The genetics of natalizumab hypersensitivity

The genetics of natalizumab hypersensitivity One learns to itch where one can scratch Many of the immune therapies that are currently approved or in development for patients with multiple sclerosis (MS) are potentially immunogenic recombinant proteins. 1 Some of these proteins have amino acid substitutions, while others may differ from their endogenous counterparts by posttransla-tional modifications. Recombinant antibodies, including natalizumab, also induce immune responses that render them inactive and that cause some recipients to display a variety of symptoms that are discussed below. Even with the development of technologies that allow the development of fully humanized monoclonal antibodies, their immunogenicity could not be fully abolished. With regard to immune responses to natalizumab, 2 curious phenomena can be discerned: (1) their incidence has substantially increased as the agent made its way through clinical development, and (2) the phenotype of hypersensitivity sensations is ill-defined. The publication of an initial small placebo-controlled trial with natalizumab does not mention hypersensitivity reaction to natalizumab at all. 2 Subsequently , several immune-related adverse events were reported in a phase 2 clinical trial. 3 One out of 68 patients in the 3 mg/kg body weight natalizu-mab treatment group experienced an anaphylactoid reaction with urticaria and bronchospasm. In addition , there were 3 reports of serum sickness, one in each natalizumab treatment group and one in the placebo group. It is interesting that all 3 of these events occurred at a single study site. In one of the phase 3 trials (AFFIRM 4), 4% of natalizumab recipients had hypersensitivity reactions, including urti-caria or generalized urticaria, allergic dermatitis, hypersensitivity, and 5 patients with anaphylactic or anaphylactoid reactions. The majority of reactions occurred on the second infusion. In the second phase 3 trial (SENTINEL 5), 1.9% of patients assigned a combination therapy of 2 potentially recombinant immunogenic proteins, natalizumab and interferon b-1a (Avonex), had a hypersensitivity reaction, 8 of which were isolated cases of urticaria. Despite the mostly benign outcomes from these hypersensitivity reactions, neurologists would like to be able to predict which of their patients is at risk. If a diagnostic test existed, a decision might be made to monitor these individuals more closely or to initiate another pharmacotherapy. In the current issue of Neurology ® Neuroimmu-nology & Neuroinflammation, de la Hera et al. 6 investigated potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic or ana-phylactoid reactions in patients …