Characterization of a Trispecific PD-L1 Blocking Antibody That Exhibits EGFR-Conditional 4-1BB Agonist Activity
Laura Rubio-Pérez1,2,3,4, Susana Frago5, Marta Compte5
1Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), 28041 Madrid, Spain.
Abstract:
Immune checkpoint blockade has changed the treatment paradigm for advanced solid tumors, but the overall response rates are still limited. The combination of checkpoint blockade with anti-4-1BB antibodies to stimulate tumor-infiltrating T cells has shown anti-tumor activity in human trials. However, the further clinical development of these antibodies has been hampered by significant off-tumor toxicities. Here, we generated an anti-4-1BB/EGFR/PD-L1 trispecific antibody consisting of a triple-targeting tandem trimerbody (TT) fused to an engineered silent Fc region. This antibody (IgTT-4E1-S) was designed to combine the blockade of the PD-L1/PD-1 axis with conditional 4-1BB costimulation specifically confined to the tumor microenvironment (TME). The antibody demonstrated simultaneous binding to purified EGFR, PD-L1, and 4-1BB in solution, effective blockade of the PD-L1/PD1 interaction, and potent 4-1BB-mediated costimulation, but only in the presence of EGFR-expressing cells. These results demonstrate the feasibility of IgTT-4E1-S specifically blocking the PD-L1/PD-1 axis and inducing EGFR-conditional 4-1BB agonist activity.
Insights
A novel trispecific antibody blocks PD-L1/PD-1 and conditionally stimulates 4-1BB costimulation in the tumor microenvironment. This approach aims to enhance anti-tumor immunity while minimizing off-tumor toxicities for advanced solid tumors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immune checkpoint blockade (ICB) has advanced cancer therapy but faces limited response rates.
- Combining ICB with anti-4-1BB antibodies shows promise for stimulating T cells but is hindered by off-tumor toxicities.
Purpose of the Study:
- To develop a trispecific antibody (IgTT-4E1-S) targeting EGFR, PD-L1, and 4-1BB.
- To achieve PD-L1/PD-1 axis blockade and conditional 4-1BB costimulation specifically within the tumor microenvironment (TME).
Main Methods:
- Generation of a triple-targeting tandem trimerbody (TT) fused to a silent Fc region.
- Assessment of antibody binding to EGFR, PD-L1, and 4-1BB.
- Evaluation of PD-L1/PD-1 interaction blockade and 4-1BB-mediated costimulation in the presence of EGFR-expressing cells.
Main Results:
- The antibody (IgTT-4E1-S) demonstrated simultaneous binding to EGFR, PD-L1, and 4-1BB.
- Effective blockade of the PD-L1/PD-1 interaction was observed.
- Potent, EGFR-conditional 4-1BB costimulation was achieved specifically in the TME.
Conclusions:
- IgTT-4E1-S shows feasibility for targeted cancer immunotherapy.
- This engineered antibody can block PD-L1/PD-1 and induce conditional 4-1BB agonism, potentially reducing toxicity.
- The strategy offers a promising approach for enhancing anti-tumor responses in solid tumors.
