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In vitro and in vivo activities of OX40 (CD134)‐IgG fusion protein isoforms with different levels of immune‐effector functions
Author(s) -
Taylor Liz,
Bachler Marcus,
Duncan Imogen,
Keen Simon,
Fallon Rosie,
Mair Catherine,
McDonald Thomas T.,
Schwarz Herbert
Publication year - 2002
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.72.3.522
Subject(s) - biology , effector , fusion protein , in vivo , immune system , gene isoform , microbiology and biotechnology , in vitro , immunology , antibody , recombinant dna , biochemistry , gene , genetics
Recombinant fusion proteins consisting of the extracellular domain of immunoregulatory proteins and the constant domain of immunoglobulin G (IgG) are a novel class of human therapeutics. IgG isofors exert different levels of immune effector functions, such as complement lysis and antibody‐dependent cell cytotoxicity (ADCC). Several OX40‐Ig fusion proteins were generated and compared in their potency to inhibit immune reactions. OX40‐IgG fusion proteins act as decoys and inhibit T cell costimulation and extravasation induced by OX40 ligand‐expressing antigen‐presenting cells (APC) and vascular endothelial cells, respectively. In addition, OX40‐IgG1 protein induces ADCC and complement lysis in OX40 ligand‐expressing cells. Replacement of the IgG1 by the IgG4 domain (OX40‐IgG4) eliminated complement lysis and reduced ADCC by half. Mutation of Leu 235 to Glu in IgG4 eliminated the remaining ADCC activity and generated a protein devoid of immune effector functions (OX40‐IgG4mut). In vitro, OX40‐IgG1 was more potent in inhibiting proliferation and cytokine release by peripheral blood mononuclear cells than OX40‐IgG4mut, as OX40‐IgG1 induced cell death in APC. However, both proteins reduced T cell‐mediated colitis in mice to the same extent, indicating that in vivo neutralization of OX40L is sufficient. This study also demonstrates that effector functions of antibodies are retained and can be rationally designed in receptor‐IgG fusion proteins.