Commentary on “Development of a novel fully functional coagulation factor VIII with reduced immunogenicity utilizing an in silico prediction and deimmunization approach” ‐ Will we ever be able to avoid inhibitor formation in hemophilia A?

Abstract

Inhibitory antibody formation against infused therapeutic factor VIII (FVIII) concentrates remains an important and unresolved risk in treatment of hemophilia A (HA). Both severe and nonsevere HA have substantial risk of inhibitor occurrence.1– 4 Inhibitor occurrence in severe HA has been a major focus of epidemiological, immunological, and genomic studies over past decades. Despite these major collaborative studies identifying candidate gene polymorphisms and epidemiological risk factors for inhibitor formation,1,5– 7 with proposed risk stratification algorithms,8 this has not converted to meaningful interventions to avoid or riskreduce inhibitor formation which typically happen early in the second year of life.9 Emicizumab (Roche) has recently emerged as the first nonfactor prophylaxis molecule for severe hemophilia A.10,11 Although an ongoing phase 3b study of emicizumab is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics in participants from birth to 12 months of age (clinicaltrials.gov NCT04431726), it is already recognized, and approved by regulators, to offer a different early prophylaxis option for infants and young boys with severe HA, with the logistical advantage of infrequent, subcutaneous injection over the more challenging early commencement of more frequent, intravenous infusion of FVIII concentrate. So, does the emergence of emicizumab, as firsttomarket nonfactor prophylaxis agent, represent the necessary paradigm shift for the hemophilia community to avoid FVIII inhibitor formation and the subsequent challenges of reestablishing tolerance to FVIII with immune tolerance induction? The answer is likely no . For those initiated on emicizumab as firstchoice prophylaxis agent from a young age, the most likely scenario is that inhibitor risk will only be deferred to later in childhood or adolescence because of the unavoidable sporadic “ondemand” FVIII concentrate requirement for trauma, breakthrough bleeds, or procedures, as seen in nonsevere HA.12 Might there be strategies to change the immunogenic risk of the FVIII molecule itself? Cell lineage of recombinant FVIII (rFVIII) manufacture and inhibitor risk has become a focus of interest in recent years.13 Despite compelling hypotheses that human cell linederived rFVIII might have posttranslational modification immunological advantage,14 this has not converted to convincing reductions in inhibitor rates in previously untreated patients (PUPs) treated with human cell line products, when unselectively compared to a breadth of hamstercell (CHO or BHK) derived rFVIII cohort studies.1– 3,15 Data are awaited from the first PUP study of a pegylated, CHOderived rFVIII molecule to gauge whether polyethylene glycol shrouds the immunogenic FVIII epitopes sufficiently to meaningfully reduce inhibitor rates (clinicaltrials.gov NCT02615691). This then focuses attention on what are the immunogenic epitopes of the FVIII molecule and are they modifiable to meaningfully reduce inhibitor risk? In this issue, Winterling et al. present preliminary preclinical data of their strategy to deimmunize the human FVIII molecule by in silico identification of predicted FVIIIpeptide MHCII binding motifs, altering