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JNCI Journal of the National Cancer Institute 1991 83(20):1470-1476; doi:10.1093/jnci/83.20.1470
© 1991 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 83, No. 20, 1470-1476, October 16, 1991
© 1991 Oxford University Press

Preclinical Evaluation of an Anti-Autocrine Growth Factor Monoclonal Antibody for Treatment of Patients With Small-Cell Lung Cancer

Ingalill L. Avis, Thomas O. G. Kovacs, Philip G. Kasprzyk, Anthony M. Treston, Richard Bartholomew, John H. Walsh, Frank Cuttitta, James L. Mulshine*,

Biotherapy Section, NCI-Navy Medical Oncology Branch, National Naval Medical Center Bethesda, Md.
Center for Ulcer Research and Education, University of California Los Angeles, Calif.
Hybritech, Inc. San Diego, Calif.
Department of Medicine, Uniformed Services University of the Health Sciences Bethesda

*Correspondence to: James L. Mulshine, M.D., NCI-Navy MOB, BIdg. 8, Rm. 5101, National Naval Medical Center, Bethesda, MD 20889.

We have evaluated an anti-autocrine growth factor monoclonal antibody for potential use in the treatment of patients with small-cell lung cancer. The monoclonal antibody, designated 2A11, binds to the C-terminal region of the autocrine growth factor gastrin-releasing peptide and neutralizes its growth-promoting effects in vitro and in vivo. Equilibrium-binding analysis demonstrated that the peptide binds to the antibody (dissociation constant = 1.5 x 10–10) at least as avidly as it binds to the tumor peptide receptor. Pharmacokinetic studies in normal BALB/c mice demonstrated an initial clearance half-life ({alpha} t1/2] of 243 ± 4 hours and a secondary clearance half-life (beta t1/2) of 1039.6 ± 309 hours, and biodistribution studies revealed a distribution pattern which generally reflected blood flow. Single intravenous infusions of 2A11 (20 mg/20–25-kg dogs) into normal mongrel dogs with surgically created gastric fistulas antagonized the stimulatory effects of exogenously infused gastrin-releasing peptide or bombesin on plasma gastrin release and gastric acid secretion. Toxicology studies in normal dogs (with gastric fistulas) infused with 50 mg 2A11 intravenously three times a week for 4 weeks failed to reveal any adverse behavioral, clinical, or pathological effects. Four of six dogs developed an immune response to 2A11. Anti-idiotypic antibodies elicited in two cases did not mimic the functional effects of the peptide. We conclude that the concept of immunoblockade of an autocrine growth factor appears feasible in vivo. [J Natl Cancer Inst 83:1470–1476, 1991]


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