DTGM fusion protein(NCI)

The renin-angiotensin system (RAS), and particularly angiotensin II, is involved in the control of energy balance, glucose homeostasis and kidney functions. The integrated impact of the RAS on glucose homeostasis is still a matter of debate.

We used a model of constitutive RAS activation in double transgenic mice (dTGM) carrying both human angiotensinogen and human renin genes. We evaluated energy balance, measured renal functions, performed glucose and insulin tolerance tests, and used ramipril to inhibit the angiotensin-converting enzyme.

dTGM had a lower physical activity and an increased food intake without change in body weight. Renal impairment was characterized by low-grade albuminuria. High urinary output secondary to polydipsia was associated with proximal tubule dysfunction. Compared to controls, dTGM had a lower hyperglycemia induced by an intraperitoneal glucose administration. This decrease was not due to changes in insulin sensitivity and/or secretion. dTGM had an increased creatinine production and a lower epididymal fat mass. Acute inhibition of angiotensin-converting enzyme with ramipril did not suppress this improved glucose tolerance profile.

Chronic RAS activation is not sufficient to cause insulin resistance in mice. Moreover, adaptation to constitutive RAS activation in mice results in a better glucose tolerance.

Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB(389)IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells.

DAB(389)IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 micro g/kg/day for up to eight cycles.

Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1-11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB(389)IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing >/==" BORDER="0">95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including >/==" BORDER="0">98% reduction in 3 patients. DAB(389)IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 micro g/ml (n = 5).

DAB(389)IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB(389)IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB(389)IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.