Background/Purpose:   B-cell depletion provides therapeutic benefits for patients with rheumatoid arthritis (RA). Ocaratuzumab, previously known as AME-133v, is a Fc- and Fab-engineered, humanized, anti-CD20 monoclonal antibody designed for optimized affinity to the CD20 antigen as well as to the CD16 (FcγRIIIa) receptor on effector cells. It demonstrates 13-20 fold higher affinity for CD20 and 6-fold higher antibody-dependent cellular cytotoxicity as compared to rituximab, which is currently approved for RA. Because patients with low affinity FcγRIIIa receptors historically have poor B-cell depletion with rituximab, there is a need for monoclonal antibodies that improve the rate of B-cell depletion in these patients. The ability of ocaratuzumab to deplete B-cells in patients with RA was studied in a dose escalation phase I study.

Methods:  Five RA patients were treated with a single intravenous (IV) dose of 5 mg of ocaratuzumab, and three patients received 7.5 mg IV of ocaratuzumab.  Patients were followed for B-cell depletion and recovery.

Results:  Rapid B-cell depletion was seen in all patients in both the 5 mg and 7.5 mg cohorts (Figure 1). This depletion, with CD20+ cells either absent or very low, was seen as early as 3 hours after the start of infusion. Although most patients began to recover their B-cell counts within seven days of the infusion, at two months, the circulating B-cell counts were less than 50% of baseline in 5 of the 8 patients treated with ocaratuzumab.

Figure 1.  B-cell depletion with a single 7.5 mg IV dose of ocaratuzumab

The subjects were followed beyond the Day 85 visit to monitor the recovery of their B-cells. Four patients had follow-ups up to 3 months after Day 85, two patients up to four months, and two patients up to 6 and 13 months, respectively. Based on review of the adverse events, no suggestion of susceptibility to infection was seen.

As expected, administration of the larger dose led to a greater C_max. In the 7.5 mg cohort, C_max was 1720 ng/mL and 1620 ng/mL in the 5 mg cohort. The AUC of the drug was 24,000 ng•hr/mL in the 7.5 mg cohort and 4160  ng•hr/mL  in the 5 mg cohort.

Conclusion: Even when administered at doses that are less than 100 fold that of rituximab, ocaratuzumab demonstrates rapid and prolonged B-cell depletion in RA patients. The majority of the patients treated with very low doses of ocaratuzumab demonstrated protracted B-cell depletion lasting for three months, with one patient recovering B-cells more than one year after receiving 7.5 mg of drug. Ocaratuzumab may provide a therapeutic option for patients with autoimmune diseases, especially those with the low affinity FcγRIIIa phenotype, who have not received optimal benefit from conventional monoclonal antibodies. Furthermore, ocaratuzumab can potentially be given at doses much smaller than that of the conventional antibodies, possibly permitting subcutaneous administration.