title: Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6.
abstract: In preclinical in vitro and in vivo systems, mAbs to human transferrin (Tf) receptors blocked iron uptake from Tf and showed antitumor activity. However, Tf receptors are also displayed by normal tissues, and a large, soluble pool of circulating serum Tf receptors has been detected. We report results of a Phase Ia trial of IgA monoclonal anti-Tf receptor antibody 42/6. Twenty-seven patients with advanced refractory cancer received 33 treatments with 42/6 administered as a 24-h infusion at doses ranging from 2.5 to 300 mg/m2. 42/6 was generally well tolerated, 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 levels of antibody were obtained at the termination of the 24-h infusion. At doses >/=25 mg/m2, there was a linear relationship between the 42/6 dose and average peak serum 42/6 levels ranging from <1 to 36 microgram/ml. Serum Tf receptors showed a dose-dependent decrease during 42/6 infusion to 20-30% of baseline, and remained depressed for at least 48 h after terminating the infusion. Serum 42/6 levels 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 patients. Anti-Tf receptor antibody was well tolerated and mediated in vivo effects on iron uptake and Tf display. Antibody concentrations capable of inhibiting malignant blood cell growth were obtained without toxicity. This represents the first clinical trial of an IgA mouse mAb, and one of only a few trials in which an antibody reacting with a broad range of normal tissues has been administered. Additional clinical trials of anti-Tf receptor antibodies in blood cell cancers are indicated.
authors.affiliation: Departments of Medicine and Pathology and Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: D
authors.initials: D
authors.lastname: Brooks
authors.forename: C
authors.initials: C
authors.lastname: Taylor
authors.forename: B
authors.initials: B
authors.lastname: Dos Santos
authors.forename: H
authors.initials: H
authors.lastname: Linden
authors.forename: A
authors.initials: A
authors.lastname: Houghton
authors.forename: T T
authors.initials: TT
authors.lastname: Hecht
authors.forename: S
authors.initials: S
authors.lastname: Kornfeld
authors.forename: R
authors.initials: R
authors.lastname: Taetle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D011990:Receptors, Transferrin / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007070:Immunoglobulin A; D011990:Receptors, Transferrin