The effect in vivo of chemotherapeutic drug—antibody conjugates in two murine experimental tumor systems

Abstract

Conjugates of daunomycin covalently coupled, either directly or through a dextran bridge, t o antibodies reacting selectively with tumor cells, were tested for their capacity t o suppress tumor development in mice. The drug-antibody conjugates, or mixtures of drug and antibody, were compared either to the free drug or t o the drug coupled to normal immunoglobulin for their effect on two tumor systems. In the f i r s t case, a plasmacytoma (PCS), both the drug and the tumor cells were administered by the same route, namely, intraperitoneally (IP). The drug bound 'to antibody had no advantage over the free drug, but was better than the drug bound t o normal immunoglobulin. The best results were obtained in this system when daunomycin was given in a mixture with the antitumor antibody. In the second system, a lymphoma (Yac), the treatment and the tumor were administered by different routes-while the tumor was transplanted IP, the treatment was given intravenously (IV). The extent of conjugation was greatly increased in this system by introducing a dextran bridge between the drug and the antibody. In the Yac system, the anti-tumor antibodies were purified for some of the in vivo experiments. A t high doses, the daunomycin-dextran-anti-Yac antibody conjugate was superior t o the free drug but no better than daunomycin bound t o dextran alone or through dextran t o normal immunoglobulin. A t low doses, an advantage for the binding t o specific tumor antibody rather than t o normal immunoglobulin was observed. O n the basis of these data we believe that further improvement in the conjugation techniques, and the development of antibodies with better specificity towards the tumor cells, could lead towards successful use of antibody carriers in chemotherapy.

Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor.

“…Conjugates with doxorubicin were prepared successfully in our laboratory (9,12,14), as well as by others (15,16). We report here the preparation of drug-mAb conjugates of high drug-to-mAb molar ratio, which specifically bind to the EGF receptor and exert cytotoxic effects on KB tumors in nude mice.…”

Chemotherapy by intravenous administration of conjugates of daunomycin with monoclonal and conventional anti-rat alpha-fetoprotein antibodies.

“…Daunomycin hydrochloride (Farmitalia, Milano, Italy) was bound to horse and monoclonal antibodies to rat AFP or to normal horse immunoglobulin via a dextran bridge as described (17).…”

The effect of an anti-membrane antibody-methotrexate conjugate on the human prostatic tumour line PC3

“…Assessments of the cytotoxic effectiveness of the antibody-methotrexate conjugates in vitro, using measurements of both 5"Cr release from pre-loaded cells (Figure 4) and cell population parameters (Figure 2) (Kulkarni et al, 1981;Lee & Hwang, 1979;Tai et al, 1979) and in some cases an enhanced effect has been observed over the conjugate (Hurwitz et al, 1978).…”