Transgenic Approaches to Human Monoclonal Antibodies

Abstract

Monoclonal antibodies (MoAbs), which combine high specificity and low toxicity, would seem to be ideal candidates for Ehrlich’s “magic bullet.” However, despite the widespread use of one MoAb product (Goldstein et al. 1985), antibodies in general have not lived up to their initial expectations. This is in part due to the intrinsic immunogenicity of nonhuman antibodies. The most commonly used technique for generating MoAbs employs rodent B cells, and patients respond to therapeutic doses of rodent monoclonals by making antibodies against the rodent immunoglobulin sequences. These human anti-mouse antibodies (HAMAs) can neutralize the therapeutic antibodies, leading to a shorter in vivo half life and reduced effectiveness (Tjandra et al. 1990), thus motivating a search for ways to generate human MoAbs. One potential route involves manipulating the mouse genome to create mice with transplanted human immunoglobulin genes and a human antibody repertoire. This is made possible by techniques developed over the last decade. In 1980 Gordon et al. reported a method for the incorporation of cloned DNA sequences into mouse embryos; the resulting transgenic mouse carries the foreign DNA within its own genetic material and passes it on to its offspring. The procedure was quickly used to generate strains of mice expressing light (Brinster et al. 1983) and heavy (Grosschedl et al. 1984) chain immunoglobulins encoded by cloned genes.