A T-cell-dependent antibody response study using a murine surrogate anti-PD-1 monoclonal antibody as an alternative to a non-human primate model
| Autor: | Stephanie Born, Lisa M. Plitnick, Ruban Mangadu, Danuta J. Herzyk, Venkataraman Sriram, Sheri Dubey, Joseph H. Phillips, Beth Hutchins, Rupesh P. Amin, Nianyu Li |
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| Rok vydání: | 2020 |
| Předmět: |
alternate model
animal diseases T-Lymphocytes Programmed Cell Death 1 Receptor 010501 environmental sciences Toxicology 01 natural sciences Mice Antineoplastic Agents Immunological Programmed cell death 1 0303 health sciences biology Vaccination Hepatitis B medicine.anatomical_structure Colonic Neoplasms Anti-PD-1 Monoclonal Antibody lcsh:Immunologic diseases. Allergy Primates Hepatitis B virus T cell Immunology chemical and pharmacologic phenomena Adenocarcinoma Antibodies Monoclonal Humanized 03 medical and health sciences lcsh:RA1190-1270 medicine Animals Humans Hepatitis B Vaccines lcsh:Toxicology. Poisons 030304 developmental biology 0105 earth and related environmental sciences Tumor microenvironment murine Non human primate business.industry anti-pd-1 biochemical phenomena metabolism and nutrition Immune checkpoint Rats Mice Inbred C57BL Antibody response Antibody Formation biology.protein Cancer research bacteria lcsh:RC581-607 business Immunologic Memory |
| Zdroj: | Journal of Immunotoxicology, Vol 17, Iss 1, Pp 175-185 (2020) |
| ISSN: | 1547-6901 |
| Popis: | The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint which may be engaged by cells in a tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/κ isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The current work was focused on developing a mouse T-Dependent Antibody Response (TDAR) model using a murinized rat anti-mouse PD-1 antibody (muDX400; a rodent surrogate for pembrolizumab) to evaluate the potential impact of treatment with a PD-1 inhibitor on immune responses to an antigen challenge (e.g. HBsAg in Hepatitis B vaccine). Despite the lower binding affinity and T1/2 compared to pembrolizumab, ligand blocking data indicated muDX400 had appropriate pharmacological activity and demonstrated efficacy in mouse tumor models, thus was suitable for pharmacodynamic and vaccination studies in mice. In a vaccination study in which mice were concomitantly administered muDX400 and the Hepatitis B vaccine, muDX400 was well-tolerated and did not result in any immune-mediated adverse effects. The treatment with muDX400 was associated with a shift in the ratio between naive and memory cells in both CD4+ and CD8+ T-lymphocytes in the spleen but did not affect anti-HBsAg antibody response profile. The mouse TDAR model using the Hepatitis B vaccine and the surrogate anti-PD1 monoclonal antibody was a useful tool in the evaluation of the potential immune-mediated effects of pembrolizumab following vaccination and appears to be a suitable alternative for the nonhuman primate TDAR models utilized for other checkpoint inhibitors. |
| Databáze: | OpenAIRE |
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