T65 antigen modulation in a phase I monoclonal antibody trial with chronic lymphocytic leukemia patients

Antigenic modulation of the T65 cell surface antigen was assessed in chronic lymphocytic leukemia patients (CLL) receiving therapy with the murine monoclonal antibody T101 in a phase I clinical trial. A total of 12 patients received 1, 10, or 40 mg doses administered over 2 hr, or 50 or 100 mg doses administered over 50 hr. Decreases in T65 antigen expression (up to 90%) coincided with decreases in the circulating leukemic cell count in those patients who received T101 over a 2-hr period, indicating that clearance of circulating T65 antigen-positive cells could account for most of the observed decreases in T65 antigen expression. In contrast, analysis of bone marrow specimens from these patients indicated that decreases in T65 antigen density in this relatively stationary population resulted not from a cell decrement but rather from antigenic modulation. Pulmonary toxicity prevented administration of doses greater than 40 mg over a 2-hr period; therefore, higher doses (50 and 100 mg) were administered over a 50-hr period. This treatment schedule resulted in greater than 90% reduction in T65 antigen density of both circulating and bone marrow leukemic cells without dramatic drops in circulating leukemic cell counts, indicating that antigenic modulation accounted for most of the observed decreases in T65 antigen density under these conditions. Reexpression of T65 antigen by modulated cells was observed both in vitro and in vivo within 2 to 4 days. Immunoperoxidase staining of in vivo-modulated specimens and in vitro modulation studies with 125I-T101 suggested that T65 antigen-T101 antibody complexes were internalized during modulation. Although antigenic modulation inhibits the potential therapeutic effectiveness of unconjugated T101 antibody in CLL patients, treatment of CLL with T101 drug or toxin immunoconjugates under conditions that bring about rapid and extensive internalization of the T65 antigen may provide an effective means of therapy.