If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies; as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.

Over the past decade, the treatment of a variety of immune-mediated diseases has improved greatly due to the introduction of biologics for therapies in cases that are nonresponsive to traditional treatments. However, a side effect not encountered in traditional treatments is the immunogenicity of the biologics themselves. Our aim was to investigate the anti-infliximab-antibody response in pediatric patients receiving infliximab for juvenile idiopathic arthritis and other pediatric rheumatic diseases, with a focus on an analysis of the binding sites of these antibodies. We show that anti-infliximab antibodies developed in 43% of patients receiving infliximab therapy. Neutralization studies showed that in all these patients, the antibodies were directed toward the variable domains of infliximab, as they inhibited binding of infliximab to TNF. A more precise determination of the antibody epitopes using synthetic peptides was not achieved, indicating that all the antibody binding sites were composed of discontinuous segments of infliximab. (Pediatr Res 69: 243-248, 2011) J uvenile idiopathic arthritis (JIA) is the umbrella term for a heterogeneous group of inflammatory arthropathies that can affect children and young adults. As the name suggests, the cause and pathogenesis of JIA are still largely unknown but are thought to include both genetic and environmental factors. Although none of the drugs available for treatment of JIA provides a cure, disease prognosis has improved greatly in recent years due to improved disease management and with the introduction of biologics that can provide an efficient alternative for patients who are nonresponsive to other treatments (1). Infliximab is one such biological agent, which acts by blocking the activity of TNF in the inflammatory response. Although infliximab is not formally approved for use in JIA, it is commonly used and its efficacy has been documented in several studies (2-5).Infliximab is a chimeric MAb composed of variable domains of murine origin and constant domains of human origin (6,7). Although it is usually well tolerated and safe for JIA therapy (8), an important aspect for consideration is its immunogenicity. It has become clear in recent years that all biologics have some degree of immunogenicity, even fully humanized ones. This can lead to the development of so-called antidrug antibodies (9), which can lead to loss of efficacy of treatment and higher incidence of adverse events (10).The generation and specificity of anti-infliximab antibodies has not been well studied in pediatric patients. Therefore, in this study, we analyzed the levels of infliximab and antiinfliximab antibodies in patients with JIA and other pediatric rheumatic diseases, from two European pediatric centers. We also looked for possible epitopes of these antibodies, using overlapping synthetic peptides that covered the amino acid sequences of both of the infliximab variable domains. METHODSPatients and sera. Twenty-one pediatric patients receiving infliximab for treatment of rhe...

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An antibody targeting ICOS increases intratumoral cytotoxic to regulatory T cell ratio and induces tumor regression Anti-tumour activity triggered by an anti-ICOS antibody