Journal article

Publication year: 2024

Pages: 1869-1879

Journal: Blood Advances

Volume number: 8

Issue number: 8

ISSN: 2473-9529

eISSN: 2473-9537

Open access status: Gold

DOI Link: https://doi.org/10.1182/bloodadvances.2023012155

Publisher: American Society of Hematology (ASH Publications)

Abstract: 
Fc gamma receptor (Fc gamma R) IIIA is an important receptor for immunoglobulin G (IgG) and is involved in immune defense mechanisms as well as tissue destruction in some autoimmune diseases including immune thrombocytopenia (ITP). Fc gamma RIIIA on macrophages can trigger phagocytosis of IgG-sensitized platelets, and prior pilot studies observed blockade of Fc gamma RIIIA increased platelet counts in patients with ITP. Unfortunately, although blockade of Fc gamma RIIIA in patients with ITP increased platelet counts, its engagement by the blocking antibody drove serious adverse inflammatory reactions. These adverse events were postulated to originate from the antibody's Fc and/or bivalent nature. The blockade of human Fc gamma RIIIA in vivo with a monovalent construct lacking an active Fc region has not yet been achieved. To effectively block Fc gamma RIIIA in vivo, we developed a high affinity monovalent single-chain variable fragment (scFv) that can bind and block human Fc gamma RIIIA. This scFv (17C02) was expressed in 3 formats: a monovalent fusion protein with albumin, a 1-armed human IgG1 antibody, and a standard bivalent mouse (IgG2a) antibody. Both monovalent formats were effective in preventing phagocytosis of ITP serum-sensitized human platelets. In vivo studies using Fc gamma R-humanized mice demonstrated that both monovalent therapeutics were also able to increase platelet counts. The monovalent albumin fusion protein did not have adverse event activity as assessed by changes in body temperature, whereas the 1-armed antibody induced some changes in body temperature even though the Fc region function was impaired by the Leu234Ala and Leu235Ala mutations. These data demonstrate that monovalent blockade of human Fc gamma RIIIA in vivo can potentially be a therapeutic strategy for patients with ITP.

Harvard Citation style: Gonzalez, L., Won, K., Tawhidi, Z., Cummins, E., Cruz-Leal, Y., Cabado, Y., et al. (2024) Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP, Blood Advances, 8(8), pp. 1869-1879. https://doi.org/10.1182/bloodadvances.2023012155

APA Citation style: Gonzalez, L., Won, K., Tawhidi, Z., Cummins, E., Cruz-Leal, Y., Cabado, Y., Sachs, U., Norris, P., Shan, Y., Bhakta, V., Li, J., Samudio, I., Silva-Moreno, B., Cerna-Portillo, L., Oro, A., Bergqvist, P., Chan, P., Moorehead, A., Sholzberg, M., ...Lazarus, A. (2024). Human Fc gamma receptor IIIA blockade inhibits platelet destruction in a humanized murine model of ITP. Blood Advances. 8(8), 1869-1879. https://doi.org/10.1182/bloodadvances.2023012155