation and include [24]:

• Infusion-related reactions (IRRs): Reported in approximately 53-65% of patients.
• Pyrexia (fever): ~43-50%
• Nausea: ~33-45%
• Chills: ~33-35%
• Hypotension: ~30%
• Fatigue: ~27-30%
• Diarrhea: ~25%

Grade 3 TRAEs have been reported, primarily consisting of asymptomatic and transient elevations in liver function tests (LFTs) or transaminases, observed in approximately 25% of patients.[14] There are conflicting reports regarding higher-grade events; while most sources state no Grade 4 or 5 TRAEs occurred [14], one source mentioned an isolated Grade 4 TRAE in the monotherapy arm.[14] Further clarification on this specific event may be needed from detailed study publications. Importantly, repeat administration of MDNA-11 appears to improve tolerability over time.[14]

6.3. Dose-Limiting Toxicities (DLTs) and Vascular Leak Syndrome (VLS)

A key finding from the ABILITY-1 trial is the absence of protocol-defined DLTs during both monotherapy and combination dose escalation phases, even at the highest dose level tested (120 µg/kg Q2W).[5] This lack of DLTs allowed for dose escalation to proceed as planned and supported the selection of the 90 µg/kg dose for expansion cohorts.

Crucially, there has been no evidence of VLS reported in patients treated with MDNA-11.[5] This is a significant distinction from high-dose aldesleukin, where VLS is a major and often dose-limiting toxicity. The absence of VLS aligns with preclinical findings showing no significant effect on eosinophils, which have been linked to VLS risk.[27] This clinical validation strongly supports the hypothesis that MDNA-11's engineered design successfully mitigates this severe IL-2-associated toxicity.

6.4. Comparison of Monotherapy vs. Combination Safety

The addition of pembrolizumab to MDNA-11 in the combination cohorts did not appear to significantly worsen the safety profile. Reports indicate that the combination demonstrated a favorable safety profile with no new or unexpected safety signals identified compared to MDNA-11 monotherapy.[14] The Safety Review Committee consistently approved dose escalation in the combination arm based on the observed safety data.[14]

The consistent lack of DLTs and VLS across doses and in both monotherapy and combination settings provides strong clinical evidence validating the molecular engineering strategy behind MDNA-11. By successfully decoupling the desired immune stimulation from the most severe toxicities of native IL-2, MDNA-11 appears to offer a significantly improved therapeutic window. While the observed Grade 1-2 TRAEs like pyrexia and chills are expected on-target effects of immune activation and require appropriate management (e.g., premedication, step-up dosing), their transient and generally manageable nature further supports the favorable safety profile. Continued monitoring, particularly of transient LFT elevations, remains warranted.

Summary Table of Common TRAEs in ABILITY-1 (Monotherapy Escalation/Evaluation)

The following table summarizes the approximate frequency of common TRAEs based on available reports, primarily from the monotherapy dose escalation/evaluation phase. Data for combination therapy specifically is less detailed in the provided sources but generally mirrors the monotherapy profile without new signals.

Treatment-Related Adverse Event (TRAE)	Approximate Frequency (%)	Predominant Grade	Notes
Infusion-Related Reactions (IRR)	53 - 65	1-2	Includes pyrexia, chills, nausea, hypotension, fatigue 24
Pyrexia (Fever)	43 - 50	1-2	Common component of IRR 24
Nausea	33 - 45	1-2	24
Chills	33 - 35	1-2	Common component of IRR 24
Hypotension	~30	1-2	26
Fatigue	27 - 30	1-2	24
Diarrhea	~25	1-2	24
LFT / Transaminase Elevation	~25	Mostly 3	Primarily asymptomatic and transient 14

Note: Frequencies are approximate based on synthesis of available data.[14] Most events were transient, resolving within 48-72 hours. No DLTs or VLS reported.

