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Case Report: An EGFR-Targeted 4-1BB-agonistic Trimerbody Does Not Induce Hepatotoxicity in Transgenic Mice With Liver
Marta Compte1, Seandean L Harwood2, Jorge Martínez-Torrecuadrada3
1Department of Antibody Engineering, Leadartis SL, Madrid, Spain.
Abstract:
Agonistic monoclonal antibodies (mAbs) targeting the co-stimulatory receptor 4-1BB are among the most effective immunotherapeutic agents across pre-clinical cancer models. However, clinical development of full-length 4-1BB agonistic mAbs, has been hampered by dose-limiting liver toxicity. We have previously developed an EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) that induces potent anti-tumor immunity without systemic toxicity, in immunocompetent mice bearing murine colorectal carcinoma cells expressing human EGFR. Here, we study the impact of human EGFR expression on mouse liver in the toxicity profile of 1D8N/CEGa1. Systemic administration of IgG-based anti-4-1BB agonist resulted in nonspecific immune stimulation and hepatotoxicity in a liver-specific human EGFR-transgenic immunocompetent mouse, whereas in 1D8N/CEGa1-treated mice no such immune-related adverse effects were observed. Collectively, these data support the role of FcγR interactions in the major off-tumor toxicities associated with IgG-based 4-1BB agonists and further validate the safety profile of EGFR-targeted Fc-less 4-1BB-agonistic trimerbodies in systemic cancer immunotherapy protocols.
Insights
Targeting 4-1BB with novel EGFR-targeted trimerbodies prevents liver toxicity seen with traditional monoclonal antibodies. This approach enhances cancer immunotherapy safety and efficacy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Agonistic monoclonal antibodies (mAbs) targeting 4-1BB show promise in cancer immunotherapy.
- Clinical use of full-length 4-1BB agonistic mAbs is limited by dose-limiting liver toxicity.
- An EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) was previously developed to induce anti-tumor immunity without systemic toxicity.
Purpose of the Study:
- To investigate the impact of human EGFR expression on the liver toxicity profile of 1D8N/CEGa1.
- To compare the toxicity of IgG-based 4-1BB agonists versus EGFR-targeted trimerbodies in a relevant model.
- To validate the safety profile of EGFR-targeted, Fc-less 4-1BB-agonistic trimerbodies for cancer immunotherapy.
Main Methods:
- Utilized a liver-specific human EGFR-transgenic immunocompetent mouse model.
- Administered systemic IgG-based anti-4-1BB agonist.
- Administered systemic EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1).
- Assessed immune stimulation and hepatotoxicity.
Main Results:
- Systemic administration of IgG-based anti-4-1BB agonist caused nonspecific immune stimulation and hepatotoxicity.
- 1D8N/CEGa1-treated mice showed no immune-related adverse effects or liver toxicity.
- FcγR interactions were implicated in the off-tumor toxicities of IgG-based 4-1BB agonists.
Conclusions:
- EGFR-targeted, Fc-less 4-1BB-agonistic trimerbodies demonstrate a favorable safety profile.
- This approach mitigates the liver toxicity associated with conventional 4-1BB agonistic mAbs.
- These findings support the use of EGFR-targeted trimerbodies in systemic cancer immunotherapy protocols.
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