PHASE IA TRIAL OF MURINE IMMUNOGLOBULIN-A ANTITRANSFERRIN RECEPTOR ANTIBODY-42 6/

In preclinical in vitro and in vivo systems, mAbs to human transferrin (Tf) receptors blocked iron uptake from Tf and shelved antitumor acti vity, However, Tf receptors are also displayed by normal tissues, and a large, soluble pool of circulating serum Tf receptors has been detec ted, We report results of a Phase Ia trial of IgA monoclonal anti-Tf r eceptor antibody 42/6, Twenty-seven patients with advanced refractory cancer received 33 treatments with 42/6 administered as a 24-h infusio n at doses ranging from 2.5 to 300 mg/m(2), 42/6 was generally well to lerated, although one patient receiving a second treatment experienced an allergic-type response associated with a human antimouse antibody response, Three patients with hematological cancers showed mixed tumor responses; there were no partial or complete remissions, Peak serum l evels of antibody were obtained at the termination of the 24-h infusio n, At doses greater than or equal to 25 mg/m(2), there was a linear re lationship between the 42/6 dose and average peak serum 42/6 levels ra nging from <1 to 36 mu g/ml. Serum Tf receptors showed a dose-dependen t decrease during 42/6 infusion to 20-30% of baseline, and remained de pressed for at least 48 h after terminating the infusion, Serum 42/6 l evels rose in an inverse relationship to the drop in Tf receptors, 42/ 6 induced an increase in serum iron and Tf saturation consistent with blockade of peripheral iron uptake, and reduced Tf receptor display by bone marrow cells, Human antimouse antibody was detected in nine pati ents, Anti-Tf receptor antibody was well tolerated and mediated in viv o effects on iron uptake and Tf display, Antibody concentrations capab le of inhibiting malignant blood cell growth were obtained without tox icity, This represents the first clinical trial of an IgA mouse mAb, a nd one of only a few trials in which an antibody reacting with a broad range of normal tissues has been administered, Additional clinical tr ials of anti-Tf receptor antibodies in blood cell cancers are indicate d.