Yu et al. examined the impact of affinity on the activity of immunomodulatory antibodies, and showed that lower affinities delivered greater agonism through increased FcγR-independent receptor clustering. A low-affinity anti-CD40 monoclonal antibody exhibited stronger agonistic activity and more effective antitumor activity in vivo compared with the high-affinity parent antibody. More potent agonism mediated by lower affinity could also be recapitulated for a human anti-CD40 antibody. Lowering the affinity converted an inert therapeutic anti-4-1BB antibody (utomilumab) and an antagonistic therapeutic anti-PD-1 antibody (nivolumab) into agonists.
Contributed by Shishir Pant
ABSTRACT: Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens(1,2). Similarly, high affinity is routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity-function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo T_cell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected T_cell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease.
Author Info: (1) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (2) Diamond Light Source, H
Author Info: (1) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (2) Diamond Light Source, Harwell Science and Innovation Campus, Didcot, UK. (3) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (4) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (5) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (6) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (7) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (8) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (9) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (10) Institute for Life Sciences, University of Southampton, Southampton, UK. School of Chemistry, University of Southampton, Southampton, UK. (11) Institute for Life Sciences, University of Southampton, Southampton, UK. Biological Sciences, University of Southampton, Southampton, UK. (12) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. (13) Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK. msc@soton.ac.uk. Institute for Life Sciences, University of Southampton, Southampton, UK. msc@soton.ac.uk.
