Conjugation of interferon alpha to a humanized monoclonal antibody (HuBrE-3vl) enhances the selective localization and antitumor effects of interferon in breast cancer xenografts.
Human mammary carcinoma xenografts (MCF-7) growing in nude mice were treated with natural interferon alpha (n-IFN-alpha) alone or conjugated to a humanized monoclonal antibody (MoAb) anti-breast mucin (HuBrE-3vl) or to irrelevant human IgG1kappa. The IFN and the conjugates were administered as 20 intra-lesional (i.l.) injections to 1 of 2 xenografts in each mouse, or i.p. The growth inhibitory effects of HuBrE-3vl/nIFN-alpha were significantly greater than those of nIFN-alpha used as a single agent or conjugated to HuIgG1kappa. These effects occurred locally in the tumors receiving i.l. injections and systemically, although to a slightly lesser extent, in the noninjected tumors of mice treated i.l. and in the xenografts of mice treated i.p. Biodistribution studies showed that the uptake of 125I-HuBrE-3vl/nIFN-alpha by the tumors 24 hours after i.l. or s.c. injection was greater than that of 125I-HuIgG1kappa/nIFN-alpha, 125I-nIFN-alpha alone, or by normal tissues, documenting a tumor targeting effect and favorable tumor:normal tissues (T:NT) ratios. The targeting effects and the resulting tumor growth inhibition were favored by the IFN-mediated up-regulation of the HuBrE-3vl reactive antigen, which was more prominent after 3 weeks of treatment with HuBrE-3vl/nIFN-alpha. These results were superior to those we obtained previously with nIFN-alpha conjugated to another MoAb of the same group (Mc5). These studies point out the potential usefulness of HuBrE-3vl/nIFN-alpha for the local and systemic treatment of breast cancer lesions by providing a means of delivering high doses of IFN to the tumors while minimizing the amount of IFN binding to normal tissues.
Ozzello
L
L
Department of Pathology, Columbia University, New York, NY, USA.
Blank
E W
EW
De Rosa
C M
CM
Ceriani
R L
RL
Tölö
H
H
Kauppinen
H L
HL
Cantell
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000032:analysis; D001682:Biological Availability; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D002277:Carcinoma / Q000473:pathology / Q000628:therapy*; D016503:Drug Delivery Systems; D005260:Female; D018796:Immunoconjugates / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D016898:Interferon-alpha