Are 25 antibodies better than 1?

In this issue of Blood, Robak et al present data suggesting that rozrolimupab, a firstin-class mixture of 25 recombinant monoclonal IgG1 antibodies against RhD, has efficacy similar to plasma-derived anti-RhD in the treatment of immune thrombocytopenia.1 P lasma-derived anti-RhD, a hyperimmune preparation of IgG that targets the RhD antigen on erythrocytes, is a standard first-line therapy in nonsplenectomized RhDpositive individuals with immune thrombocytopenia (ITP), and is also used to prevent maternal RhD-sensitization and hemolytic disease of the newborn. The primary mechanism of action in ITP is thought to involve opsonization of endogenous RhD-positive red blood cells (RBCs), resulting in preferential clearance of antibody-coated RBCs by the reticuloendothelial system and sparing of antibody-coated platelets.2 In a phase 1/2 dose escalation study, rozrolimupab was administered as a single dose of 75 to 300 g/kg to 61 nonsplenectomized, RhD-positive adults with primary ITP.1 Treatment was generally well tolerated. The most common adverse events, headache and infusion reactions, were predominantly mild and transient. As expected, most subjects experienced a fall in hemoglobin with a trend toward greater reductions with increasing dose. Across all dose cohorts, 21 patients (34%) achieved a platelet response (platelet count 30 109/L and increase from baseline of 20 109/L) at day 7. In general, response rates improved with increasing dose (see figure). In the 300 g/kg cohort, 8 of 13 patients (62%) responded, a rate on par with the 60% to 72% response rate observed in clinical trials of plasma-derived anti-RhD.2 A recombinant replacement for plasmaderived anti-RhD offers several advantages. First, plasma-derived anti-RhD is produced by fractionation of IgG from pooled plasma of donors with high anti-RhD titers. Originally, most donors were RhD-negative women who had been immunized by pregnancy. Thanks to the widespread and effective use of anti-RhD prophylaxis, such women are now scarce and most donors today are RhD-negative hyperimmunized males. If this donor pool were to become compromised, availability of plasma-derived anti-RhD would be in jeopardy.3 Indeed, several countries including Australia and Poland have endured national shortages. A recombinant product would ensure a renewable source of anti-RhD. Second, although the risk of pathogen transmission with plasma-derived anti-RhD is very small, this risk would be all but eliminated with a recombinant product. Third, a recombinant preparation would eliminate rare adverse reactions due to impurities in plasmaderived anti-RhD such as transfusionrelated acute lung injury or anaphylaxis in patients with IgA-deficiency. The concept of monoclonal anti-RhD therapy for ITP is not new. Godeau et al treated 7 RhD-positive ITP patients with a single anti-RhD monoclonal antibody (MAB).4 Only 1 patient evinced a transient platelet response. Trials of RhD prophylaxis in RhD-negative subjects were similarly disappointing.3 Why would a mixture of 25 anti-RhD MABs, but not single MAB preparations, reproduce the effects of plasma-derived antiRhD? The answer to this question is unknown, although several explanations are possible. An intuitive but probably incorrect