Monoclonal anti-D development programme.
Administration of anti-D immunoglobulin to D- women after delivery of a D+ infant has dramatically reduced the number of immunised women and cases of haemolytic disease of the fetus and newborn. The use of monoclonal anti-D might alleviate some of the pressures on maintaining adequate supplies of plasma sourced anti-D. Two human monoclonal antibodies, BRAD-3 (IgG1) and BRAD-5 (IgG3), with proven activity in in vitro functional (immunological) assays with cells bearing IgG Fc receptors (Fc gammaR) were selected for clinical studies. They were prepared by purification of IgG secreted by culture of the Epstein-Barr virus-transformed B cell lines in hollow fibre bioreactors. The mean half-lives of BRAD-3 and BRAD-5 in D- subjects were 10.2 and 22.2 days, respectively. The clearance of D+ red cells injected into D- subjects was accelerated by prior injection of the monoclonal antibodies, both individually and blended (3:1, BRAD-5/BRAD-3). The clearance rate was related to the amount of anti-D on the red cells. Clearance of the D+ red cells coated with BRAD-3 was more rapid in subjects homozygous for Fc gammaRIIIa-F/F158 than in those expressing the Fc gammaRIIIa-V158 allele. The subjects were protected from Rh D immunisation. A large multi-centre study evaluated the BRAD-3/5 blend for its ability to prevent Rh D immunisation in 95 D- subjects given 400 microg i.m. 24 h after injection of 5 ml D+ red cells. Challenge injections of D+ red cells alone were given 24 and 36 weeks later, and blood samples were taken every 4 weeks from the subjects throughout the study for detection of anti-D responses. There was one definite and one possible failure of protection; in one subject the plasma anti-D level rose from week 12 onwards, and in another individual rapid seroconversion was observed at week 28. Considering the relatively large dose of red cells and the number of subjects studied, it was concluded that the failure rate was much lower than in routine Rh D prophylaxis. The responder rate was 13% by week 36 and 24% by week 48. There was no relationship between HLA haplotype and Rh D immunisation. The low percentage of responders and the modest levels of endogenous anti-D produced suggested that administration of monoclonal anti-D had induced long-term specific suppression of anti-D responses in these subjects. The most likely mechanism of action was considered to be inhibition of B cells resulting from co-cross-linking antigen receptors with inhibitory Fc gammaR when the B cells contacted red cells that had bound passive anti-D.
Kumpel
Belinda M
BM
International Blood Group Reference Laboratory, Bristol Institute of Transfusion Sciences, UK.
D000328:Adult; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification / Q000493:pharmacokinetics; D019149:Bioreactors; D002461:Cell Line, Transformed / Q000276:immunology; D002986:Clinical Trials as Topic; D004739:England; D004899:Erythroblastosis, Fetal / Q000517:prevention & control*; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006681:HLA-D Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human; D006801:Humans; D007116:Immunization, Passive; D007165:Immunosuppression Therapy; D007231:Infant, Newborn; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification / Q000627:therapeutic use; D008297:Male; D015337:Multicenter Studies as Topic; D011247:Pregnancy; D017452:Receptors, IgG / Q000235:genetics; D012203:Rh Isoimmunization / Q000628:therapy*; D012204:Rh-Hr Blood-Group System / Q000235:genetics / Q000276:immunology; D018029:Rho(D) Immune Globulin
D000911:Antibodies, Monoclonal; D006681:HLA-D Antigens; D007518:Isoantibodies; C061961:RHO(D) antibody; D017452:Receptors, IgG; D012204:Rh-Hr Blood-Group System; D018029:Rho(D) Immune Globulin