Abstract 4335: JMB2403, a potential best-in-class PD-1-dependent IL2Rβγ-targeting tri-specific antibody for safe and potent immunotherapy

Abstract Despite the success of PD-1 axis blockade in cancer immunotherapy, it is met with limited efficacy and relapse. Addition of interleukin-2 (IL-2) may enhance treatment efficacy but its use is hampered by a severe toxicity profile. To simultaneously circumvent resistance to checkpoint inhibition and unlock the full therapeutic potential of cytokine-based immunotherapy, numerous groups have sought to engineer an attenuated or biased IL-2 in an anti-PD(L)1/IL2 molecule with limited success thus far. 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 (KD = 0.18 nM) to generate a tri-specific antibody (JMB2403, also known as 2403T62). JMB2403 retained PD-1 blocking activity and potently activated T cells. JMB2403 did not bind IL2Rα (CD25), but activated STAT5 signaling in an engineered Jurkat cell reporter assay albeit at 500-fold lower levels compared to wild type IL-2. This translated to a JMB2403-induced pSTAT5 increase in NK cells but minimal STAT5 phosphorylation in Treg cells. Notably, JMB2403 concentration-dependently induced phospho-STAT5 only in activated (PD-1+) but not in resting CD8+ T cells, indicating cis-action mediated by PD-1 engagement. In an A375 (melanoma) xenograft model, JMB2403 (4 mg/kg, i.p., twice weekly) exhibited superior anti-tumor efficacy (complete regression in 7 out of 8 animals) than its parental PD-1 antibody as well as pembrolizumab. In contrast, treatment of a clinical-stage PD-1-IL2 fusion protein at equimolar dose failed to elicit any complete responses and caused one death. In an NCI-H292 (lung cancer) model, JMB2403 (4 mg/kg, i.p., twice weekly) strongly inhibited tumor growth with complete response in 6 out of 7 animals. The minimal efficacious dose was 0.13 mg/kg. In a cynomolgus monkey study, treatment of JMB2403 at 4, 12 and 30 mg/kg i.v. on day 1 and day 15 produced a dose-dependent increase in proliferating CD8+ T cells, PD-1+ CD8+ T cells, Treg cells and NK cells were observed after the first dose which returned to baseline before the second dose. Safety wise, no abnormalities were reported in any animals especially known IL-2-related toxicities such as vascular leak syndrome and pulmonary edema. In summary, JMB2403 can induce cis-activation of PD-1+ T cells and display superior 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. Citation Format: Chunyin Gu, Deyi Wang, Yan Wang, Fangfang Jia, Fu Zhou, Shun Chang, Yu Zhao, Linlin Liu, Huawei Zhang, Peipei Liu, Xiaodan Cao, Taylor B. Guo. JMB2403, a potential best-in-class PD-1-dependent IL2Rβγ-targeting tri-specific antibody for safe and potent immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4335.