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717 Selective activation of CD8+ T cells by a CD8-targeted IL-2 results in enhanced anti-tumor efficacy and safety
  1. Kelly Moynihan1,
  2. Danielle Pappas1,
  3. Terrence Park1,
  4. Wei Chen1,
  5. Irene Ni1,
  6. Paul Bessette1,
  7. Mike Chin1,
  8. Ton Schumacher2,
  9. Andy Yeung1 and
  10. Ivana Djuretic1
  1. 1Asher Biotherapeutics, South San Francisco, CA, United States
  2. 2The Netherlands Cancer Institute, Amsterdam, Netherlands


Background High-dose IL-2 induces complete responses in a subset of cancer patients, but severe toxicity, including vascular leak syndrome (VLS), limits its clinical potential. Insights into IL2Rα's role in the development of VLS sparked a wave of second-generation IL-2 molecules referred to as “not-α” IL-2s. Emerging clinical data suggests that although not-α IL-2s avoid VLS, they induce suboptimal monotherapy activity in patients. Given the observation that CD8+ T cells are the dominant effector cells with IL-2-based therapies,1 2 we hypothesized that maximizing the activity of IL-2 on CD8+ T-cells and limiting its activity on immunosuppressive Tregs and highly IL-2-sensitive innate populations would improve IL-2's efficacy and tolerability. We developed cis-targeted IL-2 (CD8-IL2) fusion proteins that selectively activate CD8+ T cells and have minimal activity on CD8-negative cells.

Methods In vitro selectivity of CD8-IL2 molecules was tested on primary immune cells including mouse splenocytes and human PBMCs. In vivo activity was evaluated in syngeneic tumor models and non-human primates.

Results Due to the 10–20x higher expression of IL2Rβ on NK cells over other lymphocytes, not-α IL-2 induced preferential NK cell expansion in mice. Toxicity-induced body weight loss with not-α IL-2 treatment was dependent on cells expressing NK1.1 but not CD8. To avoid overt activation of IL2Rβhigh NK cells, IL-2Rα-associated toxicity, and Treg activation, we generated cis-targeted fusion proteins consisting of anti-CD8 antibodies and IL-2 muteins with attenuated binding to IL2Rα and IL2Rβ. We demonstrated that CD8-IL2 fusions preferentially activated CD8+ T cells within mouse, human, and cynomolgus immune populations, with 100–1000 fold selectivity over NK cells and Tregs for all three species. Selective expansion of CD8+ T cells over NK cells and Tregs was demonstrated in tumor and peripheral blood compartments in mice. Selective CD8+ T cell expansion was also demonstrated in cynomolgus monkeys. Furthermore, a single dose of CD8-IL2 in mice elicited strong monotherapy efficacy in MC38 tumors, with a majority of mice demonstrating complete responses without detectable body weight loss at doses that were well tolerated in cynomolgus monkeys. In contrast, not alpha IL-2 induced >10% body weight loss prior to reaching efficacious doses in mice and did not drive any complete anti-tumor responses.

Conclusions CD8-targeted IL-2 has superior efficacy and lower toxicity compared to second-generation not-α IL-2. Development of AB248, a novel CD8-targeted IL-2 molecule is underway.


  1. Rakhmilevich A, North R. Elimination of CD4+ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2. Cancer Immunol Immunother 1994;38(2):107–12.

  2. Sun Z, Ren Z. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control. Nat Commun 2019;3874:1–12.

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