Pharmacokinetic and Pharmacodynamic Analysis of Ocaratuzumab in 50 Patients with Relapsed Follicular Lymphoma and Low-Affinity FcγRIIIa (CD16a) Polymorphisms.
Authors: Du Minna , O'Reilly Adrienne , Le Phuong H , Jain Vinay 
Published: October 2019

Abstract
Abstract 2750
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 FcγRIIIa (CD16a) receptor on effector cells. It demonstrates 13–20 fold higher affinity for CD20 and 6-fold higher antibody-dependent cellular cytotoxicity compared to rituximab.
In a Phase II study, 50 patients received IV ocaratuzumab at 375 mg/m2 weekly for 4 doses, the standard dosing schedule of rituximab. The median age (range) was 61 (39–83) years and the median number of prior systemic therapies (range) was 2 (1–9). Two patients were rituximab naïve.
This abstract describes the pharmacokinetics (PK) and pharmacodynamics of ocaratuzumab. The steady state concentration of ocaratuzumab was reached by the 2nd dose and started to decline 1 week after the last dose. The PK of ocaratuzumab is best characterized by a 2-compartment model with a typical clearance estimate of 0.26 L/day. The typical volume estimates for the central and peripheral compartments were 3.15 L and 3.31 L respectively, which corresponds to a terminal half-life of approximately 19 days.
As expected, there was significant inter-patient variability in the clearance of ocaratuzumab. Analysis of the serum concentration of ocaratuzumab revealed no correlation between serum ocaratuzumab concentration and progression free survival (PFS) as some patients with low concentrations had prolonged PFS and some patients with high concentrations had short PFS (Figure 1).
Only 2 patients developed high titers of human anti-human antibody. These 2 patients maintained very low concentrations of ocaratuzumab and were amongst 3 total patients who demonstrated progressive disease in the study.
All patients had rapid and sustained B-cell depletion for at least 90 days after the last infusion. A retrospective analysis of B-cell recovery and response showed a direct correlation between time to B-cell recovery and PFS duration. Patients with prolonged B-cell depletion stayed in remission longer than patients who recovered their circulating B-cells more quickly.
In conclusion, clinical efficacy was seen across a wide range of serum concentrations of ocaratuzumab, suggesting significant potency of the drug even at low serum concentration levels. Despite all patients having low-affinity FcγRIIIa polymorphisms, the overall response rate was 32% with a median PFS of 38 weeks. Although a weekly dose of 375 mg/m2 for 4 doses was used in this trial, lower doses of ocaratuzumab, such as 100 mg/m2 given once weekly for 4 doses, may potentially be effective.
Figure 1. Patient Serum Ocaratuzumab Concentration Levels at Day 28 and PFS Shown No Correlation Figure 1. Patient Serum Ocaratuzumab Concentration Levels at Day 28 and PFS Shown No Correlation

Disclosures:
Du: Mentrik Biotech, LLC: Employment. O'Reilly:Mentrik Biotech, LLC: Employment. Le:Mentrik Biotech, LLC: Employment. Jain:Mentrik Biotech, LLC: CEO Other, Employment, Equity Ownership, Patents & Royalties.