Comparative Pharmacology of Ofatumumab vs Ocrelizumab in Humanized CD20 Transgenic Mice (S9.007)

Abstract

<h3>Objective:</h3> Benchmark the potency of subcutaneous ofatumumab (OMB-sc) and intravenous ocrelizumab (OCR-iv) at depleting B cells expressing human CD20 in transgenic mice. <h3>Background:</h3> Therapies that deplete CD20-positive B cells are effective in multiple sclerosis. Pilot work has suggested improved lymph node (LN) targeting for OMB-sc vs OCR-iv. <h3>Design/Methods:</h3> Humanized CD20 mice (C57BL/6-Ms4a1tm2[hCD20]Smoc) were treated once with OMB-sc or OCR-iv at various doses. Drug levels and B-cell counts were assessed via IgG-binding ELISA and flow cytometry, respectively, in blood and lymphoid organs (spleen, inguinal LNs, bone marrow [BM]). <h3>Results:</h3> Dose-proportional drug levels with B-cell depletion in all compartments was noted for both therapies. Three days post treatment, serum levels needed to achieve 50%/90% (EC50/EC90) efficacy were ~0.01/0.3 mg/mL, respectively, with OMB-sc and ~0.2/5.0 mg/mL, respectively, with OCR-iv, indicative of 20-fold higher B-cell–depleting potency for OMB-sc. OMB-sc reached its EC50 at the human-equivalent dose (huD) of 6 mg per mouse; OCR-iv was ~40-fold above its EC90 at the huD (200 mg). Drug level ratios (spleen and LN vs serum) were 5–20 for OMB-sc and ≤1 for OCR-iv, confirming lymphoid organ targeting for OMB-sc. Both treatments appeared equipotent at depleting noncirculating B cells (EC50s ~−0.2 mg/mL). Marginal zone and follicular B cells in secondary lymphoid organs were markedly depleted by OCR-iv but spared by OMB-sc at the huD. OMB-sc achieved drug levels 10-fold below the EC50 in BM at the huD, whereas OCR-iv reached its EC90, which suggests a lower impact on BM-resident CD20-expressing cells with OMB-sc <h3>Conclusions:</h3> OMB-sc demonstrated better efficiency in targeting lymphoid organs and greater potency for depleting circulating B cells vs OCR-iv. A sparing effect regarding marginal zone and follicular B cells was demonstrated with OMB-sc. OMB-sc may offer high efficacy and lower long-term safety risks with convenient dosing vs OCR-iv in humans. <b>Disclosure:</b> Marc Bigaud has received personal compensation for serving as an employee of Novartis Pharma. Dr. Anthony has received personal compensation for serving as an employee of University of Oxford. Dr. Anthony has received personal compensation for serving as an employee of Somerville College Oxford. Dr. Anthony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Anthony has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroplast. Dr. Anthony has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Oxomics. The institution of Dr. Anthony has received research support from Numares. The institution of Dr. Anthony has received research support from MRC UK. Mrs. Zipfel has nothing to disclose. Tatjana Uffelmann has nothing to disclose. Mrs. Vostiarova has nothing to disclose. Mr. Engelhardt has nothing to disclose. Dr. Nuesslein-Hildesheim has received personal compensation for serving as an employee of Novartis Pharma AG. Dr. Nuesslein-Hildesheim has stock in Novartis Pharma AG. Bernd C. Kieseier, MD has nothing to disclose.