Induction of immunogenicity of monoclonal antibodies by conjugation with drugs.

Human anti-mouse antibody has been a nearly consistent result of human clinical trials utilizing murine antibodies. It is generally anticipated that the problem of human anti-mouse antibody will be reduced as genetically engineered, more human ("humanized") antibodies become available. It is not clear, however, what effect chemical modification of such "humanized" antibodies will have on their immunogenicity. The present studies utilize a mouse antibody and rat host model to explore aspects of this question. Rats injected with unmodified mouse monoclonal antibodies failed to mount anti-mouse immune responses, presumably due to their phylogenetic relatedness. In contrast, rats injected with a Vinca immunoconjugate mounted strong anticonjugate antibody responses that were directed primarily against the linker portion of the conjugate. The in vivo serum pharmacokinetics of 125I-labeled antibody and conjugates were evaluated in rats with existing anticonjugate antibody. The peak serum level attained was inversely correlated with the level of reactivity of the anticonjugate antibody with the injected compound. This model provides a potentially useful tool for exploration of the immunogenicity of drug, toxin, or radionuclide monoclonal antibody conjugates.

Sensitisation to halothane-altered liver components in severe hepatic necrosis after halothane anaesthesia.

In-vitro sensitisation (inhibiton or stimulation of leucocyte migration) in response to a liver homogenate obtained from rabbits pretreated with halothane was found in eight of twelve patients with halothane-associated hepatitis. Sensitisation was not observed when the homogenates were obtained from animals pretreated with ether. Furthermore, leucocyte migration in response to "halothane homogenate" was normal in eleven patients who had shown no abnormality in liver function after halothane anaesthesia and in thirty patients with other liver diseases. These studies provide direct evidence that sensitisation to halothane-altered liver-cell components is present in those occasional patients in whom severe liver damage develops after halothane anaesthesia.