Pharmacokinetics and safety of roledumab, a novel human recombinant monoclonal anti‐RhD antibody with an optimized Fc for improved engagement of FCγRIII, in healthy volunteers

Abstract

Background and Objectives A human recombinant monoclonal anti-RhD IgG may be useful to prevent RhD allo-immunization. Roledumab is such an antibody with a glycosylation pattern optimized for biological activity. The objective of the study was to assess the safety and pharmacokinetics of roledumab in healthy RhD-negative volunteers.Materials and Methods A total of 46 subjects received doses of 30-3000 lg i.v. of roledumab or placebo using a double-blind escalating single-dose design; 12 of these subjects also received 300 lg i.m. of roledumab. Subjects were followed for 6 months after administration. Serum roledumab concentrations were determined using flow cytometry.Results Fourteen treatment-emergent adverse events related to treatment were reported in nine subjects, with no apparent difference in their frequency or nature after placebo or roledumab administration. No anti-roledumab antibodies were detected. AUC last increased from 4AE4 ng ⁄ ml.day at 30 lg i.v. to 2257 ng ⁄ ml.day at 3000 g i.v. The t ½ ranged from 18 to 22 days, and the absolute bioavailability after i.m. administration was between 73% and 80%.Conclusion Roledumab is safe and well tolerated in healthy RhD-negative volunteers and shows a pharmacokinetic profile similar to that of polyclonal anti-RhD immunoglobulin.

The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells

“…This property is related to the lower expression of the Fut8 gene in rat myeloma YB2/0 cells compared with other commonly used cell lines, such as CHO cells [30]. Two EMABling ® MAbs, the anti-RhD roledumab [41] and the anti-CD20 ublituximab [42], are currently in clinical development. Moreover, we [29, 41] and other groups [43–45] have demonstrated that such improved effector functions are associated with higher therapeutic efficacy in humans, especially in oncology.…”

Prophylactic anti‐D preparations display variable decreases in Fc‐fucosylation of anti‐D

“…The importance of core fucosylation of the IgG Fc has mainly received attention because of the possibilities to produce more efficacious therapeutic antibodies, and glycoengineered cancer antibodies carrying afucosylated Fc glycans are currently in clinical development (reviewed by Yamane‐Ohnuki and Satoh) . For this reason, Beliard and colleagues selected, in their search toward a recombinant anti‐D to replace plasma‐derived RhIG, a monoclonal anti‐D (LFB‐R297) that contains an optimized glycosylation profile characterized by a low fucose content . Since there is only little variation in the fucose content of human IgG found in serum, and on the glycopeptide level on average 93% of IgG do contain core fucose, the relevance of the fucose content of polyclonal RhIG has never been studied.…”

“…11 For this reason, Beliard and colleagues 5 selected, in their search toward a recombinant anti-D to replace plasma-derived RhIG, a monoclonal anti-D (LFB-R297) that contains an optimized glycosylation profile characterized by a low fucose content. 12 Since there is only little variation in the fucose content of human IgG found in serum, and on the glycopeptide level on average 93% of IgG do contain core fucose, the relevance of the fucose content of polyclonal RhIG has never been studied. However, recently, we observed a low Fc-fucosylation (down to approx.…”

Quantitation of fetomaternal haemorrhage and F cells in unusual maternal blood samples by flow cytometry using anti‐D and anti‐HbF

“…Anti‐D immunoglobulin is currently derived from human plasma of immunised, boosted donors. Monoclonal anti‐D is not available as a substitute and recombinant anti‐D was ineffective in several trials (Kumpel, ), although development and glycosylation research is ongoing (Olovnikova et al , ; Yver et al , ).…”