Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer Journal Article


Authors: Morris, M. J.; Divgi, C. R.; Pandit-Taskar, N.; Batraki, M.; Warren, N.; Nacca, A.; Smith-Jones, P.; Schwartz, L.; Kelly, W. K.; Slovin, S.; Solit, D.; Halpern, J.; Delacruz, A.; Curley, T.; Finn, R.; O'Donoghue, J. A.; Livingston, P.; Larson, S.; Scher, H. I.
Article 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. Patients and 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 T 1/2 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. © 2005 American Association for Cancer Research.
Keywords: adult; clinical article; protein expression; treatment outcome; aged; middle aged; unclassified drug; drug tolerability; fatigue; diarrhea; drug safety; side effect; drug targeting; anorexia; cell survival; edema; anemia; nausea; neuropathy; myalgia; bone pain; antineoplastic activity; dose-response relationship, drug; cell line, tumor; time factors; monoclonal antibody; chill; coughing; dyspnea; fever; hyperglycemia; prostate cancer; rash; prostate-specific antigen; prostatic neoplasms; hyperkalemia; monoclonal antibody j591; prostate specific membrane antigen; antibodies, monoclonal; indium radioisotopes; rigor; thorax pain; tissue distribution; pilot study; pilot projects; thrombosis; immunogenicity; neoplasm metastasis; prostate epithelium; urinary frequency; epithelium cell; area under curve; tracer; castration; orchiectomy; immunoglobulin g1; radioimmunotherapy; indium 111; dose calculation; glycoprotein; allergic reaction; dysuria; antibody dependent cellular cytotoxicity; desquamation; complement activation; gadoteric acid
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 20
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-10-15
Start Page: 7454
End Page: 7461
Language: English
DOI: 10.1158/1078-0432.ccr-05-0826
PUBMED: 16243819
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 41" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Angelo Nacca
    6 Nacca
  2. Chaitanya Divgi
    119 Divgi
  3. Susan Slovin
    184 Slovin
  4. Jerry L Halpern
    11 Halpern
  5. Michael Morris
    274 Morris
  6. William K Kelly
    108 Kelly
  7. David Solit
    431 Solit
  8. Ronald D Finn
    245 Finn
  9. Lawrence H Schwartz
    281 Schwartz
  10. Steven M Larson
    762 Larson
  11. Howard Scher
    816 Scher
  12. Nyasha Warren
    4 Warren