Lukasz Chlewicki, PhD, Principal Research Scientist, Eli Lilly and Company
Immunogenicity of biotherapeutics presents a major challenge during the clinical development of new protein drugs, including monoclonal antibodies. To address this, multiple humanization and de-immunization techniques that employ in silico algorithms and in vitro test systems have been implemented in the field. To date, no systematic study to examine the effectiveness of these approaches in the reduction of immunogenicity has been performed in vivo in humans or in a relevant animal model, such as non-human primates. Aside from retrospective analyses, there is very little direct information on the true predictability of in silico/in vitro approaches to predict immunogenicity observed in vivo. Since human and cynomolgus macaque are highly homologous and share similar mechanisms of antigen processing and presentation, it can serve as a useful model to study immunogenicity of biotherapeutics. Here, we examined an in silico-guided approach to reduce the risk of immunogenicity of two commercially available antibodies using cynomolgus macaque as a surrogate for human. The resultant engineered antibodies had a comparable affinity for TNFa, demonstrated similar biophysical properties, and exhibited significantly reduced ADA levels in cynomolgus macaque as compared to the parental antibodies, with a corresponding improvement in pharmacokinetic profile. The results point to the significant value in the investment in these engineering strategies and the relevance of testing in non-human primates as an important guide for monoclonal antibody optimization, which can contribute to improved clinical outcomes.