Pharmacology and safety assessment of humanized monoclonal antibodies for therapeutic use

The humanization of monoclonal antibodies has generated a class of therapeutic products with improved safety, longer half-lives, and greatly diminished immunogenicity. These engineered proteins are highly species specific and in many cases only cross-react in humans. Where there is cross-reactivity in nonhuman primates or other species, it is not always clear that the pharmacologic effects reflect the potential actions in human volunteers or patients. As with other biologic products, the profile of humanized monoclonal antibodies dictates the preclinical strategy. The preclinical programs for the 2 humanized monoclonal antibodies described here, anti-HLA-DR (Hu1D10) and anti-CD3 (HuM291), demonstrate several unique aspects that affected their preclinical development strategy. Hu1D10 binds to a posttranslational form of HLA-DR and recognizes this antigen in some but not all human and nonhuman primates. The second antibody, HuM291, cross-reacts with CD3 only in the chimpanzee, which is not an optimal test species. In addition, a marketed anti-CD3 product exists (OKT3), and in the preclinical development of our antibody during testing of efficacy and safety, we needed to focus on adverse effects that might be similar to those of OKT3. In these studies, the safety, pharmacokinetics, immunogenicity, and pharmacology (B- and T-cell depletion and recovery) of the 2 antibodies were evaluated. The focus in this review is on the safety and pharmacology testing and the current status of each drug.