7. Pharmacokinetics and Pharmacodynamics (PK/PD)

Understanding the pharmacokinetic (how the drug moves through the body) and pharmacodynamic (how the drug affects the body) properties of MDNA-11 is crucial for interpreting its clinical activity and safety profile. Data from the ABILITY-1 trial provide insights into both aspects.

7.1. Pharmacokinetics (PK)

Consistent with its design as a long-acting agent via albumin fusion, MDNA-11 exhibits pharmacokinetic properties suitable for the administered Q2W dosing schedule.[4] Clinical data show consistent PK profiles upon repeat administration, both when MDNA-11 is given alone and when combined with pembrolizumab.[1] PK analyses have demonstrated a dose-dependent increase in serum concentrations and exposure following IV administration.[24] While specific half-life values from the human studies are not detailed in the provided materials, the observed PK supports the extended dosing interval compared to aldesleukin.

7.2. Pharmacodynamics (PD) - Immune Cell Modulation

Pharmacodynamic assessments confirm that MDNA-11 induces significant and sustained changes in peripheral immune cell populations, consistent with its engineered mechanism of action:

• Lymphocyte Expansion: MDNA-11 treatment leads to a robust and dose-dependent expansion of total lymphocytes.[1] This expansion is sustained over repeat dosing cycles in both monotherapy and combination settings.[1] In the combination arm, lymphocyte expansion appeared to plateau at the 90 µg/kg MDNA-11 dose level.[19]
• Preferential Effector Cell Expansion: The lymphocyte expansion is characterized by a preferential increase in key anti-cancer effector cell populations, namely CD8+ T cells and NK cells.[1]
• Minimal Treg Impact: Consistent with the 'not-alpha' design, MDNA-11 induces minimal or no significant increase in the frequency or number of immunosuppressive CD4+ FoxP3+ Tregs.[5]
• Activation and Differentiation: The expanded CD8+ T cells show signs of activation, with increased expression of markers like CD25, ICOS, and OX40, particularly notable at the 90 µg/kg dose level.[15] Furthermore, MDNA-11 promotes the expansion of specific T cell subsets associated with durable immunity, including effector memory T cells and central memory T cells.[1]

This consistent pattern of immune modulation observed in clinical studies – robust expansion of CD8+ T cells and NK cells, coupled with minimal impact on Tregs – provides strong evidence that the engineered 'beta-enhanced not-alpha' selectivity successfully translates from preclinical models into the intended biological effect in humans.

7.3. Biomarker Insights

Beyond general immune cell counts, PD analyses have yielded potentially crucial biomarker insights:

• Stem-like T Cell Expansion: MDNA-11 treatment leads to a significant expansion of a unique progenitor population of CD8+ T cells characterized by the expression of TCF1 (T cell factor 1), often referred to as 'stem-like' T cells.[1] These cells possess capabilities for self-renewal and can differentiate into potent effector T cells upon antigen re-encounter. They are considered critical for maintaining long-lasting anti-tumor immunity and have been positively associated with responses to other immunotherapies like checkpoint blockade.[1]
• Correlation with Clinical Response: A key finding reported by Medicenna is that a greater expansion of these stem-like TCF1+ CD8+ T cells was significantly associated with clinical responses (CRs/PRs) observed in patients treated with MDNA-11 (based on pooled monotherapy and combination therapy data).[1]
• Other Markers: Increases in markers associated with enhanced effector function (e.g., DNAM+) and memory/stemness phenotypes in circulating CD8+ T and NK cells have also been noted.[14]

The correlation between the expansion of TCF1+ stem-like CD8+ T cells and clinical outcome is particularly significant. It suggests that the therapeutic benefit of MDNA-11 may depend not just on the quantity, but critically on the quality and persistence potential of the induced immune response. Inducing a pool of self-renewing, long-lived T cells capable of sustained anti-tumor activity appears to be a key mechanism underlying the durable responses observed. This elevates TCF1+ cell expansion from merely a pharmacodynamic marker to a potential predictive biomarker for long-term clinical success with MDNA-11, and potentially other IL-2 pathway modulators.

