mAbs · Available online 2 Aug 2026 · In press · DOI 10.1080/19420862.2026.2709956
Chunyin Gu, Deyi Wang, Yan Wang, Fangfang Jia, Fu Zhou, Shun Chang, Kedong Ouyang, Yu Zhao, Linlin Liu, Huawei Zhang, Peipei Liu, Haixiang Yu, Xiaodan Cao, Taylor B. Guo, Huanzhang Xia
PD-1-based immunocytokines, such as interleukin (IL)-2 fused with anti-PD-1, have been designed to increase efficacy, but their use is hampered by dose-limiting toxicity. To overcome this, substantial efforts have focused on engineering attenuated IL-2 variants, albeit with limited success to date. Taking an alternative approach, we screened a naïve alpaca library for weak agonistic nanobodies of IL-2/15Rβ and the common γ chain and attached a potent anti-PD-1 IgG to generate a tri-specific antibody JMB2403. JMB2403 did not bind IL2Rα (CD25), but activated STAT5 phosphorylation in an engineered Jurkat cell reporter assay albeit far less potently compared to wildtype IL-2. This translated to a JMB2403-induced pSTAT5 increase in natural killer (NK) cells, but minimal STAT5 phosphorylation in Treg cells. Notably, JMB2403 retained PD-1 blocking activity and concentration-dependently induced phospho-STAT5 only in activated (PD-1high) but not in non-activated CD8+ T cells, indicating cis-action mediated by PD-1 engagement. In A375 (melanoma) and NCI-H292 (lung cancer) xenograft models, JMB2403 exhibited superior anti-tumor efficacy compared to its parental PD-1 antibody. In a cynomolgus monkey study, JMB2403 produced a dose-dependent increase in the proliferation of CD8+ T cells, PD-1+ CD8+ T cells, Treg cells, and NK cells after the first dose which returned to baseline before the second dose. No IL-2-related toxicities such as vascular leak syndrome or pulmonary edema were observed. In summary, JMB2403 can induce cis-activation of PD-1+ T cells and display enhanced anti-tumor efficacy with good tolerability. To our knowledge, this is the first tri-specific antibody of its kind that targets specifically IL2/15 receptor signaling subunits.
Abstract from DOAJ. Public domain (CC0 1.0).
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Gu, C., Wang, D., Wang, Y., et al. (2026). JMB2403, a potential best-in-class PD-1-dependent IL2Rβγ-activating tri-specific antibody for safe and potent immunotherapy. mAbs. https://doi.org/10.1080/19420862.2026.2709956