Comparative Pharmacology of Ofatumumab vs Ocrelizumab in Humanized CD20 Transgenic Mice
Marc Bigaud1, Daniel Anthony2, Geraldine Zipfel1, Tatjana Uffelmann1, Helena Vostiarova1, Volker Engelhardt1, Barbara Nuesslein-Hildesheim1, Bernd Kieseier1
1Novartis Pharma AG, 2Departments of Pharmacology and Oncology, University of Oxford
Objective:
Benchmark the potency of subcutaneous ofatumumab (OMB-sc) and intravenous ocrelizumab (OCR-iv) at depleting B cells expressing human CD20 in transgenic mice.
Background:
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.
Design/Methods:
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]).
Results:
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
Conclusions:
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.