title: Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer.
abstract: BACKGROUND
  Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored.
  
  
  METHODS
  Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed.
  
  
  RESULTS
  Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline.
  
  
  CONCLUSIONS
  J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. morrism@mskcc.org
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Divgi
authors.forename: Neeta
authors.initials: N
authors.lastname: Pandit-Taskar
authors.forename: Maria
authors.initials: M
authors.lastname: Batraki
authors.forename: Nyasha
authors.initials: N
authors.lastname: Warren
authors.forename: Angelo
authors.initials: A
authors.lastname: Nacca
authors.forename: Peter
authors.initials: P
authors.lastname: Smith-Jones
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: W Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Susan
authors.initials: S
authors.lastname: Slovin
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: Jennifer
authors.initials: J
authors.lastname: Halpern
authors.forename: Anthony
authors.initials: A
authors.lastname: Delacruz
authors.forename: Tracy
authors.initials: T
authors.lastname: Curley
authors.forename: Ronald
authors.initials: R
authors.lastname: Finn
authors.forename: Joseph A
authors.initials: JA
authors.lastname: O'donoghue
authors.forename: Philip
authors.initials: P
authors.lastname: Livingston
authors.forename: Steven
authors.initials: S
authors.lastname: Larson
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D045744:Cell Line, Tumor; D002470:Cell Survival; D003167:Complement Activation; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D010865:Pilot Projects; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D013927:Thrombosis / Q000139:chemically induced; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; C478680:J591 monoclonal antibody; D017430:Prostate-Specific Antigen