A Phase 2b Randomized Trial of Belimumab to Reduce Atherogenic Autoantibodies in COPD Patients

We hypothesized autoantibodies with specificity for glucose-regulated protein 78 (anti-GRP78), a ubiquitous heat shock protein and key component of the unfolded protein response (UPR), are associated with development of cardiovascular disease (CVD) in chronic obstructive pulmonary disease (COPD) patients. Treatments focused on the underlying autoimmune processes reduce CVD events in those afflicted with connective tissue diseases, but analogous therapies have not yet been tested in COPD patients, in whom atherosclerotic disease is a significant cause of mortality.

Plasma anti-GRP78 IgG was measured by ELISA in two independent cohorts of COPD subjects who had coronary artery calcium (CAC) determinations by chest CT. Another COPD cohort was randomized to belimumab (10 mg/kg i.v. every two weeks x 3, followed by five monthly infusions) (n=10) or placebo (n=6). The primary endpoint was changes of circulating anti-GRP78 levels.

Anti-GRP78 levels in COPD patients (n=37) were highly correlated with CAC scores (r_s=0.56, p<0.001). Autoantibody concentrations were reduced by ~17% (from 0.50+0.11 to 0.40+0.09 OD units, p=0.02) but unchanged by placebo (p=0.75) , and the reductions were proportionate to pre-treatment autoantibody levels (r_s=-0.65, p=0.05). There were no reductions of protective anti-pneumococcal antibody levels or serious adverse events definitively attributable to belimumab treatment.

Belimumab therapy reduces circulating anti-GRP78 autoantibodies, which have been linked to CVD and other COPD comorbidities. Autoantibody reduction may be a novel approach to mitigate COPD-associated. These findings support a larger trial to thoroughly assess efficacy and safety of belimumab, or other specific autoimmune-targeted therapies, in COPD patients with CVD.