title: Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results.
abstract: Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.
authors.affiliation: Virginia Mason Medical Center, Seattle, WA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Weiden
authors.forename: H B
authors.initials: HB
authors.lastname: Breitz
authors.forename: O
authors.initials: O
authors.lastname: Press
authors.forename: J W
authors.initials: JW
authors.lastname: Appelbaum
authors.forename: J K
authors.initials: JK
authors.lastname: Bryan
authors.forename: S
authors.initials: S
authors.lastname: Gaffigan
authors.forename: D
authors.initials: D
authors.lastname: Stone
authors.forename: D
authors.initials: D
authors.lastname: Axworthy
authors.forename: D
authors.initials: D
authors.lastname: Fisher
authors.forename: J
authors.initials: J
authors.lastname: Reno
mesh_terms: D000328:Adult; D018951:Antigens, CD20 / Q000276:immunology; D001710:Biotin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008228:Lymphoma, Non-Hodgkin / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000009:adverse effects; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D018951:Antigens, CD20; C405616:DOTA-biotin; D007074:Immunoglobulin G; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D015021:Yttrium Radioisotopes; D001710:Biotin