Abstract
A bispecific mouse monoclonal antibody (mAb) that recognises carcinoembryonic antigen (CEA) with one binding site and vinblastine (VLB) with the other was used, and its in vivo immunosuppressive effect specific for anti-mouse immunoglobulin (Ig) was studied. The antibody was incubated with VLB at a molar ratio (MR) of 1:1, and administered i.v. to rabbits. Control animals received either the MAb alone, or the MAb with VLB covalently linked (MR 1:1), or the parental anti-CEA with equimolar amount of VLB. Seven days later, the rabbit anti-mouse Ig primary response was measured, and found to be almost 55% reduced in the animals that received the VLB 'loaded' MAb. In vivo kinetics and stability experiments revealed that the T1/2 of the MAb was 68 +/- 5 h, whereas free VLB disappeared within minutes. It was concluded that as soon as the drug dissociates from the antibody's binding site, it is rapidly removed. This problem was overcome by subcutaneously implanting osmotic mini-pumps containing VLB. The pumps released the drug at a constant rate for a period greater than 1 week, saturating the antibody's binding site. Under these conditions rabbits developed 80% less anti-mouse Ig antibodies when the bispecific antibody was administered (compared with the parental anti-CEA). The immunosuppression observed was specific for the mouse Ig, under conditions compatible with the full clinical therapeutic potential of the MAb. In conclusion, these experiments show, that it is possible to develop hybrid antibodies that can act as a 'lethal bait' to any specific lymphocyte in vivo, thus preventing undesirable responses against the xenogeneic MAb.
Highlights
A major limitation to the successful in vivo clinical application of Monoclonal antibodies (MAbs) is that the majority of diagnostic and therapeutic antibodies are of rodent origin, and are recognised by the host as foreign
The drug was rapidly removed from the circulation; 10 min after administration approximately 1% of the injected dose remained in the blood (Figure 1)
We have used a novel drug-conjugate consisting of a bispecific mouse monoclonal antibody, that recognises Vinca alkaloids with one binding site and carcinoembryonic antigen (CEA) with the other
Summary
A major limitation to the successful in vivo clinical application of MAbs is that the majority of diagnostic and therapeutic antibodies are of rodent origin, and are recognised by the host as foreign. Even if a successful treatment protocol is devised, the production of human antimouse immunoglobulin (Ig) antibodies can limit the efficiency of the administered therapeutic antibody by removing it from circulation (Zimmer et al, 1988). The amount of the therapeutic antibody that could reach the tumour is very low, and continuously decreases upon further injections, as the anti-mouse Ig response rises.
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