GN Ramachandran Biology Seminar Series: Immunogenicity of Protein Therapeutics - the Case of Factor VIII Neutralising Antibodies in Hemophilia A
Replacement therapy using protein-based drugs can sometimes lead to the development of anti-drug antibodies, including neutralizing antibodies. This is particularly true for patients with hemophilia A, an X-linked bleeding disorder caused by insufficient levels of functional coagulation factor VIII (FVIII). Intravenous administration of therapeutic FVIII to prevent or treat bleeding episodes triggers the development of neutralizing anti-FVIII IgG antibodies—commonly known as “FVIII inhibitors”—in up to 30% of patients. The presence of FVIII inhibitors renders further use of therapeutic FVIII ineffective, complicating patient management and significantly impacting quality of life.
Over the past two decades, research has focused on understanding why therapeutic FVIII is immunogenic. Genetic factors are the primary contributors to the development of FVIII inhibitors. These include the specific mutations causing hemophilia (such as intron inversions, large gene deletions, or nonsense and missense mutations), the patient’s HLA haplotype, and the presence of single nucleotide polymorphisms in the promoter regions of immune-related genes like TNF-α, IL-10, and CTLA-4. However, many patients with these genetic risk factors do not develop inhibitors after FVIII treatment, highlighting the importance of non-genetic risk factors.
This presentation will explore current understanding of the mechanisms driving the anti-FVIII immune response. We will examine various proposed risk factors, including structural and functional properties of the FVIII protein itself and inflammatory signals associated with the bleeding phenotype. A shift in the current paradigm of FVIII immunogenicity will be introduced. In addition, we will describe innovative strategies aimed at inducing immune tolerance to therapeutic FVIII—at least as demonstrated in preclinical models of hemophilia A. Finally, we will consider whether insights gained from studying FVIII can be applied to other protein-based therapeutics.
