| Title: |
A therapeutic strategy to target distinct sources of IgE and durably reverse allergy. |
| Authors: |
Limnander, Andre; Kaur, Navneet; Asrat, Seblewongel; Tasker, Carley; Boyapati, Anita; Ben, Li-Hong; Janczy, John; Pedraza, Paulina; Abreu, Pablo; Chen, Wen-Chi; Godin, Stephen; Daniel, Benjamin J.; Chin, Harvey; DeVeaux, Michelle; Rodriguez Lorenc, Karen; Sirulnik, Andres; Harari, Olivier; Stahl, Neil; Sleeman, Matthew A.; Murphy, Andrew J. |
| Source: |
Science Translational Medicine; 12/13/2023, Vol. 15 Issue 726, p1-16, 16p |
| Subject Terms: |
Immunoglobulin E; Bispecific antibodies; Immunologic memory; Plasma cells; Kra |
| Abstract: |
Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE+ plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell–targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE+ memory B cells that require class switching and long-lived IgE+ plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity. Editor's summary: IgE antibodies are primary drivers of allergic disorders, and a strategy to both eliminate existing IgE-producing plasma cells and prevent new IgE-producing plasma cells from forming may be sufficient to reset an allergic response. Here, Limnander et al. used a combination therapy incorporating a transient dose of a BCMAxCD3 bispecific antibody to deplete plasma cells and ongoing IL-4Rα blockade to block IgE class switching. This approach was sufficient to prevent allergic reactions in mice while still allowing renewal of other antibody isotypes. Further data collected from nonhuman primates and from a clinical trial of the bispecific antibody support the feasibility of this approach, warranting further clinical investigation. —Courtney Malo [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |