Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes.
Anti-cytokine antibodies that block interactions between cytokines and cytokine receptors have been used to inhibit endogenous cytokine function. However, injection of mice with mixtures of IL-4 and either of two neutralizing anti-IL-4 mAb, at a cytokine/anti-cytokine mAb molar ratio of approximately 2:1, enhances and prolongs in vivo IL-4 activity, as measured by induction of increased spleen cell Ia expression. Although splenocyte Ia expression returns to baseline two days after mice are injected with free IL-4, soluble IL-4-anti-IL-4 mAb complexes still induce several-fold increases in Ia expression 3 days after injection. Complexes that contain as little as 400 ng of IL-4 have considerable in vivo stimulatory activity, and a maximal effect on splenocyte Ia expression is induced by injection of 2 micrograms of complexed IL-4. The stimulatory effect of IL-4-containing complexes on splenocyte Ia expression can be blocked by increasing the ratio of anti-IL-4 mAb to IL-4, by injection of anti-IL-4R mAb, and by in vivo aggregation of the complexes. Complexes of IL-4 with a non-neutralizing anti-IL-4 mAb do not have increased IL-4 agonist activity in vivo. These observations are most consistent with the possibility that neutralizing anti-IL-4 mAb act as carrier proteins that increase the in vivo half-life of IL-4 by preventing its excretion, and possibly, by preventing modification of its active site. The enhanced agonist effect of IL-4-anti-IL-4 mAb complexes is not unique; complexes of IL-3 with a neutralizing anti-IL-3 mAb have a greatly increased ability, compared with free IL-3, to stimulate mucosal mastocytosis, and complexes of IL-7 with a neutralizing anti-IL-7 mAb have a greatly increased ability, compared with free IL-7 or IL-7 complexed with a non-neutralizing anti-IL-7 mAb, to stimulate an increase in pre-B cell number. These observations suggest that complexes of cytokines and neutralizing anti-cytokine mAb may provide a generally useful way to increase the magnitude and duration of cytokine effects in vivo.
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
F D
FD
Finkelman
K B
KB
Madden
S C
SC
Morris
J M
JM
Holmes
N
N
Boiani
I M
IM
Katona
C R
CR
Maliszewski
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001854:Bone Marrow Cells; D016207:Cytokines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007377:Interleukin-3 / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D015851:Interleukin-7 / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D000936:Antigen-Antibody Complex; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007377:Interleukin-3; D015851:Interleukin-7; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4