Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer.
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.
Morris
Michael J
MJ
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. morrism@mskcc.org
Divgi
Chaitanya R
CR
Pandit-Taskar
Neeta
N
Batraki
Maria
M
Warren
Nyasha
N
Nacca
Angelo
A
Smith-Jones
Peter
P
Schwartz
Lawrence
L
Kelly
W Kevin
WK
Slovin
Susan
S
Solit
David
D
Halpern
Jennifer
J
Delacruz
Anthony
A
Curley
Tracy
T
Finn
Ronald
R
O'donoghue
Joseph A
JA
Livingston
Philip
P
Larson
Steven
S
Scher
Howard I
HI
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
D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; C478680:J591 monoclonal antibody; D017430:Prostate-Specific Antigen