Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity

DOI: 10.1038/s42003-022-03183-5

Authors: Dapeng Li (Duke University School of Medicine) , Simon Brackenridge (University of Oxford) , Lucy C. Walters (University of Oxford) , Olivia Swanson (Duke University School of Medicine) , Karl Harlos (Wellcome Centre for Human Genetics, University of Oxford) , Daniel Rozbesky (Wellcome Centre for Human Genetics, University of Oxford; Charles University) , Derek W. Cain (Duke University School of Medicine) , Kevin Wiehe (Duke University School of Medicine) , Richard M. Scearce (Duke University School of Medicine) , Maggie Barr (Duke University School of Medicine) , Zekun Mu (Duke University School of Medicine) , Robert Parks (Duke University School of Medicine) , Max Quastel (University of Oxford) , Robert J. Edwards (Duke University School of Medicine) , Yunfei Wang (Duke University School of Medicine) , Wes Rountree (Duke University School of Medicine) , Kevin O. Saunders (Duke University School of Medicine) , Guido Ferrari (guido ferr) , Persephone Borrow (University of Oxford) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , S. Munir Alam (Duke University School of Medicine) , Mihai L. Azoitei (Duke University School of Medicine) , Geraldine M. Gillespie (University of Oxford) , Andrew J. Mcmichael (University of Oxford) , Barton F. Haynes (Duke University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 5

State: Published (Approved)
Published: March 2022

Abstract: The non-classical class Ib molecule human leukocyte antigen E (HLA-E) has limited polymorphism and can bind HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we report the isolation of 3H4, a murine HLA-E-VL9-specific IgM antibody that enhances killing of HLA-E-VL9-expressing cells by an NKG2A+ NK cell line. Structural analysis reveal that 3H4 acts by preventing CD94/NKG2A docking on HLA-E-VL9. Upon in vitro maturation, an affinity-optimized IgG form of 3H4 showes enhanced NK killing of HLA-E-VL9-expressing cells. HLA-E-VL9-specific IgM antibodies similar in function to 3H4 are also isolated from naïve B cells of cytomegalovirus (CMV)-negative, healthy humans. Thus, HLA-E-VL9-targeting mouse and human antibodies isolated from the naïve B cell antibody pool have the capacity to enhance NK cell cytotoxicity.

Journal Keywords: Antibodies; Antibody therapy; NK cells; X-ray crystallography

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 07/04/2022 09:07

Documents:
s42003-022-03183-5.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)