Author: Lin, John C ; Ullman, Erica ; Antao, Olivia Q. ; Krueger, Pamela ; Yancopoulos, George D. ; Murphy, Andrew J ; Wang, Qingqing ; Ahmed, Hassan ; Garg, Vidur ; Chang, Aaron Y. ; Dudgeon, Drew ; DiLillo, David J ; Yan, Yuetian ; Olson, William C ; DiLillo, David J. ; Davis, Samuel ; Bhavsar, Ramandeep ; Wei, Yi ; Olson, William C. ; Mohrs, Katja ; Patel, Supriya ; Huang, Tammy ; Zhang, Tong ; Antao, Olivia Q ; Amatulli, Michael ; Yancopoulos, George D ; Hermann, Aynur ; Wang, Shunhai ; Ramos, Willy ; Vazzana, Kristin ; Ni, Min ; Wu, Jiaxi ; Murphy, Andrew J. ; Adler, Christina ; Smith, Eric ; Bloch, Nicolin ; Chang, Aaron Y ; Guo, Chunguang ; Macdonald, Lynn ; Crawford, Alison ; Lin, John C.

The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8⁺ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1⁺ T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and "α-maintained" IL-2 therapy for cancer.

01 Jul 2024·International Immunopharmacology

Site-specific pegylated IL2 mutein with biased IL2 receptor binding for cancer immunotherapy

Article

Author: Gai, Yanan ; Leong, Sirou Grace ; Meng, Xiuhua ; Chen, Jian ; Dong, Xianchi ; Jian, Tunyu ; Tong, Bei ; Ding, Xiaoqin ; Niu, Guanting ; Lv, Han

While Interleukin 2 (IL2) has the capability to activate both NK and T cells robustly, its limited in vivo half-life, considerable toxicity, and tendency to boost Treg cells pose significant challenges, restricting its widespread application in cancer therapy. In this investigation, we engineered a novel IL2 variant (IL2-4M-PEG) with reduced CD25 binding activity and an extended half-life by substituting amino acids associated with CD25 binding and implementing site-directed PEGylation. IL2-4M-PEG notably amplifies effector cells over Treg cells. Furthermore, our findings reveal that IL2-4M-PEG, characterized by an extended half-life, exhibits anti-tumor effects in a mouse model. Consequently, this innovative IL2 holds the potential for enhancing combined cancer therapies in the future.

01 Jul 2024·Cancer Discovery

Targeted Bias: The Next Swing at IL2 Therapy

Article

Author: Kulhanek, Kayla R. ; Kalbasi, Anusha

Summary:Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells.See related article by Moynihan et al., p. 1206 (6).See related article by Kaptein et al., p. 1226 (7).

100 Deals associated with IL-2(Shanghai Xinshengyuan Biological Medicine Co. Ltd.)

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2012 Manual	Phase 1/2	Metastatic melanoma	12	TG1042+TIL+IL2	(ybjzwhploc) = uytkrabefi nhfmqpzpgf (flgygsusqf ) View more	Positive	20 May 2012
IAS2004	Not Applicable	Immune Reconstitution Inflammatory Syndrome	-	Enfuvirtide(T20)	(ltgbskxidd) = cqyfttdeao qepuqjtugc (xnxolepvvn )	-	01 Jan 2004
IAS2004	Not Applicable	Immune Reconstitution Inflammatory Syndrome	-	Interleukin-2(IL2)	(ltgbskxidd) = flbgycqqlh qepuqjtugc (xnxolepvvn )	-	01 Jan 2004

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