PB0221 - Neutralizing antidrug antibody to emicizumab: Detailed laboratory evaluation and review of the literature

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

Hande Kizilocak, MD

Research Scientist
Children's Hospital Los Angeles
Los Angeles, California, United States

Co-Author(s)

JB

Joshua Brown

Clinical Laboratory Specialist
Children's Hospital Los Angeles
Los Angeles, California, United States
Guy Young, MD

Director, Hemostasis and Thrombosis Center
Children's Hospital Los Angeles
Los Angeles, California, United States

Background: Emicizumab is a monoclonal bispecific antibody which has been shown to be safe and effective in patients with hemophilia A (HA) with and without inhibitors. Treatment with monoclonal antibodies can result in the formation of antidrug antibodies (ADA).

Aims: To report 5 persons with HA (PwHA) treated with emicizumab who developed ADA (some previously published).

Methods: A literature review was conducted to identify previously reported cases of anti-emicizumab ADA from around the world and these cases were supplemented by additional patients tested in our specialized laboratory by methods we previously published (see figure). Essentially, we developed a Bethesda-like assay using the human chromogenic FVIII activity (humCHR) to determine the presence of ADA from patient plasma with a known concentration of emicizumab in control plasma.

Results: Five PwHA with and without inhibitors with a median age of 7 (2-62) have been identified with anti-emicizumab ADA (see table). According to the manufacturer, ~12,000 individual PwHA have been treated with emicizumab. The presentation was unexpected/excessive bleeding and a prolonged aPTT in all cases. Four of the 5 cases had FVIII inhibitors and one did not. Four of the 5 were found to have a neutralizing ADA and one had a non-neutralizing ADA which resulted in increased/rapid clearance of emicizumab. Interestingly, all the cases presented in the first year and 4/5 in the first 24 weeks after emicizumab initiation.

Conclusion(s): Emicizumab is very effective at bleed prevention, however, albeit rare, ADA can still occur. Breakthrough bleeding and aPTT prolongation are the first signs of ADA to emicizumab which should prompt further evaluation. There currently are no commercially available assays to determine ADA to emicizumab. Suspected cases can be identified using a modified Bethesda assay with commercially available reagents and an approximate level of ADA can be calculated.