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Re-engineered Molecules: Alkermes Approach to IL-2

Authors: Expert interview with Heather Losey, Director, Program Lead, Immuno-Oncology, Alkermes, Dublin, Ireland

Heather Losey was trained in protein biochemistry, structure and function, with a PhD from Harvard Medical School and a postdoc in the Harvard Chemistry Department. Heather joined Wyeth in 2006 in metabolic diseases and hemophilia research before moving to Alkermes in 2011 to support the expansion of protein therapeutics and oncology research. There, Heather led the protein engineering efforts, including ALKS 4230, for which she has been program lead from inception into ongoing clinical studies.

Q. In the age of immune checkpoint inhibitors, why is there continued interest in interleukin-2 (IL-2)? 

While FDA-approved immune checkpoint inhibitor drugs can provide improved survival for patients with advanced cancers, they only help a subset of patients. A cross-sectional study found that in 2018, only about 12% of patients who are eligible for checkpoint inhibitor drugs were estimated to respond to them.1 Therefore, there is significant need for new treatment options and combinations for many people affected by cancer.

High-dose IL-2 has demonstrated significant anti-cancer efficacy,2 however its use in cancer treatment has been limited by its toxicity profile. There is continued interest in exploring the IL-2 pathway because IL-2 can activate and expand both cancer fighting CD8+ T cells and Natural Killer (NK) cells. However, its effect on immune suppressive regulatory T cells (Tregs) and on vascular endothelial cells are undesirable from a therapeutic perspective. Therefore, our goal underlying the design of investigational ALKS 4230 is to leverage and expand on the proven anti-tumour effects of existing IL-2 therapy, while mitigating certain limitations.

Q. What are the limitations of IL-2 in treating cancer?

While currently available high-dose IL-2 treatment has shown significant anti-tumour efficacy, its use is limited by the toxicity profile and side effects. One of the major side effects is capillary leak syndrome, in which fluids within the vascular system leak into tissue outside the bloodstream, which can result in low blood pressure and poor blood flow to internal organs, potentially leading to organ failure.3

Q. How does the design of ALKS 4230 seek to overcome the limitations of IL-2?

The diverse effects of IL-2 are controlled by two different types of IL-2 receptor complexes expressed on cells, referred to as the high-affinity and intermediate-affinity receptors. The high-affinity IL-2 receptor is found primarily on Tregs, and when IL-2 binds to this receptor, it can activate and expand the number of these cells, resulting in a dampening of the immune response. Furthermore, binding of IL-2 to the high-affinity receptor on vascular endothelial cells is thought to mediate capillary leak syndrome. The intermediate-affinity IL-2 receptor is found on cancer-fighting CD8+ T cells and NK cells, and when IL-2 binds to this receptor, it activates and expands these cells which drive an immune response to destroy cancer cells.

In developing ALKS 4230, our goal was to leverage the natural differences between the two receptors to create a molecule that may exclusively bind to the intermediate-affinity receptor and avoid binding to the high-affinity receptor – thereby selectively expanding CD8+ T cells and NK cells while avoiding the IL-2 derived expansion of Tregs. We hypothesised that by fusing a component of the high-affinity receptor with IL-2, we might create a molecule that is unable to bind to the high-affinity receptor due to a phenomenon called ‘steric hindrance’. Therefore, we engineered ALKS 4230 utilising circular permutation, harnessing a naturally occurring process that rearranges amino acids in a protein while maintaining the protein’s overall three-dimensional shape and function. Our PICASSO™ technology allowed us to use circular permutation to permanently join IL-2 with IL-2 receptor α in the natural orientation, to create a stable fusion protein to bind only to the intermediate-affinity IL-2 receptor as desired.

Q. Could you tell us a little about the recently published data on ALKS 4230?

Preclinical data demonstrating the selectivity and anti-tumour efficacy of ALKS 4230 were recently published in the Journal for ImmunoTherapy of Cancer.4

The data from multiple assays show investigational ALKS 4230 activated the expansion of CD8+ T cells and NK cells with negligible effects on Treg expansion. In fact, ALKS 4230 was ~1,000 times less potent than IL-2 in activating Treg cells. These differences in cell expansion correlated well with enhanced mouse anti-tumour efficacy of investigational ALKS 4230 relative to IL-2. Of note, data from a mouse B16F10 lung metastasis model demonstrated that treatment with ALKS 4230 achieved a maximum of 100% inhibition of tumour growth with one of the doses tested, as compared to treatment with recombinant human IL-2 (rhIL-2), which achieved a maximum of 70% inhibition of tumour growth with one of the doses tested. In this model, equivalent anti-tumour activity of ALKS 4230 was observed whether it was administered intravenously or subcutaneously. 4

The preclinical safety data of ALKS 4230 showed lower indices of toxicity, as measured by systemic inflammatory cytokine production and changes in lung weight, compared to rhIL-2.4

Q. What will be the next steps in the clinical development of ALKS 4230?

We are encouraged by ALKS 4230’s preclinical profile, including its selectivity for immune effector cells, pharmacokinetics and preclinical efficacy. Based on these data, ALKS 4230 has progressed into multiple clinical studies including two ongoing Phase 1/2 studies as part of our ARTISTRY clinical program: ARTISTRY-1, our intravenous dosing study and ARTISTRY-2, our subcutaneous dosing study. Both studies are evaluating ALKS 4230 as a monotherapy and in combination with pembrolizumab. In November 2019, we presented initial efficacy and safety data from ARTISTRY-1 at the SITC meeting.

We continue to enroll patients in both ARTISTRY-1 and ARTISTRY-2 clinical trials, and we expect activation of select ex-US sites in the coming months.

 

References

  1. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2:e192535.
  2. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–8.
  3. www.proleukin.com/health-care-professional/tools/pi.html (accessed 13 May 2020)
  4. Lopes JE, Fisher JL, Flick HL, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. 2020;8:e000673.

 

Support: Commissioned, developed and supported by Touch Medical Media.

Published: 13 May 2020

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    touchONCOLOGY is for informational purposes and intended for healthcare professionals only. Its content should not be considered medical advice, diagnosis or treatment recommendations.