Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy.
CD20 Abs induce clinical responses in lymphoma patients, but there are considerable differences between individual patients. In (51)Cr release assays with whole blood as effector source, RAJI cells were effectively killed by a mouse/human chimeric IgG1 construct of CD20 Ab 1F5, whereas ARH-77 proved resistant to killing by this Ab. When whole blood was fractionated into plasma, mononuclear cells, or granulocytic effector cells, RAJI cells were effectively killed in the presence of complement-containing plasma, whereas the mature B cell line ARH-77 proved complement resistant. However, with a bispecific Ab (BsAb) against the myeloid receptor for IgA (CD89; FcalphaRI) and CD20, a broad range of B cell lines were effectively killed. FcalphaRI is expressed on monocytes/macrophages, neutrophils, and eosinophils. As the numbers of these effector cells and their functional activity can be enhanced by application of G-CSF or GM-CSF, lysis via (FcalphaRI x CD20) BsAb was significantly enhanced in blood from patients during therapy with these myeloid growth factors. Interestingly, the major effector cell population for this BsAb were polymorphonuclear neutrophils, which proved ineffective in killing malignant B cells with murine, chimeric IgG1, or FcgammaRI- or FcgammaRIII-directed BsAbs against CD20. Experiments with blood from human FcalphaRI/FcgammaRI double-transgenic mice showed corresponding results, allowing the establishment of relevant syngenic animal models in these mice. In conclusion, the combination of myeloid growth factors and an (FcalphaRI x CD20) BsAb may represent a promising approach to improve effector cell recruitment for CD20-directed lymphoma therapy.
Stockmeyer
B
B
Division of Hematology/Oncology, Department of Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany. Bernhard.Stockmeyer@med3.imed.uni-erlangen.de
Dechant
M
M
van Egmond
M
M
Tutt
A L
AL
Sundarapandiyan
K
K
Graziano
R F
RF
Repp
R
R
Kalden
J R
JR
Gramatzki
M
M
Glennie
M J
MJ
van de Winkel
J G
JG
Valerius
T
T
D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000276:immunology*; D011961:Receptors, Fc / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C036832:Fc(alpha) receptor; D006131:Growth Inhibitors; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor