Depletion of Suppressor-cytotoxic T-Lymphocytes by Administration of a Murine Monoclonal Antibody

Abstract

We administered anti-Leu 2a, a murine monoclonal antibody to the human suppressor-cytotoxic T-cell subset, to 20 patients with advanced cancer to determine the toxicity and its ability to deplete circulating Leu 2(+) lymphocytes. Four doses were tested, 1, 5, 25, and 100 mg, and the infusion rate varied from 2 to 24 h. Administration of anti-Leu 2a produced rapid (within 4 h) depletion of circulating Leu 2(+) lymphocytes, the magnitude and duration of which were dose dependent: the 1-mg dose caused a <50% fall in circulating Leu 2(+) lymphocytes, while the higher doses caused 75–98% depletion of those cells in 10 of 17 patients so treated. The duration of depletion of Leu 2(+) cells was 1–2 days after 5 mg of anti-Leu 2a, 3–4 days after 25 mg, and 4–30+ days after 100 mg. In seven patients (3–5, 3–25, and 1–100 mg), there was persistence of variable numbers of circulating mouse Ig-coated Leu 2(+) cells, possibly indicating impaired capacity to clear these cells. Modulation of the Leu 2a antigen after antibody treatment was not observed. Peak serum levels of anti-Leu 2a were (medians): 5-mg dose = 350 ng/ml, 25-mg dose = 5500 ng/ml, and 100-mg dose = 48,000 ng/ml; murine antibody was detectable in the serum for 7–14 days after the 100-mg dose. All patients had increased titers of antimouse antibody following treatment with peak titers on day 14. The most common toxicity was shaking chills. This occurred within 1.5 h of beginning the infusion, lasted for no more than 30 min, and did not require cessation of the treatment. Anti-Leu 2a administration caused a clinically unimportant, but statistically significant fall in hematocrit (mean = -7%) and platelet (mean = -23%) count and a transient (<1 day duration) fall in the total lymphocyte count. Thus, infusion of murine monoclonal anti-Leu 2a can cause substantial depletion of the suppressor-cytotoxic T-cell subset with modest toxicity.