On August 7, 2023 Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune, ophthalmology and other major diseases, reported that the preclinical results of IBI363 were published in Nature Cancer (IF=22.7). The publication entitled, "IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells" (Press release, Innovent Biologics, AUG 7, 2023, View Source [SID1234633889]).

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Interleukin 2 (Interleukin-2, IL-2) is the first cytokine to be discovered and identified as playing a pivotal role in T-cell growth and expansion. Aldesleukin (IL-2) was approved by U.S. Food and Drug Administration for metastatic renal cell carcinoma and metastatic melanoma in the early 1990s, but it has not been widely used in clinic due to poor selectivity, narrow therapeutic window, and side effects. As a bi-functional cytokine, IL-2 can not only activate CD4+ regulatory T cells (Treg) via interaction with IL-2 receptor αβγ to suppress the immune system, but also stimulate CD8+ T cells and natural killer cells via its interaction with IL-2 receptor βγ to exert its anti-tumor effects. Most developers use the approach of eliminating IL-2 and IL-2 receptor α (IL-2Rα) as a strategy to reduce Treg activation while maximizing the anti-tumor effect of IL-2. However, these "not-α" IL-2 muteins performed poorly in clinical studies. The published manuscript describes the mechanism underlying this discrepancy. The major observations include:

In comparison with "not-α" IL-2, α-biased IL-2 which retains intact IL-2Rα (CD25) binding showed superior anti-tumor efficacy and lower toxicity in multiple murine tumor models.
In tumor, α-biased IL-2 can more effectively activate tumor-specific T cells (TSTs) because TSTs highly express CD25, which increases their interactions with α-biased IL-2. In contrast, "not-α" IL-2 is prone to expand CD25 negative bystander T cells, and this limits its anti-tumor efficacy. In the periphery, "not-α" IL-2 can significantly expand peripheral T cells, while α-biased IL2 preferentially expand peripheral Treg to restrain systemic toxicity.
Intratumoral CD25+PD-1+CD8+ T cells exert more potent polyfunctionalities, including secreting effector molecules such as IL-2, IFN-γ, TNF-α and GZMB, than CD25-PD-1+CD8+ and CD25-PD-1+CD8- T cells. CD25-blocking or IL-2-neutralizing antibodies can limit the activation of TSTs and negatively affect the anti-tumor effects of PD-1 blockade.
The corresponding author, Dr. Kaijie He of Innovent Biologics stated, "We are very pleased that the results of this study are published and highlighted in the current issue of Nature Cancer. IL-2 is one of the most important cytokines in immune-oncology, but the mechanism of action underlying its potent antitumor activity is still elusive. In this study, we propose a previously underappreciated function of CD25 in regulating IL-2 autocrine signaling in TST cells to exert their antitumor functions, and challenge the "IL-2 dogma" that has dominated the whole field in the past decades, suggesting a new approach to designing safer and more effective IL-2 drugs. At the same time, this study also proposes to use "IL-2 signature" as a novel biomarker to predict the clinical benefits of anti-PD-1 antibody in cancer patients, and provides scientific rationales of combining IL-2 and PD-1 antibody in individuals who do not respond to PD-1 blockade. Based on the findings of this study, we designed IBI363, a PD-1/IL-2 bispecific antibody fusion protein, to expand and re-invigorate the TST cells in the cold tumors and overcome resistance to PD-1 antibodies in certain populations. At present, IBI363 is in clinical Phase 1 studies to evaluate the safety and preliminary antitumor efficacy in cancer patients who have failed or are not suitable for anti-PD-1 treatment. "

IBI363 is a potential First-in-Class candidate drug independently developed by Innovent. Its active ingredient is PD-1/IL-2 bispecific antibody fusion protein. The IL-2 arm of IBI363 has been engineered to maximize efficacy and reduce toxicity, whereas the PD-1 binding arm achieves PD-1 blockade and selective IL-2 delivery. Therefore, IBI363 has both functions of simultaneously blocking PD-1/PD-L1 pathway and activating IL-2 pathway, allowing more precise and efficient targeting and activation of tumor specific T cells. IBI363 not only showed promising anti-tumor activity in a variety of tumor-bearing pharmacological models, but also exhibited prominent antitumor efficacy in PD-1 resistant and metastatic models; meanwhile, IBI363 demonstrated a good safety profile in preclinical models. Currently, Phase 1 studies of IBI363 are conducted in China and Australia to assess the safety, tolerability, and preliminary efficacy in subjects with advanced solid tumors or lymphoma.