4:44 PM
Jan 10, 2019
 |  BC Extra  |  Preclinical News

UW team builds protein that avoids IL-2 toxicities, forms Neoleukin to develop

University of Washington researchers published a Nature paper Wednesday detailing the construction of a synthetic protein that selectively binds to IL-2 to avoid toxicities that have previously overshadowed interest in the receptor as a therapeutic target. Several of the study authors have formed Neoleukin Therapeutics Inc. (Seattle, Wash.) to develop the synthetic protein, dubbed NEO-201.

Because the IL-2 receptor has two variants expressed on different cell types, targeting the receptor can lead to severe toxicities, including life-threatening pulmonary edema, hypotension and capillary leak syndrome. Binding to the intermediate-affinity form -- comprising CD122 and CD132 -- found on CD8+ T cells and NK cells stimulates proliferation and activation of the tumor-killing cells. But IL-2 preferentially binds high-affinity receptors, which include CD25, on Tregs, inducing proliferation of the immunosuppressive cells and potentially counteracting the effects of the cytotoxic T and NK cells (see "Clever Pegylation Pay Off").

To mitigate IL-2 toxicities and retain efficacy, the University of Washington group used computational modeling and interaction data of helices isolated from IL-2 and IL-15 to construct NEO-201, a synthetic protein that binds to CD122 and CD132, but not CD25.

It showed that NEO-201 bound with a higher affinity to the CD122 and CD132 receptor complex than natural IL-2 cytokines, was hyper-stable and did not lose binding affinity even when incubated at high temperatures.

In a mouse model of melanoma, NEO-201 plus an anti-TYRP1 mAb reduced tumor growth and toxicity compared with IL-2 plus the mAb. Mice treated with the natural protein eventually required euthanasia due to decline in overall health.

NEO-201 also increased the intratumoral CD8+:Treg cell ratio, which is known to correlate with effective antitumor immune responses, and reduced tumor growth in a mouse model of colon cancer.

Neoleukin has hired Jonathan Drachman, the former CMO of Seattle Genetics Inc. (NASDAQ:SGEN), as CEO. Study authors Daniel-Adriano Silva, Shawn Yu, Umut Ulge, Alfredo Quijano-Rubio, Carl Walkey and David Baker are co-founders of the company. The University of Washington has previously spun out several companies from Baker’s lab, including Virvio Inc. (Seattle, Wash.), which is developing artificial mini proteins to treat influenza (see “Artificial Mini Proteins”).

Other groups have employed different methods to solve IL-2 toxicity.

Nektar Therapeutics (NASDAQ:NKTR) used pegylation to develop NKTR-214, an immunostimulatory cytokine engineered to selectively activate CD122 on CD8+ T cells and NK cells.

Stanford University's Christopher Garcia has suggested that synthetic IL-2 cytokine-receptor pairs could improve T cell therapies by mitigating toxicities and off-target effects of IL-2 as an adjuvant (see "Synthetic IL-2 Cytokine-Receptor Pairs Could Improve T Cell Cancer Therapies").

CD25 - Interleukin 2 receptor α chain; CD122 (IL2RB) - Interleukin 2 receptor β chain; CD132 (IL2RG) - Interleukin 2 receptor γ chain; TYRP1 - Tyrosinase related protein 1

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