DUBLIN – The concept of harnessing interleukin-2 (IL-2) signaling to boost immune responses to cancer is almost as old as the biotechnology industry. Up until now, however, the idea has only been imperfectly realized because of the limitations of using recombinant IL-2.
The flagship IL-2 product, Proleukin (aldesleukin), gained approval in metastatic renal cell carcinoma (RCC) in 1992 and in metastatic melanoma in 1998 on the strength of its complete response rates of 7 percent and 6 percent, respectively. But its commercial and clinical potential have been limited by its narrow therapeutic window and by the necessity of having access to intensive care facilities.
Although Proleukin is a potent T-cell activator, it is burdened with numerous drawbacks. It has a short half-life, which necessitates intravenous infusion three times daily; it causes neutrophil impairment, which increases the risk of bacterial endocarditis and sepsis; and it can induce capillary (also called vascular) leak syndrome, a potentially catastrophic loss of fluid and proteins from the vasculature into the surrounding tissues. An additional complication of IL-2 therapy is its stimulatory effect on regulatory T cells (Treg cell) as well as on cytotoxic T cells.
Swiss startup Anaveon is one of a clutch of companies to revisit IL-2-based immunotherapy, armed with new biological insights, which, it hopes, will enable it to capture the benefits of IL-2 signaling while minimizing the harmful consequences. It has secured significant backing for its strategy and its science. The Zurich-based company has just raised CHF35 million (US$35 million) in a series A round to develop selective IL-2 receptor agonists to act as immune adjuvants.
Co-founder Onur Boyman, who chairs the department of immunology at the University of Zurich in Switzerland, has played a prominent role in unpicking important aspects of IL-2 signaling over much of the past decade and a half. Back in 2006, Boyman and colleagues reported that IL-2-antibody complexes could, depending on their composition, selectively boost either CD8 T-cell or Treg cell populations. That initial insight enabled them – and others – to unlock further details of how IL-2 mediates its multiple effects.
The IL-2 receptor (IL-2R) comprises three polypeptide chains, alpha (CD25), beta (CD122) and gamma (CD132), different forms of which bind IL-2 with differing affinities. The high-affinity receptor comprises all three chains associating in a heterotrimeric configuration; the intermediate-affinity receptor consists of the beta and gamma chains; and the low-affinity receptor comprises the alpha chain only. Selective targeting of different receptors can have significantly different downstream consequences.
For example, Boyman's lab reported in 2010 that IL-2-induced pulmonary edema – caused by vascular leak syndrome – was due to direct binding of IL-2 to the high-affinity IL-2R expressed on lung endothelial cells. The antitumor effects of IL-2, in contrast, were mediated by the cytokine activating the intermediate-affinity IL-2R, which is highly expressed on CD8 cytotoxic T cells and natural killer cells. Additional work has identified the IL-2R alpha chain – or CD25 – as the main culprit for inducing vascular leak syndrome, as well for inducing a Treg cell response to IL-2 activation. Although it does not actively signal, CD25 greatly increases the binding affinity of IL-2 to the heterotrimeric form of IL-2R.
Aiming for best in class
Anaveon was established in late 2017 by Boyman and CEO Andreas Katopodis, former director of autoimmunity, transplantation and inflammation at the Basel lab of the Novartis Institutes of Biomedical Research, to translate the research tools and insights Boyman developed into drug candidates. The most advanced was described in a 2017 paper in the Nov. 30, 2016, issue of Science Translational Medicine. It consists of a complex comprising IL-2 and a CD25-directed antibody, NARA1, which was difficult to obtain. "People have tried before. It was only Boyman's lab in the end that succeeded," Katopodis told BioWorld.
The combination selectively triggers a CD8-positive T-cell response, while damping down the Treg cell response. As well as eliciting the desired form of immune activation, the complex has an antibody-like half-life due to the presence of the antibody. "These are very tight complexes that behave like a single molecule," Katopodis said. The absence of CD25 binding also cuts its toxicity – by five- to 10-fold in animal models, he said.
The company now has enough cash to conduct a high-quality phase I/IIa study, although it has not yet decided on the precise design. "We are about a year and a half from the clinic," Katopodis said. Although it will need to demonstrate activity as a monotherapy, the complex's future lies in combination settings. "I see it more as an incredibly useful adjuvant, which will dial up just about any immuno-oncology approach," he said. "We firmly believe we have a best-in-class [molecule]. We need to show we have a best in class."
Several other novel approaches to IL-2 stimulation are at varying stages of development. Bempegaldesleukin (NKTR-214), a pegylated form of IL-2, which San Francisco-based Nektar Therapeutics Inc. is developing, is in phase III combination trials in RCC and melanoma with the PD-1 inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.). La Jolla, Calif.-based Synthorx Inc. grossed $131 million in an IPO in December to take forward its IL-2 variant, THOR-707, for which it plans to file an IND in the second half of this year. That molecule incorporates an unnatural amino acid residue at a specific location, which allows for site-specific attachment of polyethylene glycol. As with bempegaldesleukin, the modification not only increases the molecule's half-life, it also blocks its interaction with the CD25 receptor.
A newer venture, Neoleukin Therapeutics Inc., has been formed around a computational approach for recapitulating the binding sites of IL-2 and other cytokines in unrelated protein structures. The group, based at the Institute for Protein Design, at the University of Washington in Seattle, described the development of an IL-2 mimic that selectively binds the IL-2R-alpha-beta-c heterodimer in a paper published in the Jan. 9, 2019, issue of Nature.