Induction of in vitro and in vivo antigenic modulation by the anti-human T-cell monoclonal antibody T101.

Because of its implications for the therapeutic application of monoclonal antibodies, we have studied antigenic modulation in vitro and in vivo in patients receiving T101 monoclonal antibody. Incubation of normal peripheral blood T-cells, chronic lymphocytic leukemia cells, and cutaneous T-cell lymphoma cells with an excess of T101 at 37 degrees induced modulation of the T65 antigen. When assayed by indirect immunofluorescence, a change in cellular reactivity with T101 was seen after 1 hr. After 24 hr, normal T-cells showed a 94 +/- 4% (S.D.) decrease in fluorescence, compared to an 82 +/- 6% decrease for chronic lymphocytic leukemia cells and a 56 +/- 4% decrease for cutaneous T-cell lymphoma cells. When T101 was removed from the culture, the cells reexpressed T65. Modulation was inhibited by cold temperatures, suggesting that it is energy dependent. Patients with chronic lymphocytic leukemia, cutaneous T-cell lymphoma, or T-cell lymphoma have received 24-hr infusions of 3 to 500 mg T101 in therapeutic trials. After infusion, in vivo binding of T101 was observed in 39 of 43 treatments not associated with endogenous host anti-T101 antibodies. T65-target cells were seen in all 39 treatments associated with in vivo bound T101, suggesting that modulation had occurred. When cultured in vitro for 24 hr, these cells reexpressed T65. In vivo, reexpression of T65 occurred following disappearance of the serum T101 titer. The extent and duration of in vivo modulation were related to both the T101 dose and the tumor burden. These data suggest that the rapid rate of antigenic modulation may prevent potential target cell destruction by antibody-mediated cytotoxicity. However, if the process of modulation involves internalization of the antibody:antigen complex, it would be an advantage for the use of cytotoxic immunoconjugates.