Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer.
BACKGROUND
Small cell lung cancer (SCLC) cells express and secrete gastrin-releasing peptide (GRP) which binds to receptors and stimulates growth of these cells. A murine monoclonal antibody, 2A11, which binds GRP with high affinity, decreased growth of SCLC cells in vitro and in athymic nude mice. A phase 1 trial and pharmacokinetic modeling in patients with lung cancer has defined the phase 2 dose of 2A11 but the antitumor activity in patients is unknown.


METHODS
Thirteen patients with previously treated SCLC received 2A11 at 250 mg/m2 over 1 h three times per week for 4 weeks. Serum GRP, urine GRP, serum levels of 2A11, and human antimouse antibodies (HAMA) were determined.


RESULTS
One of 12 (8%; 95% confidence interval, 0 to 38%) evaluable patients had complete resolution of radiographically detectable tumor lasting 4 months. Four patients (33%) had stable disease. No toxic reactions were observed. The pretreatment serum GRP level of the responding patient was 3.1 fmol/mL and the median of nine nonresponding patients was 7.3 fmol/mL (range, <1.0 to 29.0). The mean trough serum 2A11 level was 49+/-18 microg/mL in the responding patient and 32 to 487 mg/mL (median, 117) in 10 nonresponding patients. HAMA did not increase during 2A11 administration in any patient.


CONCLUSIONS
Interruption of the GRP autocrine growth factor loop with 2A11 results in clinical antitumor activity in a minority of patients with previously treated SCLC. Further evaluation of the antitumor effects of 2A11 is warranted to define characteristics associated with response to 2A11.
Kelley
M J
MJ
Navy Medical Oncology Branch, National Cancer Institute, Bethesda, Md 20889-5105, USA. mk4m@nih.gov
Linnoila
R I
RI
Avis
I L
IL
Georgiadis
M S
MS
Cuttitta
F
F
Mulshine
J L
JL
Johnson
B E
BE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001839:Bombesin / Q000276:immunology*; D018288:Carcinoma, Small Cell / Q000628:therapy*; D005260:Female; D019886:Gastrin-Releasing Peptide; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010455:Peptides / Q000276:immunology*
D000911:Antibodies, Monoclonal; D010455:Peptides; D019886:Gastrin-Releasing Peptide; D001839:Bombesin