A therapeutic strategy to target distinct sources of IgE and durably reverse allergy.

Autor:	Limnander A; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Kaur N; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Asrat S; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Tasker C; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Boyapati A; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Ben LH; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Janczy J; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Pedraza P; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Abreu P; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Chen WC; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Godin S; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Daniel BJ; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Chin H; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., DeVeaux M; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Rodriguez Lorenc K; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Sirulnik A; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Harari O; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Stahl N; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Sleeman MA; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Murphy AJ; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Yancopoulos GD; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA., Orengo JM; Regeneron Pharmaceuticals, Tarrytown, New York, 10591, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Dec 13; Vol. 15 (726), pp. eadf9561. Date of Electronic Publication: 2023 Dec 13.
DOI:	10.1126/scitranslmed.adf9561
Abstrakt:	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.
Databáze:	MEDLINE
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