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

• Main Authors: Lisa M. Plitnick, Beth Hutchins, Sheri Dubey, Nianyu Li, Rupesh P. Amin, Stephanie Born, Ruban Mangadu, Joseph H. Phillips, Venkataraman Sriram, Danuta J. Herzyk
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: Journal of Immunotoxicology
• Subjects: anti-pd-1; vaccination; murine; alternate model
• Online Access: http://dx.doi.org/10.1080/1547691X.2020.1826020
• ISSN: 1547-691X; 1547-6901

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.