Obinutuzumab induces superior B-Cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples
Obinutuzumab induces superior B-Cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples
Objective A proportion of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) patients treated with standard doses of rituximab (RTX) display inefficient B cell deletion and poor clinical responses which can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients. To investigate whether better responses could be achieved with mechanistically different anti-CD20 mAbs.
Methods We compared RTX with Obinutuzumab (OBZ), a new-generation, glycoengineered type II anti-CD20 mAb in a series of in vitro assays measuring B cell cytotoxicity in RA and SLE patient samples.
Results We found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in-vitro whole blood assays. Dissecting this difference, we found that RTX elicited more potent complement-dependent cellular cytotoxicity (CDC) than OBZ. In contrast, OBZ was more effective at evoking Fc gamma receptor (FcγR)-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with FcγRs and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized. OBZ was also more efficient at inducing direct cell death. This was true for all CD19+ B-cells as a whole and in naïve (IgD+CD27-); and switched (IgD-CD27+) memory B-cells specifically, a higher frequency of which is associated with poor clinical response after RTX.
Conclusions Taken together, these data provide a mechanistic basis for resistance to Rituximab induced B-cell depletion, and for considering Obinutuzumab, as an alternative B-cell depleting agent in RA and SLE.
1227–1237
Reddy, Venkat
615826e9-84f3-4053-8ce6-26a2eb214bdc
Klein, Christian
caa11264-c9f6-48f2-80e7-e20b1647da63
Isenberg, David
e1564216-42fc-40c9-a638-8c9d64a5f14e
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cambridge, Geraldine
091965b3-d415-44f4-a79a-604796a27812
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Leandro, Maria
47412987-6937-4a86-aac9-42f42b669c1c
1 July 2017
Reddy, Venkat
615826e9-84f3-4053-8ce6-26a2eb214bdc
Klein, Christian
caa11264-c9f6-48f2-80e7-e20b1647da63
Isenberg, David
e1564216-42fc-40c9-a638-8c9d64a5f14e
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cambridge, Geraldine
091965b3-d415-44f4-a79a-604796a27812
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Leandro, Maria
47412987-6937-4a86-aac9-42f42b669c1c
Reddy, Venkat, Klein, Christian, Isenberg, David, Glennie, Martin, Cambridge, Geraldine, Cragg, Mark and Leandro, Maria
(2017)
Obinutuzumab induces superior B-Cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.
Rheumatology, 56 (7), .
(doi:10.1093/rheumatology/kex067).
Abstract
Objective A proportion of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) patients treated with standard doses of rituximab (RTX) display inefficient B cell deletion and poor clinical responses which can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients. To investigate whether better responses could be achieved with mechanistically different anti-CD20 mAbs.
Methods We compared RTX with Obinutuzumab (OBZ), a new-generation, glycoengineered type II anti-CD20 mAb in a series of in vitro assays measuring B cell cytotoxicity in RA and SLE patient samples.
Results We found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in-vitro whole blood assays. Dissecting this difference, we found that RTX elicited more potent complement-dependent cellular cytotoxicity (CDC) than OBZ. In contrast, OBZ was more effective at evoking Fc gamma receptor (FcγR)-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with FcγRs and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized. OBZ was also more efficient at inducing direct cell death. This was true for all CD19+ B-cells as a whole and in naïve (IgD+CD27-); and switched (IgD-CD27+) memory B-cells specifically, a higher frequency of which is associated with poor clinical response after RTX.
Conclusions Taken together, these data provide a mechanistic basis for resistance to Rituximab induced B-cell depletion, and for considering Obinutuzumab, as an alternative B-cell depleting agent in RA and SLE.
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Accepted/In Press date: 10 November 2016
e-pub ahead of print date: 11 April 2017
Published date: 1 July 2017
Organisations:
Cancer Sciences
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Local EPrints ID: 402668
URI: http://eprints.soton.ac.uk/id/eprint/402668
ISSN: 1462-0324
PURE UUID: a7dcc72b-f2eb-42cb-9c51-f7cb64a6bd16
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Date deposited: 22 Nov 2016 14:36
Last modified: 16 Mar 2024 02:58
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Author:
Venkat Reddy
Author:
Christian Klein
Author:
David Isenberg
Author:
Geraldine Cambridge
Author:
Maria Leandro
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