Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration

Abstract

Approval of B-cell-depleting therapies signifies an important advance in the treatment of multiple sclerosis (MS). However, it is unclear whether the administration route of anti-CD20 monoclonal antibodies (mAbs) alters tissue distribution patterns and subsequent downstream effects. This study aimed to investigate the distribution and efficacy of radiolabeled ofatumumab and ocrelizumab in humanized-CD20 (huCD20) transgenic mice following subcutaneous (SC) and intravenous (IV) administration. For distribution analysis, huCD20 and wildtype mice (n = 5 per group) were imaged by single-photon emission computed tomography (SPECT)/CT 72 h after SC/IV administration of ofatumumab or SC/IV administration of ocrelizumab, radiolabeled with Indium-111 (111In-ofatumumab or 111In-ocrelizumab; 5 µg, 5 MBq). For efficacy analysis, huCD20 mice with focal delayed-type hypersensitivity lesions and associated tertiary lymphoid structures (DTH-TLS) were administered SC/IV ofatumumab or SC/IV ocrelizumab (7.5 mg/kg, n = 10 per group) on Days 63, 70 and 75 post lesion induction. Treatment impact on the number of CD19+ cells in select tissues and the evolution of DTH-TLS lesions in the brain were assessed. Uptake of an 111In-labelled anti-CD19 antibody in cervical and axillary lymph nodes was also assessed before and 18 days after treatment initiation as a measure of B-cell depletion. SPECT/CT image quantification revealed similar tissue distribution, albeit with large differences in blood signal, of 111In-ofatumumab and 111In-ocrelizumab following SC and IV administration; however, an increase in both mAbs was observed in the axillary and inguinal lymph nodes following SC versus IV administration. In the DTH-TLS model of MS, both treatments significantly reduced the 111In-anti-CD19 signal and number of CD19+ cells in select tissues, where no differences between the route of administration or mAb were observed. Both treatments significantly decreased the extent of glial activation, as well as the number of B- and T-cells in the lesion following SC and IV administration, although this was mostly achieved to a greater extent with ofatumumab versus ocrelizumab. These findings suggest that there may be more direct access to the lymph nodes through the lymphatic system with SC versus IV administration. Furthermore, preliminary findings suggest that ofatumumab may be more effective than ocrelizumab at controlling MS-like pathology in the brain.

Effect of Previous Disease-Modifying Therapy on Treatment Effectiveness for Patients Treated With Ocrelizumab

“…Anti-CD20 antibodies are thought to penetrate lymphoid tissues more effectively than alemtuzumab, 3 but recent studies indicated persistence of B cells in lymphoid tissues following ocrelizumab or ofatumumab. 21 Although the peripheral CD19 + B-cell levels were not different in stable or relapsing patients having received FTY as last previous DMT, we were of course unable to evaluate whether this B-cell reservoir has been substantially altered. Generally, these compartment-specific effects might render development of durable biomarkers determined from peripheral blood difficult.…”

Assessment of the treating physicians’ first-hand experience with handling and satisfaction of ofatumumab therapy: findings from the PERITIA survey conducted in Europe

“…In the Phase 3 ASCLEPIOS trials [ 9 ], ofatumumab was administered in a pre-filled syringe; however, ofatumumab is approved in Europe [ 14 ] as a pre-filled syringe and an autoinjector pen. Injection tolerability and patient satisfaction due to convenience of administration is improved with autoinjectors versus manual injection, thereby increasing adherence [ 28 , 29 ].…”

Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment

“…Ofatumumab’s greater CDC than rituximab, ocrelizumab and ublituximab [ 66 , 67 , 71 , 73 , 74 ] is thought to mediate its greater efficacy at lower doses and suitability for subcutaneous administration compared with rituximab, ocrelizumab and ublituximab [ 67 , 68 ]. Furthermore, although CDC is ofatumumab’s primary mechanism of action, ofatumumab has also been shown to induce twofold higher ADCC than rituximab, with levels similar to ocrelizumab and reduced compared with ublituximab (Table 1 ) [ 41 , 75 , 76 ].…”

“…The majority of anti-CD20 mAbs for MS are administered via intravenous infusion, with the subcutaneous injection of ofatumumab being the exception. Studies have shown that these different routes of administration have biological and clinical consequences for the treatment of B cell-associated disease, including MS. For instance, subcutaneous administration of anti-CD20 therapies in mice has been shown to result in similar levels of depletion of circulating and lymph-node-localized CD20+ B cells when administered at a low dose, compared with the high-dose intravenous administrations [ 76 ]. Furthermore, low-dose subcutaneous administration is clinically associated with reduced administration-related reactions [ 41 ].…”

“…Subcutaneously administered anti-CD20 mAbs have a different antibody distribution and localization when compared with intravenous administration. For example, subcutaneous administration resulted in direct and increased penetration of anti-CD20 mAb into the axillary, subiliac, sciatic and inguinal lymph nodes, as well as CNS components, in murine models of experimental autoimmune encephalomyelitis, compared with intravenous administration [ 76 , 88 ]. Subcutaneous administration also limits transportation of the antibody into the capillaries, and they instead enter systemic circulation via an indirect route through the lymphatic system [ 69 ].…”