A study on OX39, a murine anti-rat interleukin 2 receptor antibody. A report on receptor binding and effects on allograft survival.
OX39, a murine IgG1 monoclonal antibody (MoAb) that recognizes the 55 kDa alpha chain of the rat interleukin 2 receptor (R-IL2), was studied in vitro for its ability to interfere with IL2 binding and IL2-induced proliferation on rat concanavalin A (ConA) blasts and in vivo in a model of rat heart allografts. In vitro studies indicated that OX39 MoAb interacts with a single class of sites on the alpha chain of the rat R-IL2 with a high affinity (KD = 0.8 nm) and competes with IL2 binding on this chain (KI = 0.53 nm). In contrast, OX39 MoAb was found to be 10-20 times less efficient in competing with IL2 binding to the high-affinity R-IL2 (KI approximately 10 nm). It is proposed that the epitope recognized by OX39 on the alpha chain (low-affinity R-IL2) is modified on (or buried in) the high-affinity R-IL2 configuration. Accordingly, OX39 was found to be a weak inhibitor in vitro on IL2-induced proliferation and in vivo on allograft rejection. Allograft survival was unaffected by doses of OX39 of 20 and 50 micrograms/rat for 9 days; only a borderline effect was noted when doses as high as 250 micrograms/rat were used. A significant, but restricted, effect of OX39 could be further detected when combined with low doses of cyclosporine A (1.5 mg/kg), which were ineffective by themselves. Together, our data suggest that in order to be efficient in vivo, anti-R-IL2 MoAbs must bind with high affinity to epitopes involved in the high-affinity IL2 binding site.
Jacques
Y
Y
Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Nantes, France.
Paineau
J
J
Chevalier
S
S
Le Mauff
B
B
Soulillou
J P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001666:Binding Sites, Antibody; D002478:Cells, Cultured; D006085:Graft Survival; D016027:Heart Transplantation; D007376:Interleukin-2 / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D015375:Receptors, Interleukin-2