The Goldilocks Solution: Uncoupling CD137 Agonism from Hepatotoxicity via Nanoparticle-Mediated Ligand Multimerization

The clinical history of CD137 (4-1BB) agonism is a tale of two extremes. On one side stands urelumab, an antibody with tremendous potency that failed due to severe, dose-limiting hepatotoxicity. On the other stands utomilumab, a molecule with an excellent safety profile but insufficient clinical efficacy. This "Goldilocks dilemma", finding a therapeutic that is potent enough to drive tumor regression yet safe enough to spare the liver, has stalled the progress of TNFRSF9-targeted therapies for years.

In a 2026 study published in Theranostics, Lee et al. propose a bioengineering solution that may finally resolve this impasse. By conjugating recombinant human CD137 ligand (rhCD137L) to mesoporous silica nanoparticles (MSNs), the researchers created a multimeric agonist that outperforms clinical benchmark antibodies in potency while completely avoiding their characteristic liver toxicity.

The Engineering Logic: Mimicking and Amplifying Physiology

The physiological signaling unit of CD137 is a homotrimer. Soluble ligands or bivalent antibodies often fail to induce the higher-order clustering required for robust TNFR signaling, or they rely on Fc-gamma receptor crosslinking, which drives off-target toxicity.

Lee et al. utilized MSNs approximately 50 nm in diameter as a scaffold to present high-density arrays of rhCD137L. Optimization studies revealed that a specific ratio of ligand-to-nanoparticle (conjugating 20 micrograms of rhCD137L to 6.4 x 1010 MSNs) was critical; excessive loading caused protein aggregation and loss of function, while optimal loading facilitated the formation of a durable "signalosome".

Clinical Benchmarking: The Role of ichorbio Reagents

To validate the translational relevance of their platform, the authors required rigorous comparisons against the current clinical standards. The study utilized specific reagents from ichorbio to establish these baselines:

Urelumab (Agonistic anti-CD137): Used as the high-potency positive control.
Utomilumab (Agonistic anti-CD137): Used as the high-safety/low-potency comparator.
Human IgG4 Isotype Control: Used to establish baseline immune activity.

These reagents were crucial for the study's validity. The authors compared their rhCD137L-MSNs against both soluble ichorbio antibodies and MSN-conjugated versions (ure-MSN and uto-MSN).

Key Comparative Findings:

In Vitro Potency: At equal molar concentrations of receptor binding sites, rhCD137L-MSNs induced significantly higher T-cell cytotoxicity against nasopharyngeal carcinoma (NPC) cell lines than soluble urelumab or utomilumab.
Superiority over ADCC-dependent formats: Even when urelumab was conjugated to MSNs (ure-MSN) to mimic the multimerization effect, the rhCD137L-MSN formulation still elicited superior tumor control and T-cell infiltration in vivo.

Mechanism of Action: Dual Targeting of the "Cold" Tumor

A unique feature of this study is the focus on Nasopharyngeal Carcinoma (NPC), a malignancy where tumor cells often ectopically express CD137. The authors hypothesized that CD137 on tumor cells acts as a "sink" that strips CD137L from antigen-presenting cells via trogocytosis, dampening immunity.

The rhCD137L-MSNs turn this immune evasion mechanism into a therapeutic advantage. The nanoparticles act as a bridge, anchoring to CD137-expressing tumor cells while simultaneously engaging CD137 on cytotoxic T cells. This dual-targeting mechanism creates a dense immunological synapse, effectively converting the tumor cell into a scaffold for T-cell hyper-activation. Consequently, the study found that rhCD137L-MSNs were significantly more effective against CD137-positive NPC variants (C666-CD137) than CD137-deficient controls.

The Hepatotoxicity Breakthrough

The most significant finding for the broader field of immunotherapy is the safety profile. In humanized mouse models, treatment with ure-MSNs (MSNs conjugated with the ichorbio urelumab biosimilar) recapitulated the severe hepatotoxicity seen in human trials, causing extensive hepatocyte necrosis, steatosis, and 100% mortality/endpoint-reaching by day.

In stark contrast, mice treated with rhCD137L-MSNs showed no signs of liver damage, maintained healthy body weight, and exhibited liver histology comparable to PBS-treated controls. This confirms that the toxicity of antibody-based agonists is likely driven by Fc-gamma receptor-mediated hyper-crosslinking on Kupffer cells and sinusoidal endothelium, a mechanism that the Fc-free rhCD137L-MSN design successfully circumvents.

Implications for the Cancer Field

Revival of TNFSF Agonists: This study provides a blueprint for targeting other members of the TNF superfamily (e.g., OX40, GITR, CD40) where antibody development has been hindered by similar toxicity/potency trade-offs.
Importance of Valence: The data suggests that high-order multimerization (beyond trimerization) via nanoparticle scaffolds may be necessary to achieve optimal signaling for these receptor types, superior to standard bivalent antibodies.
Tumor-Intrinsic Biomarkers: The study highlights CD137 expression on tumor cells not just as a marker of malignancy, but as a handle for targeted drug delivery and immune bridging

Conclusion

The MSN-based ligand delivery platform represents a significant advancement in TNFRSF agonism, effectively decoupling therapeutic efficacy from systemic toxicity. By replacing traditional antibody-based approaches with localized, multivalent ligand presentation, this strategy addresses the critical limitations of conventional immunotherapy.

Mechanistic Validation: The enhanced safety profile of ure-MSNs is fundamentally attributed to the omission of the Fc domain. Data from Fc\gamma RIIb-/- models confirm that bypassing Fc-receptor-mediated hepatic sequestration is essential for mitigating off-target hepatotoxicity.

Combinatorial Potency: The modularity of the MSN architecture facilitates synergistic interventions, specifically the integration of CD137 agonism with PD-1/PD-L1 blockade. This dual-action approach effectively transitions immunologically "cold" microenvironments into "hot" niches via simultaneous T-cell priming and checkpoint disinhibition.

Translational Versatility: This "bridging" mechanism proves scalable across a broad oncological spectrum, including solid tumors and hematological malignancies expressing TNFRSF members.

In summary, this research establishes a robust, modular framework for the clinical translation of costimulatory agonists, providing a high-affinity delivery system that maximizes the therapeutic index.

Reference: Lee, K. Y., et al. (2026). Development of a nanoparticle-based immunotherapy targeting CD137 for nasopharyngeal carcinoma treatment. Theranostics, 16(1), 17-36. 23