Biosimilars and biobetters as tools for understanding and mitigating the immunogenicity of biotherapeutics

In this article, we review key steps for the development of biosimilars and biobetters and related bioanalytical challenges, with a focus on how they are associated with immunogenicity. We analyze the factors that can impact antidrug antibody (ADA) responses and their correlations with preclinical and clinical outcomes to provide relevant insights and to answer questions, including what types of aggregate are immunogenic. We also address strategies for developing less-immunogenic biotherapeutics. Using interferon-β (IFN-β) as a case study, we explore the correlation between aggregation and immunogenicity. We dissect and integrate with clinical data the IFN-β preclinical immunogenicity and aggregation predictions and discuss the feasibility of developing an IFN-β with lower aggregation and/or immunogenicity.

► Unwanted immunogenicity is a hurdle for the development of biotherapeutics.
► Host and/or protein factors may affect clinical anti-biotherapeutic antibody responses.
► Concerted efforts to correlate preclinical and clinical immunogenicity prediction/mitigation are needed.
► Biosimilars and biobetters can provide insights on protein immunogenicity.
► Careful design of testing strategies will be central to advance knowledge.