7.4. Tumor Microenvironment (TME) Modulation

Evidence suggests that the systemic immune activation induced by MDNA-11 translates to effects within the tumor itself:

• Analysis of paired tumor biopsies (pre-treatment vs. on-treatment) showed increased infiltration of activated immune cells, specifically CD25+ CD8+ T cells and NK cells, following MDNA-11 administration.[14]
• Increased levels of cytotoxic molecules like granzymes were also detected in post-treatment biopsies.[25]
• Gene expression analyses hinted at a shift within the TME, with degradation of cancer-promoting pathways and enhancement of immune-related anti-cancer pathways following treatment.[29] Preclinical studies similarly showed increased infiltration of Granzyme B-positive CD8+ T cells into the TME.[6]

These findings indicate that MDNA-11 not only boosts systemic immunity but also promotes the trafficking and activation of effector cells within the tumor microenvironment, a necessary step for direct tumor cell killing.

8. Regulatory Status and Future Outlook

MDNA-11 remains an investigational agent undergoing clinical development. Its path towards potential regulatory approval involves ongoing trials, global expansion, and strategic planning based on emerging data.

8.1. Current Development Stage

MDNA-11 is currently in Phase 1/2 clinical development through the ABILITY-1 trial (NCT05086692).[1] It has not yet received marketing approval from the FDA, EMA, or other regulatory agencies.[35]

8.2. Global Trial Expansion

The ABILITY-1 study is actively enrolling patients at clinical sites across multiple countries, including the United States, Canada, Australia, and South Korea.[24] In June 2024, Medicenna announced that the European Medicines Agency (EMA) had approved its Clinical Trial Application (CTA) to expand the ABILITY-1 study into Europe.[30] This expansion is anticipated to accelerate patient enrollment across the various monotherapy and combination cohorts.[30] The EU clinical trial registry indicates a trial start date in Europe of October 2024.[52] This strategic geographic expansion signals Medicenna's commitment to advancing MDNA-11 into later-stage development phases that typically require larger, more diverse patient populations.

8.3. Planned Future Steps

Based on company communications, key upcoming milestones for the MDNA-11 program include [1]:

• Completion of enrollment in the monotherapy expansion and combination dose escalation portions of ABILITY-1, anticipated around mid-calendar year 2025.
• Initiation and continuation of the combination dose expansion cohorts, also expected around mid-calendar year 2025. These cohorts will focus on specific tumor types deemed promising based on earlier data or biological rationale, such as MSI-H/dMMR, TMB-H, cutaneous melanoma, and gynecological tumors for the combination arm, and potentially virally associated tumors for the monotherapy arm.
• Continued presentation of updated clinical data (safety, efficacy, PK/PD) from all arms of the ABILITY-1 study at major medical conferences throughout 2025 and beyond.[1]

8.4. Regulatory Designations

The provided information does not indicate that MDNA-11 itself has received any specific regulatory designations from the FDA or EMA, such as Fast Track, Breakthrough Therapy, or Orphan Drug Designation (ODD).[1] It is noteworthy that another Medicenna product candidate, bizaxofusp (MDNA55), has obtained Fast Track designation from the FDA and ODD from both the FDA and EMA for recurrent glioblastoma.[2] This demonstrates the company's capability in navigating the processes for obtaining such designations. While MDNA-11 is currently being studied in broader solid tumor populations, it is possible that specific ODDs could be pursued later if compelling data emerge in rare tumor subtypes included within the expansion cohorts (e.g., specific MSI-H cancers, rare virally associated tumors). The current Phase 1/2 strategy might precede applications for designations targeting narrower, potentially orphan, indications identified during the trial.

