Emerging principles of cytokine pharmacology and therapeutics

Protein-based therapeutics have led to new paradigms in disease treatment. Projected to be half of the top ten selling drugs in 2023, proteins have emerged as rivaling and, in some cases, superior alternatives to historically used small molecule-based medicines. This review chronicles both well-established and emerging design strategies that have enabled this paradigm shift by transforming protein-based structures that are often prone to denaturation, degradation, and aggregation in vitro and in vivo into highly effective therapeutics. In particular, we discuss strategies for creating structures with increased affinity and targetability, enhanced in vivo stability and pharmacokinetics, improved cell permeability, and reduced amounts of undesired immunogenicity. 

Engineering protein-based therapeutics through structural and chemical design

Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-med-073118-011031

Engineering IL-2 to Give New Life to T Cell Immunotherapy

Cytokines have pivotal roles in immunity, making them attractive as therapeutics for a variety of immune-related disorders. However, the widespread clinical use of cytokines has been limited by their short blood half-lives and severe side effects caused by low specificity and unfavourable biodistribution. Innovations in bioengineering have aided in advancing our knowledge of cytokine biology and yielded new technologies for cytokine engineering. In this Review, we discuss how the development of bioanalytical methods, such as sequencing and high-resolution imaging combined with genetic techniques, have facilitated a better understanding of cytokine biology. We then present an overview of therapeutics arising from cytokine re-engineering, targeting and delivery, mRNA therapeutics and cell therapy. We also highlight the application of these strategies to adjust the immunological imbalance in different immune-mediated disorders, including cancer, infection and autoimmune diseases. Finally, we look ahead to the hurdles that must be overcome before cytokine therapeutics can live up to their full potential. Cytokines are key regulators of the immune system and can be recombinantly designed as therapeutics for immune-related disorders. However, the severe toxicity of recombinant cytokines limits their clinical translation. In this Review, the authors highlight bioengineering approaches for the design of clinically applicable and safe cytokine-based therapeutics. 

/pdf/engineering-cytokine-therapeutics-1tmsant7.pdf

Engineering cytokine therapeutics

Engineering interferons and interleukins for cancer immunotherapy.

The implementation of applied engineering principles to create synthetic biological systems promises to revolutionize medicine, but application of fundamentally redesigned organisms has thus far not impacted practical drug development. Here we utilize an engineered microbial organism with a six-letter semi-synthetic DNA code to generate a library of site-specific, click chemistry compatible amino acid substitutions in the human cytokine IL-2. Targeted covalent modification of IL-2 variants with PEG polymers and screening identifies compounds with distinct IL-2 receptor specificities and improved pharmacological properties. One variant, termed THOR-707, selectively engages the IL-2 receptor beta/gamma complex without engagement of the IL-2 receptor alpha. In mice, administration of THOR-707 results in large-scale activation and amplification of CD8+ T cells and NK cells, without Treg expansion characteristic of IL-2. In syngeneic B16-F10 tumor-bearing mice, THOR-707 enhances drug accumulation in the tumor tissue, stimulates tumor-infiltrating CD8+ T and NK cells, and leads to a dose-dependent reduction of tumor growth. These results support further characterization of the immune modulatory, anti-tumor properties of THOR-707 and represent a fundamental advance in the application of synthetic biology to medicine, leveraging engineered semi-synthetic organisms as cellular factories to facilitate discovery and production of differentiated classes of chemically modified biologics.

/pdf/an-engineered-il-2-reprogrammed-for-anti-tumor-therapy-using-wzshxm1tcj.pdf

An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism.

THOR-707, a novel not-alpha IL-2, promotes all key immune system anti-tumoral actions of IL-2 without eliciting vascular leak syndrome (VLS)

Aldesleukin is a recombinant form of IL-2 approved for metastatic melanoma and renal cell carcinoma that induced complete, durable remissions in certain patients. Yet, its use is infrequent because of vascular leak syndrome (VLS), a severe dose-limiting adverse event stemming from the engagement of the high affinity IL-2 receptor (IL-2R) alpha chain in type 2 innate lymphoid cells, eosinophils and vascular endothelial cells. THOR-707 is a site-directed, singly pegylated form of IL-2 completely lacking IL-2R alpha chain engagement yet retaining normal binding to the intermediate affinity IL-2R beta-gamma signaling complex expressed by natural killer (NK) and CD8+ T tumor-killing cells. We studied THOR-707 pharmacokinetics (PK) and pharmacodynamics (PD) in non-human primates (NHP) to evaluate peripheral biomarkers of immune cell activation (expansion of NK, CD8+ T and CD4+ regulatory T (Treg) cells and the induction of pSTAT5 and the proliferation marker Ki67). Here we show that in NHP, THOR-707 elicits the expansion of peripheral CD8+ T cells and the persistence of that response with different administration regimes. We also show that in the mouse syngeneic colon tumor model CT-26, THOR-707 induced Ki67 and the expansion of peripheral NK and CD8+ T cells. Within the tumor, THOR-707 promoted an increase in the numbers of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Immunohistochemical (IHC) analysis showed that in THOR-707 treated animals, CD8+ T cells were mostly seen around the edges of the tumor and at areas of necrosis. Evaluation of T cell receptor (TCR) clonality revealed that treatment with THOR-707 increased intra-tumoral T cell diversity compared to the untreated animals. THOR-707 induction of CD8+ T cell tumor infiltration resulted in single agent dose-dependent anti-tumor efficacy, and additive efficacy in combination with PD-1 checkpoint inhibitor, increasing the survival of CT-26 tumor-bearing mice over either group alone. The pharmacodynamics, T cell infiltration and clonality, and efficacy of THOR-707 in two additional syngeneic models, have also been studied. Filing of an investigational new drug application for THOR-707 is expected in the second quarter of 2019 and thereafter initiation of a Phase 1/2 clinical trial in multiple tumor types as a single agent and in combination with an immune checkpoint inhibitor. Citation Format: Ingrid B. Joseph, Lina Ma, Jerod L. Ptacin, Carolina E. Caffaro, Hans R. Aerni, Kristine M. San Jose, Michael J. Pena, Robert W. Herman, Yelena Pavlova, David B. Chen, Ken Bragstad, Shukuan Li, Jasmine Nguyen, Laura K. Shawver, Lilia K. Koriazova, Marcos E. Milla. THOR-707, a novel not-alpha IL-2, elicits durable pharmacodynamic responses in non-human primates and efficacy as single agent and in combination with anti PD-1 in multiple syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3258.

Abstract 3258: THOR-707, a novel not-alpha IL-2, elicits durable pharmacodynamic responses in non-human primates and efficacy as single agent and in combination with anti PD-1 in multiple syngeneic mouse models

2603Background: Recombinant interleukin-2 (rIL-2; aldesleukin) is an approved immunotherapy in melanoma and renal cell carcinoma based on complete durable remissions. The anti-neoplastic properties...

THOR-707: Using synthetic biology to reprogram the therapeutic activity of interleukin-2 (IL-2).

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Lina Ma

Author Tools

Chat about Author

Papers

An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism.

THOR-707, a novel not-alpha IL-2, promotes all key immune system anti-tumoral actions of IL-2 without eliciting vascular leak syndrome (VLS)

Abstract 3258: THOR-707, a novel not-alpha IL-2, elicits durable pharmacodynamic responses in non-human primates and efficacy as single agent and in combination with anti PD-1 in multiple syngeneic mouse models

THOR-707: Using synthetic biology to reprogram the therapeutic activity of interleukin-2 (IL-2).