Abstract LB176: Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics
| العنوان: | Abstract LB176: Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics |
|---|---|
| المؤلفون: | Seung-Hyun Lee, Jin Kyung Choi, Sun Woo Im, Bora Hwang, HoonSung Jeh, Jin Sung Park, Han Na Lee, SeungHee Han, Yeonji Oh, Byoung S. Kwon |
| المصدر: | Cancer Research. 81:LB176-LB176 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | chemistry.chemical_classification, Cancer Research, biology, Effector, T cell, Cancer, medicine.disease, Molecular biology, Immune checkpoint, Amino acid, medicine.anatomical_structure, Oncology, chemistry, biology.protein, medicine, Antibody, Receptor, CD8 |
| الوصف: | 4-1BB and PD-1 are both T cell costimulatory receptors/immune checkpoint regulators. 4-1BB/4-1BBL provides stimulatory signals while PD-1/PD-L1, suppressive ones to T lymphocytes. Various forms of agonists to 4-1BB or blockers to PD-1 have shown a potent anti-cancer activity by modulating mainly CD8+ T cells. Thus, synergistic or additive anti-cancer effect may be achieved by combining the agonists to 4-1BB and blockers to PD-1. We have tested various combinations of antibodies and proteins with consideration of overall size of the therapeutic candidates. The best anti-cancer activities were obtained by combination of an agonistic anti-4-1BB antibody and soluble PD-1 that binds to PD-L1 with high affinity. To obtain molecularly-evolved PD-1 we first used the 3D complex between PD-1 and PD-L1 to select the major contributing PD-1 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The affinity-matured resulting PD-1 is called euPD-1. We finally constructed EU505 that composed of a scFv of anti-4-1BB and euPD-1. Through cell binding and dual antigen assays, we confirmed that EU505 binds both targets independently at the same time. The result of 4-1BB bioassays, a biologically relevant MOA-based assay, showed that potent PD-L1-dependent T cell activation with EU505. In-vitro killing assays showed that EU505 selectively activated T cells which in turn killed high PD-L1-expressing cells, but not low-PD-L1-expressing ones. EU505 demonstrated much stronger tumor-killing effect compared with each component alone when we tested against human PD-L1-expressing tumor cells in a 4-1BB Knock-in mouse model. Furthermore, it was observed that number of effector CD8+ T cells increased in the peripheral blood upon EU505 injection and consequently tumor size was reduced. EU505, a promising anti-cancer drug, appears to enhance CD8+ T cell infiltration and activate T cells in situ at the tumor sites by binding two different targets of 4-1BB and PD-L1 simultaneously. Citation Format: Byoung S. Kwon, Hanna Lee, Jin Sung Park, Yeonji Oh, SeungHee Han, Jin Kyung Choi, Bora Hwang, Sun Woo Im, Seunghyun Lee, HoonSung Jeh. Anti-4-1BB x PD-1, a bispecific anti-cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB176. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::32909864c4de4516904dd29a83d669d4 https://doi.org/10.1158/1538-7445.am2021-lb176 |
| رقم الأكسشن: | edsair.doi...........32909864c4de4516904dd29a83d669d4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
|---|