CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice.

Abstract

The CD32a immunoglobulin G (IgG) receptor (Fcγ receptor IIa) is a potential therapeutic target for diseases in which IgG immune complexes (ICs) mediate inflammation, such as heparin-induced thrombocytopenia, rheumatoid arthritis, and systemic lupus erythematosus. Monoclonal antibodies (mAbs) are a promising strategy for treating such diseases. However, IV.3, perhaps the best characterized CD32a-blocking mAb, was recently shown to induce anaphylaxis in immunocompromised "3KO" mice. This anaphylactic reaction required a human CD32a transgene because mice lack an equivalent of this gene. The finding that IV.3 induces anaphylaxis in CD32a-transgenic mice was surprising because IV.3 had long been thought to lack the intrinsic capacity to trigger cellular activation via CD32a. Such an anaphylactic reaction would also limit potential therapeutic applications of IV.3. In the present study, we examine the molecular mechanisms by which IV.3 induces anaphylaxis. We now report that IV.3 induces anaphylaxis in immunocompetent CD32a-transgenic "FCGR2A" mice, along with the novel finding that IV.3 and 2 other well-characterized CD32a-blocking mAbs, AT-10 and MDE-8, also induce severe thrombocytopenia in FCGR2A mice. Using recombinant variants of these same mAbs, we show that IgG "Fc" effector function is necessary for the induction of anaphylaxis and thrombocytopenia in FCGR2A mice. Variants of these mAbs lacking the capacity to activate mouse IgG receptors not only failed to induce anaphylaxis or thrombocytopenia, but also very potently protected FCGR2A mice from near lethal doses of IgG ICs. Our findings show that effector-deficient IV.3, AT-10, and MDE-8 are promising candidates for developing therapeutic mAbs to treat CD32a-mediated diseases.

• Authors: Todd Meyer, Liza Robles-Carrillo, Monica Davila, Meghan Brodie, Hina Desai, Mildred Rivera-Amaya, John L Francis, Ali Amirkhosravi
• Journal: Blood (Blood) Vol. 126 Issue 19 Pg. 2230-8 (Nov 05 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26396093 (Publication Type: Journal Article)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Antibodies, Neutralizing
• Fc gamma receptor IIA
• Receptors, IgG

Topics

• Anaphylaxis (chemically induced, immunology, pathology)
• Animals
• Antibodies, Monoclonal, Murine-Derived (adverse effects, immunology, pharmacology)
• Antibodies, Neutralizing (adverse effects, immunology, pharmacology)
• Humans
• Mice
• Mice, Transgenic
• Receptors, IgG (antagonists & inhibitors, genetics, immunology)
• Thrombocytopenia (chemically induced, genetics, immunology, pathology)