Related Experiment Video
Updated: Oct 27, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and
Cecile Geuijen1, Paul Tacken1, Liang-Chuan Wang2
1Merus NV, Utrecht, The Netherlands.
Abstract:
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.
Insights
A novel bispecific antibody, MCLA-145, enhances T cell activation and anti-tumor activity, offering a potentially safer and more effective cancer immunotherapy option. This approach overcomes limitations of current immune checkpoint inhibitors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but benefit only a subset of patients.
- Preclinical studies suggest combining CD137 agonists with ICIs enhances anti-tumor effects, yet clinical translation is hindered by toxicity.
Purpose of the Study:
- To develop a novel bispecific antibody, MCLA-145, targeting CD137 and PD-L1 to improve anti-tumor immunity.
- To evaluate the efficacy and safety of MCLA-145 in preclinical models and non-human primates.
Main Methods:
- Functional screening of antibody combinations targeting CD137 and PD-L1.
- In vitro assessment of T cell activation, priming, differentiation, and memory recall.
- In vivo efficacy studies in tumor models and safety evaluation in non-human primates.
Main Results:
- MCLA-145 potently activates T cells, enhancing immune responses even in suppressive conditions.
- In vivo, MCLA-145 demonstrated superior anti-tumor activity compared to ICIs, associated with CD8+ T cell recruitment and expansion.
- MCLA-145 did not induce graft-versus-host disease and showed no adverse effects in non-human primates at high doses.
Conclusions:
- MCLA-145 represents a promising bispecific antibody for cancer immunotherapy, combining CD137 agonism with PD-L1 blockade.
- Conditional CD137 activation by MCLA-145, dependent on PD-L1 expression levels, may offer both enhanced safety and potency.
- MCLA-145 warrants further clinical investigation as a novel therapeutic strategy for cancer patients.
Related Concept Videos
01:27Tumor Immunotherapy
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...