Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic.
Iñaki EtxeberríaElixabet BolañosAlvaro TeijeiraSaray GarasaAlba YanguasArantza AzpilikuetaWilliam M KavanaughOlga VasiljevaMarcia BelvinBruce HowngBryan IrvingKimberly TiptonJames WestLi MeiAlan J KormanEmanuela SegaIrene OliveraAssunta CirellaMaría Carmen OchoaMaria E Rodríguez-RuizAna MeleroMiguel F SanmamedJohn J EngelhardtIgnacio Melero BermejoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation-related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor-dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.
Keyphrases
- cell therapy
- lymph node
- oxidative stress
- heavy metals
- nk cells
- monoclonal antibody
- minimally invasive
- stem cells
- magnetic resonance
- endothelial cells
- mesenchymal stem cells
- early stage
- rectal cancer
- metabolic syndrome
- squamous cell carcinoma
- radiation therapy
- skeletal muscle
- robot assisted
- percutaneous coronary intervention
- transcription factor
- risk assessment
- coronary artery bypass
- drug induced
- high fat diet induced