NL-201: CD25-Independent IL-2/IL-15 Agonist Immunotherapy

NL-201 is believed to be the first computationally-designed de novo protein therapeutic to enter clinical development.

IL-2 is a powerful immune-stimulating cytokine. Recombinant IL-2 (aldesleukin) has been used to treat cancer, but its toxicity has greatly limited clinical application.

In the body, IL-2’s effects are mediated by interactions with a receptor that has three parts: alpha (CD-25), beta (CD122), and gamma (CD132). The toxicity of IL-2 is exacerbated by its interaction with CD25. For decades, protein engineers have been searching for ways to limit IL-2’s interaction with CD25. While these approaches have yielded some success, they have been hampered by IL-2 naturally high affinity for CD25.

By applying the innovative Neoleukin Platform, Neoleukin’s scientists have succeeded in creating a protein that potently stimulates IL-2 signaling without any binding to CD25. This protein, NL-201, interacts exclusively with the beta and gamma chains of the IL-2 receptor to selectively expand anti-tumor effector T-cells. In addition, because IL-15 shares the same beta/gamma chains as IL-2, NL-201 has full IL-15 activity, enabling the simultaneous expansion of anti-tumor NK cells.

NL-201 is designed for use as a single-agent or in combination with complementary therapeutic modalities. NL-201 has also shown promise in combination with allogenic cell therapy to expand and maintain populations of transplanted CAR-T and NK cells. Detailed technical information about this program is available in “De novo design of potent and selective mimics of IL-2 and IL-15” published in Nature (2019).

NL-201 is the only IL-2/IL-15 agonist designed without a CD25 binding interface

IL-2 vs NEO-201image


The Neoleukin research team has investigated the Neoleukin Platform for design of de novo cytokine receptor agonists and antagonists for multiple targets of interest.


Cytokine signaling is central to the regulation of the immune response to cancer. Neoleukin’s first program, NL-201, is focused on the expansion of anti-tumor T and NK cells in patients. Beyond NL-201, Neoleukin scientists have explored de novo cytokine mimetics that agonize or inhibit other important immunological pathways. They have harnessed the unique properties of de novo proteins to develop targeted and conditionally-active cytokine receptor agonists that have the potential for enhanced specificity and activity in some tumor types.

Autoimmunity & Allergy

Dysregulated cytokine receptor signaling plays a critical role in the initiation and progression of many autoimmune and allergic diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, and atopic dermatitis. Neoleukin scientists have explored de novo cytokine mimetics to enable the restoration of balance in cytokine receptor signaling to ameliorate autoimmune and allergic diseases. In addition, Neoleukin scientists have explored ways to take advantage of the unique properties of de novo proteins to enable more potent and patient-friendly methods of administration as compared to traditional biologics.