Development of a Human Antibody Tolerant Mouse Model to Assess the Immunogenicity Risk Due to Aggregated Biotherapeutics

Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges

“…34 However, in some studies in wild-type mice, the immunogenicity induced by the native recombinant human therapeutic protein is so high that it is difficult to observe any additional effects from factors (e.g., aggregation or chemical degradation) that are believed to increase the risk of immunogenicity. 21,35–41 Nevertheless, wild-type mice might be useful for studying effects of therapeutic replacement proteins that are used to treat patients who are unable to produce certain enzymes, hormones and clotting factors; in these patients the therapeutic human proteins might be perceived by the immune system as foreign.…”

“…21–23,47 The major advantage of this approach is that these animals can be used to study the effects of different factors that may lead to immunogenicity of recombinant human protein drugs for which they are immune tolerant within an intact immune system, just like many patients at the start of a therapy. Disadvantages of this approach (in addition to the differences between humans and animals such as physiology and dosing regimen that are common to all animal model systems) are that the mice can be used for only one type of protein, the expressed human protein may exert unpredictable biological effects in mice, and expression levels may not match those in humans.…”

“…Although historically a variety of animal models has been used to study immunogenicity of proteins, most of the studies that have been conducted over the past few years to examine the potential importance of various product-related attributes (as defined above) have been conducted in murine models. 21–29 Others have used these in vivo models (see Table 1 for an overview) to study the effects of route of delivery, 26,30 as well as the potential molecular mechanisms behind immune responses that could help mitigating such reactions in the future. 31 The mouse strains used in these studies were very diverse.…”

“…22,23 Similarly, a human immunoglobulin G2 (IgG2)-tolerant and immune-competent heterozygous mouse model (Xeno-het) derived from a C57BL/6J wild-type strain expressed both mouse and human immunoglobulin G (IgG) genes, resulting in B-cells expressing human and mouse IgG, and secretion of human and mouse immunoglobulins into serum. 21 The cross breeding with the C57BL/6J strain ensured robust B cell signaling and diverse repertoires.…”

An optimized approach to the rapid assessment and detection of sequence variants in recombinant protein products

“…However, given the near impossibility to isolate and test SVs at these low levels in in vitro assays to predict immune response, the findings presented by the above data place more pressure on the need for high-quality models to predict potential immunogenicity due to these variants. Such predictive models [16] could help inform a risk assessment [17] for a candidate biosimilar product's clinical development program, but the clinical immunogenicity profile should in any case be evaluated in comparative clinical studies.…”