PowerPoint Presentation

HFB202501, a Novel Anti-PD-1 Antibody with Enhanced Effector Functions for Precision Depletion of Pathogenic T Cells in Autoimmune Diseases

Authors
Roshan Kumar, Qian Zhang, Chun Gao, Wenhua Xu, Pin Cai, Tengfei Wang, Qiu Jin, Song Cheng, Jia Wu, Jinxu Liao, Ling Dong, Hillary Shah, Juying Li, Yun-Yueh Lu, Jinping Gan, Francisco Adrian, Liang Schweizer

BACKGROUND

Precision depletion of pathogenic immune cells is an attractive therapeutic strategy with the potential to reset immune responses and restore tolerance while retaining aspects of protective immunity. The immune checkpoint PD-1 has drawn interest as a therapeutic target in autoimmune and inflammatory diseases where it marks multiple pathogenic T cell subtypes. These include T peripheral and follicular helper (Tph and Tfh) cells, critical for the maturation and development of autoreactive B cells, which express very high levels of PD-1, and activated effector cells which contribute to inflammation and tissue damage and express lower levels of PD-1. Antibodies that agonize PD-1-expressing T cells and deplete PD-1(high) T cells have recently demonstrated clinical proof-of-concept in rheumatoid arthritis.

RESULTS | In Vitro Antibody Characterization

We present here HFB202501, an anti-PD-1 agonist antibody engineered for enhanced depletion of PD-1+ cells. HFB202501 shows more potent and deeper depletion of PD-1+ T cells in vitro compared to clinical-stage benchmark antibodies. HFB202501 is able to deplete multiple PD-1+ cell populations from human tonsils in vitro and is highly efficacious in a mouse model of lupus. Deep depletion of PD-1+ cells has the potential for broad application in autoantibody-mediated autoimmune diseases and other indications where activated PD-1+ effector cells play a pathogenic role. HFB202501 is progressing towards preclinical development with a biomarker strategy for identifying patients with expanded PD-1+ cell populations.

Mechanism of Action

RESULTS | Target analysis

Single cell analysis of PD-1 Expression in HiFiBiO Disease Cell Atlas

REFERENCES

Figure 1. Expression of PD-1 by immune cells in HiFiBiO’s single-cell database from patients with autoimmune and inflammatory diseases. PD-1 is most highly expressed by T peripheral and follicular helper cells (Tph and Tfh), followed by exhausted/activated CD8 T cells.

‘Here come the PD-1 agonists.’ (2023) https://www.evaluate.com/node/18854/amp
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K Suzuki et al., ‘Anti-PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases.’ Sci Immunol (2023) 8: eadd4947.
J Tuttle et al., ‘A phase 2 trial of peresolimab for adults with rheumatoid arthritis.’ N Engl J Med (2023) 388: 1853−1862.
AnaptysBio corporate presentation: Rosnilimab updated Phase 2b data in RA https://ir.anaptysbio.com/static-files/6cd574c5-b4fa-42f8-873f-93e9af2de251.

Combined Suppressive and Depleting Effect on Activated T Cells

Primary Cell Killing

NK cell killing of SEA-activated human PD-1+ CD4+ T cells

NK cell killing of T cells from primary human tonsils

Activation of T cells in the presence of other PBMCs without adding exogenous NK cells allows testing of the net effect of depletion + agonism.