In a collaboration between researchers in Norway (Oslo University Hospital/University of Oslo and Nextera AS), USA (John Hopkins University) and Australia (Monash University), Nextera’s unique NextCore-Ab technology was employed to generate and characterize extremely sensitive TCR-Like antibodies towards gluten T cell epitopes. Their utility expand insight into celiac disease pathogenesis and opens the door for targeted therapeutic intervention
Gluten-containing food underlies the gastrointestinal (GI) damage of individuals suffering from the autoimmune-like condition celiac disease (CeD). CeD has one of the strongest genetic HLA signatures seen in man, where more than 90% of the patients express the disease-associated HLA class II molecule HLA-DQ2.5. By virtue of a unique capacity to present deamidation modified gluten peptides from food, HLA-DQ2.5+ antigen presenting cells are believed to license pathogenic gluten-specific CD4+ T cells which subsequently orchestrate the aberrant inflammatory GI tissue destruction characteristic of CeD. Exhibiting a Western World prevalence of more than 1% and with an upwards trajectory, there is a need for improved CeD disease mechanism understanding to guide consumer behavior, as well as offering diagnostic and therapeutic options.
Nextera’s unique NextCore-Ab technology was employed to generate and characterize extremely sensitive TCR-Like antibodies towards a pathogenic immunodominant signature gluten T cell epitope seemingly shared across all HLA-DQ2.5+ patients. The picomolar affinity lead antibody 3.C11 efficiently and completely blocked activation and proliferation of gluten-responsive human CD4+ TH cells both in vitro and in TCR/HLA-DQ2.5 transgenic mice in an HLA and epitope-specific manner. When used to characterize pathogenic GI gluten exposure in HLA permissive patients, this ultrasensitive antibody also reinforces previous observations on the importance of B lymphocytes and GI plasma cells as potential T cell licensors driving and underpinning CeD pathogenesis.
TCR-like antibodies that block immunodominant public T cell epitopes have potential as highly targeted intervention to silence gluten-activated T cell responses without compromising systemic immunity.
“TCR-like antibodies represent a new and unique drug class with transformational therapeutic potential employing drug targets by nature only accessible to T cells. What we show in our study is that this highly successful and well-recognized drug class, namely monoclonal antibodies, also may find its place in the growing therapeutic toolbox under investigation in celiac disease. TCR-like antibodies represent a prevailing challenging antibody type in discovery. Thus, we also see this very promising example focused on celiac disease as an important validation of NextCore-Ab and which has gained us confidence in its use to further broadening our portfolio of TCR-like antibodies for therapeutic interventions both in cancer and autoimmunity” CEO/CSO, Dr. Geir Åge Løset says in a comment.
Read the paper here: Frick, et al., Science Immunology 2021