JMB2403, a potential best-in-class PD-1-dependent IL2Rβγ-activating tri-specific antibody for safe and potent immunotherapy.
JMB2403 shows promise in activating T cells and enhancing anti-tumor efficacy without significant IL-2-related toxicities, but further research is needed to confirm these findings in humans.
Where it sits
this study against the rest of the tb-500 (thymosin beta-4 fragment) corpusSummary and findings
This study investigates the tri-specific antibody JMB2403, designed to activate IL2Rβγ and block PD-1, in various models. The antibody was tested in engineered Jurkat cells and xenograft models for anti-tumor efficacy and immune cell activation. The results indicated a dose-dependent increase in CD8+ T cell proliferation without IL-2-related toxicities.
Abstract
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-1<sup>high</sup>) but not in non-activated CD8<sup>+</sup> T cells, indicating <i>cis</i>-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<sup>+</sup> T cells, PD-1<sup>+</sup> CD8<sup>+</sup> 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 <i>cis</i>-activation of PD-1<sup>+</sup> 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.
Background
This paper addresses the limitations of PD-1-based immunocytokines, particularly the dose-limiting toxicities associated with IL-2. Prior research has focused on engineering attenuated IL-2 variants, but with limited success. The introduction of JMB2403 aims to provide a novel approach to enhance anti-tumor efficacy while minimizing toxicity.
Methods
The study utilized a naïve alpaca library to screen for weak agonistic nanobodies of IL-2/15Rβ and the common γ chain, which were then combined with an anti-PD-1 IgG to create JMB2403. The antibody was tested in engineered Jurkat cell assays and xenograft models, with primary outcomes focusing on STAT5 activation and anti-tumor efficacy.
Results
JMB2403 was shown to activate STAT5 phosphorylation in Jurkat cells, albeit less potently than wildtype IL-2. In xenograft models, it demonstrated superior anti-tumor efficacy compared to the parental PD-1 antibody. In cynomolgus monkeys, a dose-dependent increase in CD8+ T cell proliferation was observed after the first dose.
Interpretation
The findings suggest that JMB2403 may provide a novel mechanism for activating PD-1+ T cells with enhanced anti-tumor effects. However, the clinical significance of these results remains uncertain, particularly given the reliance on preclinical models and the absence of human data. The lack of observed IL-2-related toxicities is noteworthy but requires further investigation in human trials.
Key findings
- JMB2403 induced phospho-STAT5 in activated CD8+ T cells but not in non-activated cells.
- In A375 and NCI-H292 xenograft models, JMB2403 exhibited superior anti-tumor efficacy compared to its parental PD-1 antibody.
- In cynomolgus monkeys, JMB2403 produced a dose-dependent increase in CD8+ T cell proliferation after the first dose, returning to baseline before the second dose.
- No IL-2-related toxicities such as vascular leak syndrome or pulmonary edema were observed.
Limitations
- Preclinical study with no human data.
- Small sample size in animal models.
- Short follow-up period in cynomolgus monkey study.
- Potential confounding factors not controlled for in xenograft models.