Background/Purpose: Programmed cell death protein 1 (PD-1) is expressed on activated T cells and serves as a key co-inhibitory checkpoint molecule in immune regulation. Aberrant in PD-1 signaling increases human susceptibility to multiple autoimmune diseases, while insufficient PD-1 signaling can lead to dysregulated T cell responses. By targeting PD-1 regulatory mechanisms to modulate disease-driving T cells, LBL-057 aims to dampen the inflammatory cycle and restore immune balance. LBL-057 is an ADCC (antibody-dependent cellular cytotoxicity) enhanced PD-1 agonistic VHH-Fc antibody that stimulates the endogenous PD-1 inhibitory pathway, inhibits activated T cells, and reduces T cell proliferation and inflammatory cytokine secretion. In addition, the ADCC-enhanced design enables effective depletion of PD-1+ T follicular helper cells and T effector cells, offering an attractive therapeutic approach for the treatment of PD-1+ T cells driven autoimmune disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).

Methods: A panel of diverse VHH antibodies against PD-1 were developed via alpaca immunization and phage library screening. Candidates underwent rigorous in vitro evaluation, including PD-1+ cell binding, PD-L1/PD-L2-PD-1 blockade, ADCC activity and PD-1 agonist activity. In addition, the inhibitory effect of LBL-057 on graft-versus-host disease (GvHD) was validated in a human PBMC transplantation mouse model.

Results: LBL-057 binds to PD-1 with an epitope distinct from pembrolizumab and enhances PD-1 interaction with to PD-L1/PD-L2 rather than blocking it. In vitro assays confirmed that LBL-057 significantly activates PD-1 pathway, suppresses PD-1+ T-cell proliferation and activation in a dose-dependent manner. Furthermore, LBL-057 exhibits potent ADCC activity, effectively reducing PD-1+ T cell populations. In vivo, LBL-057 demonstrated a better efficacy than benchmarks in inhibition of GvHD progression in mice.

Conclusion: LBL-057, a VHH-Fc antibody, specifically binds to a unique epitope on PD-1, with dual mechanisms of action. On the one hand it depletes PD-1+ T cells with enhanced ADCC ability, on the other it enhances PD-1-PD-L1/PD-L2 interactions while activates PD-1 downstream signaling. Taken together, it potently suppresses T cell proliferation and activation in vitro and alleviates pathological damage in a GvHD mouse model. These findings support its therapeutic potential for PD-1+ T cells driven autoimmune disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lbl-057-a-novel-adcc-enhanced-pd-1-agonist-vhh-fc-antibody/