MDNA55

TARGETING GLIOBLASTOMA

There are around 23,800 brain and nervous system cancers diagnosed each year in the United States. The most common and also a uniformly fatal form of primary brain cancer in adults is glioblastoma multiforme (GBM).

Regrettably, despite decades of research, very few treatment options are available for GBM and patients diagnosed with the disease typically survive fewer than 15 months.

The current international standard-of-care is surgery, followed by radiation and chemotherapy (typically temozolomide). But not everyone responds to this treatment, and those that do almost invariably find that the tumour becomes resistant or comes back.

The difficulty in developing new treatments for brain tumours is that the central nervous system is unique in the body because it is separated from the circulatory system by the blood-brain barrier (BBB). This membrane tightly controls the traffic of immune cells, cytokines, or drugs into the brain.

Additionally, the specialized cells that exist around a brain tumour, known as the tumour microenvironment (TME), are often immunosuppressive. This dampens the impact of any infiltrating immune cells that seek to destroy the cancer.

The good news is that a growing understanding of how the immune system functions within the brain has led to some promising early-stage trials using immunotherapy, such as oncolytic viruses, vaccines and checkpoint inhibitors.

But in order to meaningfully tackle the disease entails overcoming this immunosuppressive TME and implementing a delivery mechanism able to bypass the BBB.

Medicenna has taken a multi-pronged approach to tackling GBM using our Empowered™ IL-4 cytokine, MDNA55.

The GBM micro-environment is supported by a robust population of immunosuppressive Myeloid Derived Suppressor Cells (MDSCs) and tumour associated macrophages (TAMs) which over-express the receptor for IL-4 (IL4R).

Crucially, in glioblastoma tumours, the IL4R is significantly increased, while being almost completely absent in normal brain tissue

MDNA55 is an engineered version of IL-4 that exploits this discrepancy by carrying a cell-killing payload. When MDNA55 binds to the IL4R, the entire molecule is transported into the cell where the payload is delivered, triggering cell death.

In our previous and ongoing clinical trials, this MDNA55 is locally administered after surgery by directly infusing the drug onto the tumour itself after the tumour has recurred. This delivery method means that the treatment can bypass the BBB and reduce systemic side effects.

By neutralizing MDSCs and TAMs that highly express IL-4R, MDNA55 is also able to influence the local tumour microenvironment, reducing the tumours inherent immunosuppression and potentially enhancing any follow up immunotherapy treatments.

The uniqueness of this approach allows MDNA55 to potentially treat glioblastoma with minimal side effects, ease of drug delivery and reduce the immunosuppression inherent in these tumours.

OUR APPROACH

MDNA55 is a novel first in class Interleukin-4 Empowered Cytokine (IL4-EC). This proprietary targeted Molecular Trojan Horse is designed to harness the exceptional specificity and affinity of Superkines™ (engineered cytokines) to selectively and simultaneously deliver cell killing Payloads to the bulk tumor, tumor microenvironment (TME) and cancer stem cells (CSC).

A Powerful Molecular Trojan Horse

MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the bacterial pseudomonas exotoxin A (PE). The resulting fusion protein is designed such that the exotoxin is only active in the cytoplasm of the target cell following receptor-mediated endocytosis via the IL-4/IL-4R axis.

MDNA55

The interleukin-4 receptor (IL4R) is an attractive target for the development of cancer therapeutics, because it is frequently and intensely expressed on a wide variety of human carcinomas. The recent determination of a pivotal role for IL4R in the emergence and advancement of the malignant phenotype, overexpression on cancer stem cells (CSCs) and its dominant role in the tumor micro-environment (TME) validates our approach of pursuing with the IL4R as an important cancer target.

Components of the TME, such as Tumor Associated Macrophages (TAMs), Myeloid Derived Suppressor Cells (MDSCs) and a Th2>>Th1 profile, are each attributed to a robust IL-4/IL-4R bias and generally associated with highly aggressive forms of cancer and poor survival outcomes. We believe that major improvement in cancer outcomes can be achieved if a multi-pronged approach was deployed. Medicenna’s IL4-ECs are capable of ablating the bulk tumor, depleting cancer stem cells (CSCs) weakening the angiogenic pro-tumoral microenvironment (TAMs) and stripping the immunosuppressive cloak protecting the tumor (MDSCs). By doing so, IL4-ECs have the potential to radically improve patient outcomes.

WHY TARGET THE IL4R

  • Expression levels of IL4R are low on the surface of healthy and normal cells, but increase several fold on cancer cells and non-malignant cells of the TME
  • Analysis of over 2,000 cancer biopsies, shows that the IL-4R is over-expressed in 20 different types solid and hematological cancers corresponding to an annual incidence rate of over a million IL4R positive cancers
  • The IL-4/IL-4R axis plays a prominent role in supporting the establishment and maintenance of a robust TME, thereby protecting the cancer from the body’s own immune system and immunotherapies
  • The IL-4/IL-4R bias continues to be identified as a marker for highly aggressive forms of cancer and is generally associated with poor survival outcomes
  • Cancer stem cells also thrive in the presence of IL-4

Examples of IL-4R Over Expression

Examples of IL-4R Over Expression

CLINICAL DEVELOPMENT HISTORY

REGULATORY STATUS:

MDNA55 has been granted Orphan Drug status by USFDA and EMA (European Medicines Agency) for the treatment of gliomas and Fast Track designation for the treatment of GBM and anaplastic astrocytoma (AA) by the USFDA. MDNA55 is currently in late stage development for the treatment of recurrent GBM, a uniformly fatal form of brain cancer.

PATIENTS:

To date 72 patients with recurrent or progressive malignant gliomas (GBM and AA) have been treated with MDNA55. More than 40% of the recurrent GBM (rGBM) subjects had multiple relapses or large tumors (>4cm in diameter) and 25% had a poor performance status (Karnofsky Performance Score; KPS of <70) prior to treatment with MDNA55. In two sponsor-initiated Phase 1/2a trials, all patients received a single infusion of MDNA55 using convection enhanced delivery (CED). In the first study, tumors were not resected, whereas in the second study, the tumors were resected 3 weeks post-treatment. Tumor response analysis was only performed in the first study.

SAFETY:

There were no detectable levels of MDNA55 in the blood stream, nor any evidence of significant systemic toxicity following treatment. There were no deaths attributed to MDNA55. Adverse events (AEs) were primarily neurological which were generally transient and an aggravation of pre-existing neurological deficits anticipated in this patient population.

EFFICACY:

In the non-resected study, single treatment with MDNA55 was associated with a tumor response rate of 56% with a complete response (CR) rate of 20%. Further, the disease control rate (including stable disease) was 68%. Responses and tumor stabilization were durable, with a median duration of disease stabilization and response being 16 weeks.

These findings are compelling when compared with response rates of less than 10% for historical controls and the 28% response rate that led to accelerated approval of Avastin. Further, among 25 unresected rGBM patients treated with MDNA55, an unprecedented CR rate of 20% was achieved when compared to 1.2% for Avastin. MDNA55 data are particularly promising given the poor baseline characteristics of the subjects.

1https://seer.cancer.gov/statfacts/html/brain.html
2https://www.braintumour.ca/2494/brain-tumour-facts
3https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234/
4https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786905/
5https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084676/
6https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619015/
7https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735528/
8https://www.ncbi.nlm.nih.gov/pubmed/15830341

Top