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576 NL-201, a de novo IL-2 and IL-15 agonist, demonstrates enhanced in vivo antitumor activity in combination with multiple cancer immunotherapies
  1. Carl Walkey,
  2. Ryan Swanson,
  3. Umut Ulge,
  4. Daniel Adriano Silva Manzano and
  5. Jonathan Drachman
  1. Neoleukin Therapeutics, Seattle, WA, USA


Background NL-201 is a de novo IL-2 and IL-15 receptor agonist designed with enhanced affinity for IL-2Rβγ and no binding interface for IL-2Rα (CD25). Previously, we reported that NL-201 stimulates selective proliferation of CD8+ effector T cells and NK cells, leading to increased CD8:Treg and NK:Treg ratios in the tumor microenvironment. As a result, NL-201 treatment led to robust single-agent antitumor activity in syngeneic murine tumor models at well-tolerated doses.

Methods Here, we evaluated the antitumor activity of NL-201 in combination with established and exploratory cancer immunotherapies, including tumor-targeting monoclonal antibodies and immune checkpoint inhibitors (CPIs). Specifically, we evaluated NL-201 in combination with an anti-gp75 antibody (TA99) in a murine melanoma model, or anti-PD-1 and anti-PD-L1 antibodies in a CPI-resistant murine colon cancer model.

Results NL-201 synergizes with TA99, anti-PD-1, and anti-PD-L1 to inhibit tumor growth more effectively than either agent alone. The synergy of NL-201 with TA99 may result from enhanced NK-mediated antibody-dependent cellular cytotoxicity (ADCC), while the synergy with CPIs may result from CD8+ T cell stimulation, which can turn ‘cold’ tumor microenvironments ‘hot’.

Conclusions The broad activity of NL-201 across diverse tumor models and its potential to be combined with a variety of established and exploratory cancer immunotherapies to achieve synergistic antitumor activity highlights the opportunity for NL-201 to become a critical component of future immunotherapy regimens.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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