title: Enhancement of the therapeutic index: from nonmyeloablative and myeloablative toward pretargeted radioimmunotherapy for metastatic prostate cancer.
abstract: OBJECTIVE
  New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer.
  
  
  METHODS
  A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. (111)In/90Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgen-independent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage ((111)In/90Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1 scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1 and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1 epitopes.
  
  
  RESULTS
  The nonmyeloablative maximum tolerated dose of 90Y-m170 was 0.74 GBq/m2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m2 of 90Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules.
  
  
  CONCLUSIONS
  The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients. Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.
authors.affiliation: School of Medicine, University of California Davis, Sacramento, California 95816, USA. sjdenardo@ucdavis.edu
authors.forename: Sally J
authors.initials: SJ
authors.lastname: DeNardo
authors.forename: Carol M
authors.initials: CM
authors.lastname: Richman
authors.forename: Huguette
authors.initials: H
authors.lastname: Albrecht
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Burke
authors.forename: Arut
authors.initials: A
authors.lastname: Natarajan
authors.forename: Aina
authors.initials: A
authors.lastname: Yuan
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Gregg
authors.forename: R T
authors.initials: RT
authors.lastname: O'Donnell
authors.forename: Gerald L
authors.initials: GL
authors.lastname: DeNardo
mesh_terms: D000911:Antibodies, Monoclonal; D000941:Antigens / Q000737:chemistry; D000951:Antigens, Neoplasm; D001853:Bone Marrow / Q000378:metabolism; D002403:Cathepsins / Q000737:chemistry; D003131:Combined Modality Therapy; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes / Q000737:chemistry; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008301:Maleimides / Q000737:chemistry; D020714:Maximum Tolerated Dose; D008956:Models, Chemical; D018396:Mucin-1; D009077:Mucins / Q000737:chemistry; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D011485:Protein Binding; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D015021:Yttrium Radioisotopes / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D000951:Antigens, Neoplasm; D000939:Epitopes; D006023:Glycoproteins; C060192:MUC1 protein, human; D008301:Maleimides; D018396:Mucin-1; D009077:Mucins; D019151:Peptide Library; D010455:Peptides; D015021:Yttrium Radioisotopes; C043592:maleimide; D011092:Polyethylene Glycols; D002403:Cathepsins; D017239:Paclitaxel