CONJUGATION OF INTERFERON-ALPHA TO A HUMANIZED MONOCLONAL-ANTIBODY (HUBRE-3VL) ENHANCES THE SELECTIVE LOCALIZATION AND ANTITUMOR EFFECTS OFINTERFERON IN BREAST-CANCER XENOGRAFTS

Human mammary carcinoma xenografts (MCF-7) growing in nude mice were t reated with natural interferon alpha (n-LFN-alpha) alone or conjugated to a humanized monoclonal antibody (MoAb) anti-breast mucin (HuBrE-3v l) or to irrelevant human IgG(1) kappa. The IFN and the conjugates wer e administered as 20 intra-lesional (i.l.) injections to 1 of 2 xenogr afts in each mouse, or i.p. The growth inhibitory effects of HuBrE-3vl /nIFN-alpha were significantly greater than those of nIFN-alpha used a s a single agent or conjugated to HuIgG(1) kappa. These effects occurr ed locally in the tumors receiving i.l. injections and systemically, a lthough to a slightly lesser extent, in the noninjected tumors of mice treated i.l. and in the xenografts of mice treated i.p. Biodistributi on studies showed that the uptake of I-125-HuBrE-3v/nIFN-alpha by the tumors 24 hours after i.l. or s.c. injection was greater than that of I-125-HuIgG(1) kappa/nIFN-alpha, I-125-nIFN-alpha alone: or by normal tissues, documenting a tumor targeting effect and favorable tumor:norm al tissues (T:NT) ratios. The targeting effects and the resulting tumo r 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 t o those we obtained previously with nIFN-alpha conjugated to another M oAb of the same group (Mc5). These studies point out the potential use fulness of HuBrE-3vl/nIFN-alpha for the local and systemic treatment o f breast cancer lesions by providing a means of delivering high doses of IFN to the tumors while minimizing the amount of IFN binding to nor mal tissues.