Background/Purpose: IgG4-related disease (IgG4-RD) is an immune-mediated condition responsible for fibro-inflammatory lesions that can lead to irreversible damage. No approved therapies for IgG4-RD exist. We report the use of a novel monoclonal antibody, XmAb5871, in IgG4-RD. XmAb5871 is a humanized anti-CD19 antibody with an Fc portion engineered for increased affinity (200- to 400-fold over native IgG) to FcgRIIb, the only Fc receptor on B cells. Co-ligation of CD19 and FcgRIIb leads to downregulation and inhibition of B lineage cells bearing these targets. Reversible inhibition of B cell function without B cell ablation is one potential advantage of this approach.

Methods: The trial is an open-label investigation of XmAb5871 in active IgG4-RD, defined as an IgG4-RD Responder Index of ≥3. XmAb5871 (5 mg/kg) is administered IV every 14 days for 12 doses. Positron emission tomography (PET) scans are performed at baseline and at three months. The primary outcome measure is the proportion of patients on day 169 with decrease in the IgG4-RD RI ≥2 compared to baseline. Glucocorticoids are permitted but not required at entry and must be discontinued by two months. Other immunosuppressive medications are not allowed. Mechanistic studies are performed at baseline and at selected intervals.

Results: The first patient was infused in March 2016. As of June 2016, 8 of the targeted 15 patients have been enrolled. The mean age among the 8 patients enrolled to date is 58 years (range: 47 to 77 years). Four patients are male, 4 female. All are Caucasian. Seven of the 8 patients had elevated serum IgG4 concentrations at screen, with a mean serum IgG4 of 526 mg/dL (range: 27 – 1877; normal < 86 mg/dL). The mean baseline IgG4-RD RI score was 12.4 (range: 3 – 22), with active inflammatory disease in at least one organ system (range: 1-8, mean 5). The organs most commonly affected were submandibular glands (7 patients), parotid glands (6), lymph nodes (6), lacrimal glands (5). Two patients had bile duct involvement and kidneys, lungs, pancreas were affected in 1 each. Six of the 8 patients are being treated with XmAb5871 alone. One patient was started on prednisone 40 mg/day concomitantly with enrollment because of serious IgG4-related kidney disease (tubulointerstitial nephritis; serum Cr 2.6 mg/dL). PET scans at baseline identified disease involvement of organs that had not been suspected by other diagnostic means in 5 of 8 patients. Six of 6 patients with major salivary or lacrimal gland enlargement on physical examination demonstrated improvement on follow-up, some as early as one week. One patient had been on glucocorticoid treatment for 2 years and was on prednisone 15 mg/day at baseline, but was able to discontinue prednisone by 2 months after baseline treatment. Three patients experienced minor, transient gastrointestinal side-effects during the 1st infusion. One patient had GI symptoms on the 5^thinfusion. This patient also developed symptoms suggestive of serum sickness and has discontinued the study.