8.5. Intellectual Property (IP) Landscape

Medicenna has secured intellectual property protection for its IL-2 Superkine platform, including MDNA-11.[49] A key patent is U.S. Patent No. 11,542,312, granted in January 2023, which covers methods of treating cancer using an IL-2 Superkine (such as MDNA-11) in combination with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 checkpoint inhibitor.[49] This patent provides protection extending to at least 2039 and is highly relevant given the clinical focus on combination therapy with pembrolizumab in the ABILITY-1 trial and the potential for future combination strategies.[49] The company highlights that this IP could be particularly valuable as patents for major checkpoint inhibitors begin to expire from 2028 onwards.[49] Additional patents and applications covering IL-2 fusion proteins and their uses are held or pending in major global markets, including Europe, Japan, China, Canada, India, and Australia.[49] This focus on securing robust IP, especially for combination therapies, underscores the company's long-term strategic planning for MDNA-11.

9. Expert Perspective and Conclusion

MDNA-11 represents a scientifically well-rationalized attempt to engineer a safer and more effective IL-2 immunotherapy by addressing the known liabilities of aldesleukin. The 'beta-enhanced not-alpha' design, coupled with albumin fusion for extended half-life, aims to achieve preferential activation of anti-cancer effector lymphocytes (CD8+ T cells, NK cells) while minimizing Treg stimulation and systemic toxicity.

Data emerging from the Phase 1/2 ABILITY-1 trial provide compelling, albeit still early, evidence supporting this approach. The consistent lack of dose-limiting toxicities and, notably, the absence of vascular leak syndrome across evaluated doses up to 120 µg/kg, strongly suggest that the engineering strategy has successfully mitigated the most severe safety concerns associated with traditional IL-2 therapy. This improved safety profile is a critical achievement, potentially enabling sustained administration at biologically active doses and facilitating combination therapies.

The pharmacodynamic data align remarkably well with the intended mechanism, demonstrating robust and sustained expansion of CD8+ T and NK cells with minimal impact on Tregs. The identification and expansion of TCF1+ stem-like CD8+ T cells, and its significant correlation with clinical response, offers profound mechanistic insight. It suggests that MDNA-11 may induce a qualitatively superior immune response characterized by persistence and memory, potentially explaining the durable responses observed in some patients. This finding warrants further investigation as a potential predictive biomarker.

Clinically, MDNA-11 has demonstrated encouraging single-agent activity, particularly in patients with melanoma and MSI-H pancreatic cancer who are resistant to prior checkpoint inhibitors. Achieving objective responses, including complete responses, in this difficult-to-treat population highlights its potential to overcome immunotherapy resistance. Furthermore, the early combination data with pembrolizumab, showing responses in historically less responsive tumor types like MSS CRC and anal SCC, suggests a potent synergistic effect and the potential for MDNA-11 to act as an immune sensitizer, broadening the reach of checkpoint blockade.

However, several considerations remain. The clinical data, while promising, are derived from relatively small patient numbers in ongoing Phase 1/2 cohorts. Larger, randomized trials will be necessary to definitively establish efficacy compared to standard-of-care or other investigational agents. The optimal dose and schedule, particularly for combination therapy (with exploration of 120 µg/kg ongoing), need confirmation in the expansion cohorts. Long-term safety data will also be important. While VLS appears mitigated, managing the expected on-target, cytokine-related adverse events (IRRs, fever, etc.) will be crucial for patient experience in broader clinical practice.

In conclusion, MDNA-11 stands out as a promising next-generation IL-2 candidate based on its rational design, validated mechanism of action in humans, favorable safety profile to date, and encouraging signals of durable clinical activity, both as monotherapy in ICI-resistant settings and in combination with checkpoint inhibitors. The correlation of stem-like T cell expansion with clinical response provides a strong biological rationale for its efficacy. If the positive results observed in the ABILITY-1 trial are confirmed and extended in ongoing and future studies, MDNA-11 has the potential to become a valuable therapeutic option, particularly for patients with advanced solid tumors who have exhausted standard treatment options or harbor tumors resistant to current immunotherapies. Its development addresses a clear unmet need and represents a significant advancement in the field of cytokine engineering for cancer therapy.

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