Title : Autoimmunity to GRP78 is associated with atherosclerosis in COPD patients, and a pilot trial of autoimmune therapy with belimumab
Abstract:
Atherosclerotic cardiovascular disease (CVD) is the single greatest cause of death in patients with chronic obstructive pulmonary disease (COPD). The prevalence of CVD in this population exceeds that attributable to traditional risk factors (hypertension, age, smoking hyperlipidemia, diabetes, etc.). We previously reported autoimmunity with specificity for glucose-regulated protein 78 (GRP78), a heat shock protein and important element of the unfolded protein response, is highly associated with the severity of COPD (PMID:25216103). Further, patient-derived anti-GRP78 IgG autoantibodies activate human macrophages and endothelium, causing these cells to exert pro inflammatory and pro-atherosclerotic phenotypes. Subsequent studies found anti-GRP78 was associated with carotid artery disease in humans, especially among males with COPD (PMID:32086320). We hypothesized anti-GRP78 autoantibodies may also be linked to coronary artery disease (CAD) in COPD patients.
Anti-inflammatory treatments reduce CVD morbidity in other autoimmune syndromes, but these therapies have not yet been tested in COPD patients. We also hypothesized that belimumab, a monoclonal antibody that inhibits B-cell activating factor (BAFF), could safely reduce antiGRP78 autoantibodies in COPD patients.
We found plasma anti-GRP78 IgG levels were correlated with coronary artery calcification (CAC) scores (per chest CT) in COPD subjects, especially among the 17 males (rs=0.67, p=0.006). We also conducted a randomized, double-blinded Phase IIa trial in another COPD cohort to test efficacy and safety of belimumab (NCT03865927). The primary endpoint was change in plasma anti-GRP78 levels.
Belimumab treatment reduced circulating anti-GRP78 by 17.0 ± 5.4% (p=0.016) in 10 COPD patients vs. 2.6 ± 5.1% (p=0.31) in six placebo controls and the reductions were proportionate to pre-treatment autoantibody levels (rs=-0.65, p=0.05). Belimumab did not reduce protective antipneumococcal antibody levels nor cause serious adverse events.
This pilot trial indicates belimumab treatment safely reduces levels of an autoantibody that is associated with lung disease and CVD in COPD patients. Treatment with specific autoimmune therapies may be a novel approach to reduce the extreme morbidity of CVD in patients with COPD. These findings support a larger and longer duration trial to better evaluate belimumab, or other autoimmune-targeted therapies, in COPD.
