Towards the Application of a Label-Free Approach for Anti-CD47/PD-L1 Bispecific Antibody Discovery.

The engineering of bispecific antibodies that exhibit optimal affinity and functional activity presents a significant scientific challenge. To tackle this, investigators employ an assortment of protein assay techniques, such as label-free interaction methodologies, which offer rapidity and convenience for the evaluation of extensive sample sets. These assays yield intricate data pertaining to the affinity towards target antigens and Fc-receptors, instrumental in predicting cellular test outcomes. Nevertheless, the fine-tuning of affinity is of paramount importance to mitigate potential adverse effects while maintaining efficient obstruction of ligand-receptor interactions. In this research, biolayer interferometry (BLI) was utilized to probe the functional characteristics of bispecific antibodies targeting cluster of differentiation 47 (CD47) and programmed death-ligand 1 (PD-L1) antigens, encompassing affinity, concurrent binding to two disparate antigens, and the inhibition of ligand-receptor interactions. The findings derived from BLI were juxtaposed with data from in vitro signal regulatory protein-α (SIRP-α)/CD47 blockade reporter bioassays for two leading bispecific antibody candidates, each demonstrating distinct affinity to CD47.

Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis.

Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.