Preclinical evaluation of recombinant human interleukin-4.
Recombinant human IL-4 (rhuIL-4) is primate-specific and produces multiple biologic effects on lymphoid cells involved in protection against cancer. RhuIL-4 was evaluated in the cynomolgus monkey to support clinical studies for the immunotherapy of cancer. Administration of rhuIL-4 to monkeys by SC injection of 0, 0.5, 2.5 or 12.5 micrograms/kg BID for one-month (with two-week recovery) resulted in alterations in clinical chemistry and hematology (CCH) parameters consistent with a consumptive coagulopathy. Histomorphologic evaluation revealed increased granulopoiesis, testicular atrophy, and proliferative and inflammatory vascular lesions (VL). IVL principally affected the arterial tree with some proliferation of medial smooth muscle. During the latter part of the treatment and recovery period. CCH parameters approached or returned to pretreatment values, the former finding attributed to the production of antibody to rhuIL-4. At final necropsy, bone marrow appeared normal, and IVL decreased in incidence and severity. ELISA studies of serum indicated 50-90% of the monkeys developed antibody titers > 1000 by Day 22 (not observed in man). The frequency and severity of adverse effects due to rhuIL-4 in the clinic appear to be does-related and reversible with few objective responses to therapy observed. Common toxicities included milk to moderated fever and fatigue and an occasional change in hematopoietic, hepatic and renal function. The monkey predicted hematologic findings, but not all target organ effects.
Cornacoff
J B
JB
Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, NY 12144.
Gossett
K A
KA
Barbolt
T A
TA
Dean
J H
JH
D000818:Animals; D000906:Antibodies / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D005260:Female; D015847:Interleukin-4 / Q000276:immunology / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011994:Recombinant Proteins / Q000633:toxicity; D012709:Serum Albumin / Q000032:analysis
D000906:Antibodies; D011994:Recombinant Proteins; D012709:Serum Albumin; D015847:Interleukin-4