The quest to find innovative immuno-oncology (IO) therapies to help more people with cancer has never been more active.  Immunotherapies can be game-changing in the way cancer is treated, particularly in the later stages of the disease. Yet, despite this innovation, immunotherapies only help a subset of patients. We know that many cancer types are not eligible for treatment with certain immunotherapies, and only a small portion (~12%) of patients eligible for immunotherapies are estimated to respond to them. [1] What if the answer to succeeding in next-generation IO is to first look back in order to look forward – leverage the past in seeking to develop new therapies that are efficacious and safe in the future?

Numerous companies are embracing this concept by creating novel investigational drugs, re-engineered from “older” – or existing – cancer treatments. For example, antibody-drug conjugates were developed by taking two established cancer treatment approaches – antibodies and cytotoxic drugs – and engineering them together to create a new class of therapy of approved drugs. [2] As another example, CAR T-cell therapy is built on the foundation of a cancer treatment called tumor-infiltrating lymphocyte (TIL) therapy and then enhanced by adding an engineered receptor protein.[3]

The Case for Re-Exploring Existing Therapies
Drug discovery is a long, arduous, and cost-intensive journey, and particularly so for cancer treatments. The rate of R&D failures exceeds successes despite well-rationalized hypotheses and clinical study rigor. [4] Thus, the ability to shorten that timeframe and increase the likelihood of finding a “winner” is incredibly valuable. Pharmaceutical and biotech companies look to a variety of sources to help make more informed decisions including predictive modeling, in addition to company experience and proprietary technology. Increasingly, companies have also started to look at older therapies – ones that may have shown promise but failed to create a positive impact on the treatment landscape due to certain drawbacks – to see if they can be re-engineered for better efficacy and safety to increase the chance of success. IL-2-based therapy is one such target.

The IL-2 Renaissance
Due to its ability to activate cancer-fighting immune cells, IL-2-based therapy has shown significant anti-tumor efficacy. However, the development and use of therapies that target the IL-2 pathway has been limited by a burdensome tolerability profile. One such therapy is aldesleukin, approved to treat adults with metastatic renal cell carcinoma and metastatic melanoma. The pathway shows valuable efficacy but brings with it serious side effects such as capillary leakage, reduced neutrophil function, and increased infection.[5]

In the last eight years, there has been a renewed interest in exploring the IL-2 pathway, building on learnings, and hopefully reducing limitations by developing new investigational treatments via protein engineering approaches. Native IL-2 can activate and expand several types of cells, including immune-suppressive regulatory T cells (Tregs), anti-cancer CD8+ T cells, natural killer (NK) cells, and vascular endothelial cells – all with important roles in cellular and immune health. [6] However, to overcome the current limitations of IL-2-based immunotherapy, it would be important to selectively expand the anti-cancer CD8+ T and NK cell populations, without affecting the others.

The key challenge in this approach is to develop novel molecules with less toxicity without diminishing the proven efficacy of IL-2 treatment. Re-engineering proteins for better efficacy and/or safety may one day prove to offer other benefits such as: creating a protein with better stability and a longer half-life; improving binding specificity for a target; or preventing a target from binding to its naturally occurring partner/ligand. Protein engineering is commonly accomplished through structural redesign or blocking via PEGylation.

PEGylation
PEGylation is one of the earliest and most widely used blocking methods for extending serum half-life and involves the chemical attachment of a polyethylene glycol (PEG) “mask” to part of a protein.[7] In the case of IL-2 therapies, multiple PEGs can be used to create a pro-drug that requires an “activation” of the drug itself once inside the body, via metabolic removal of the PEG modifications, to arrive at an active IL-2 species, some of which have altered specificity for IL-2 receptors. PEG modifications can also be incorporated to prevent binding with the site responsible for the unwanted effects elicited by IL-2 therapy. [8][9] PEGylation is not without potential challenges, though. Patients can mount an immune response against PEG, resulting in antibodies that clear the pegylated drug from the patient’s body before it has time to try to be effective.[10]  Some PEGylated proteins are designed to have “releasable” PEG molecules; however, the rate of PEG release can be variable, and the pharmacokinetics of such drugs must be carefully monitored.[11]

Structural Redesign
Redesigning a protein’s physical structure, such as by creating a stable fusion protein, is one way that the function of naturally occurring IL-2 might be changed to bind receptors more selectively. This approach may offer a stable molecule that is inherently active and does not require any metabolic breakdown inside the body to become active. Theoretically, increased selectivity is hoped to lead to the desired efficacy while minimizing adverse events. An additional question is whether the lack of a “foreign” entity such as a PEG may minimize the chances of developing an immune response against the drug itself.

One such approach to structural redesign that is being investigated leverages a natural process called a circular permutation. In nature, circular permutation rearranges amino acids in a protein while maintaining the protein’s overall three-dimensional shape and function. [12] At Alkermes, we have harnessed this process, using our PICASSO® technology, to investigate a novel molecule reengineered from IL-2 that is designed to selectively expand tumor-killing immune cells while avoiding activation of immunosuppressive cells. We are currently investigating the selectivity, efficacy, and safety of this investigational molecule as part of our ARTISTRY clinical development program.

The path from bench research to immunotherapy requires significant dedication and patience. Protein redesign is believed to present an efficient and potentially more cost-effective avenue for cancer research and development by building on established pathways and evolving technology in protein engineering. The potential to improve the tolerability of validated cellular pathways with proven efficacy creates a distinct opportunity to speed the process of cancer therapy advancement.

References
[1] Haslam, Alyson, et al. “Estimation of the Percentage of US Patients with Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs.” JAMA Network. May 2019. Online. Last accessed on May 11, 2020.
[2] Pengxuan Zhao, et al. “Recent advances of antibody drug conjugates for clinical applications.” Acta Pharmaceutica Sinica B. April 2020. Online. Last accessed on May 29, 2020.
[3] Maartje W. Rohaan, et al. “Adoptive cellular therapies: the current landscape.” Virchows Arch. November 23, 2018. Online. Last accessed on May 29, 2020
[4] Schumacher, Alexander, et al. “Changing R&D models in research-based pharmaceutical companies.” Journal of Translational Medicine. 2016.
[5] Proleukin (aldesleukin) Prescribing Information. Online. Last accessed on May 29, 2020.
[6] Tao Jiang, et al. “Role of IL-2 in cancer immunotherapy.” OncoImmunology. June 2016. Online. Last accessed on May 29, 2020.
[7] Kintzing, James R., et al. “Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment” Trends Pharmacological Science. December 2016. Online. Last accessed on May 19, 2020.
[8] Romualdo Barroso-Sousa, et al. “Transformation of Old Concepts for a New Era of Cancer Immunotherapy: Cytokine Therapy and Cancer Vaccines as Combination Partners of PD1/PD-L1 Inhibitors.” Current Oncology Reports. November 2018. Online. Last accessed on May 29,2020.
[9] Abul K Abbas, et al. “Revisiting IL-2: Biology and Therapeutic Prospects.” Science Immunology. July 2018. Online. Last accessed on May 29, 2020.
[10] Zhang Fan, et al. “Discussion About Several Potential Drawbacks of PEGylated Therapeutic Proteins.” Biological & Pharmaceutical Bulletin. 2014. Online. Last accessed on May 19, 2020.
[11] Swierczewska Magdalena, et al. “What Is the Future of PEGylated Therapies?” Expert Opinion on Emerging Drugs. 2015. Online. Last accessed on May 19, 2020.
12] Spencer Bliven, et al. “Circular Permutation in Proteins” PLoS Computational Biology. 2012. Online. Last accessed on May 29, 2020.

Advertisement