IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice.
High affinity IL-2R5 is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL-2R is an attractive therapy for many T cell-dependent cytopathic disease processes. A variety of rodent mAbs directed against the alpha-chain of the IL-2R, as well as IL-2 fusion toxins, have been used in animals and humans to achieve selective immunosuppression. Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein. This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t1/2 of 25 h following systemic administration. To subsequently explore the mechanisms of the antidiabetogenic effects of IL-2/Fc, we have mutated the FcR binding and complement C1q binding (Fc-/-) domains of the Fc fragment to render the Fc unable to direct Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. In a model of passive transfer of diabetes in nonobese diabetic mice, lytic IL-2/Fc, but not nonlytic IL-2/Fc-/-, exhibited striking antidiabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a new therapeutic approach for selective targeting of auto and alloimmune T cells.
Zheng
X X
XX
Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Steele
A W
AW
Hancock
W W
WW
Kawamoto
K
K
Li
X C
XC
Nickerson
P W
PW
Li
Y
Y
Tian
Y
Y
Strom
T B
TB
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015153:Blotting, Western; D015704:CD4 Antigens / Q000276:immunology; D018791:CD4 Lymphocyte Count; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D018390:Gene Targeting; D015316:Genetic Therapy; D006207:Half-Life; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins