B-Cell Depletion In Vitro and In Vivo with an Afucosylated Anti-CD19 Antibody

Herbst, Ronald; Wang, Yue; Gallagher, Stephen; Mittereder, Nanette; Kuta, Ellen; Damschroder, Melissa; Woods, R. Jeremy; Rowe, Daniel C.; Cheng, Li; Cook, Kim; Evans, Krista; Sims, Gary P.; Pfarr, David S.; Bowen, Michael A.; Dall’Acqua, William F.; Shlomchik, Mark J.; Tedder, Thomas F.; Kiener, Peter A.; Jallal, Bahija; Wu, Herren; Coyle, Anthony J.

doi:10.1124/jpet.110.168062

Cited by 114 publications

(118 citation statements)

References 46 publications

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“…Additionally, we validated the sensitivity and specificity of this signature using ex vivo experiments and confirmed its utility in scleroderma patients enrolled in a phase I dose-escalation trial of MEDI-551, an anti-CD19 mAb with enhanced effector function (26). Furthermore, we identified multiple autoimmune diseases with increases in the PC signature, which may be indicative of a relationship between PCs and the pathogenesis of these diseases and which may aid in identifying patients who may benefit from PCdepleting therapy.…”

mentioning

confidence: 60%

The Plasma Cell Signature in Autoimmune Disease

Streicher¹,

Morehouse²,

Groves³

et al. 2013

Arthritis & Rheumatology

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Objective. Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.Methods. We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases.Results. The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r ‫؍‬ 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs.Conclusion. This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.

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confidence: 60%

The Plasma Cell Signature in Autoimmune Disease

Streicher¹,

Morehouse²,

Groves³

et al. 2013

Arthritis & Rheumatology

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“… 107 Humanized IgG1 Inebilizumab/MEDI-551CD19afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced B-cell depletion in huCD19/CD20 transgenic mouse over rituximabHerbst et al. 105 Humanized IgG1 A direct comparison between MEDI-551 and the fucosylated anti-CD19 in CD19 + Raji and Daudi cells lymphoma xenograft SCID mouse model only showed minor or insignificant improvement in tumor inhibition respectivelyWard et al. 104 Prolonged animal survival in SCID mice engrafted with human pre-B cells over afucosylated control IgG1Matlawska-Wasowska et al.…”

Section: Enhanced Adcc Activities By Afucosylated Antibodies In In VImentioning

confidence: 99%

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

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Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.

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“…We reported previously that NK cells, and not monocytes, were the major effector population mediating cytotoxicity with SMIP-016, 8 but the importance of the role of monocytes and macrophages in the function of therapeutic antibodies is emerging, [22][23][24][25] especially in anti-CD20 therapy. Similar to what we had seen previously, we saw low ADCC function with SMIP-016 and SMIP-016 GV in monocytes against CLL B cells (data not shown).…”

Section: Resultsmentioning

confidence: 99%