Abstract
To address the unmet needs for human polyclonal antibodies both as therapeutics and diagnostic reagents, building upon our previously established transchromosomic (Tc) cattle platform, we report herein the development of a Tc goat system expressing human polyclonal antibodies in their sera. In the Tc goat system, a human artificial chromosome (HAC) comprising the entire human immunoglobulin (Ig) gene repertoire in the germline configuration was introduced into the genetic makeup of the domestic goat. We achieved this by transferring the HAC into goat fetal fibroblast cells followed by somatic cell nuclear transfer for Tc goat production. Gene and protein expression analyses in the peripheral blood mononuclear cells (PBMC) and the sera, respectively, of Tc caprine demonstrated the successful expression of human Ig genes and antibodies. Furthermore, immunization of Tc caprine with inactivated influenza A (H7N9) viruses followed by H7N9 Hemagglutinin 1 (HA1) boosting elicited human antibodies with high neutralizing activities against H7N9 viruses in vitro. As a small ungulate, Tc caprine offers the advantages of low cost and quick establishment of herds, therefore complementing the Tc cattle platform in responses to a range of medical needs and diagnostic applications where small volumes of human antibody products are needed.
Highlights
IntroductionThese Tc cattle can be hyperimmunized with a pathogen of choice to produce highly potent pathogen-specific human IgG (hIgG) which have been successfully used to treat a list of viral and bacterial infection diseases in animal models, and some of these hIgG products have entered into human clinical trials[7,8,9,10,11,12,13,14,15]
To address the unmet needs for human polyclonal antibodies both as therapeutics and diagnostic reagents, building upon our previously established transchromosomic (Tc) cattle platform, we report the development of a Tc goat system expressing human polyclonal antibodies in their sera
We engineered a human artificial chromosome (HAC), named isKcHAC∆, that comprises the entire human Ig genetic repertoire in the germline configuration in which the regulatory genomic sequences involved in pre-B cell receptor and BCR signaling during B cell development and those mediating human Ig class switch recombination are replaced with the respective genomic sequences from an ungulate[6]
Summary
These Tc cattle can be hyperimmunized with a pathogen of choice to produce highly potent pathogen-specific hIgG which have been successfully used to treat a list of viral and bacterial infection diseases in animal models, and some of these hIgG products have entered into human clinical trials[7,8,9,10,11,12,13,14,15] Building upon this Tc bovine platform, we recently initiated efforts to establish a Tc goat (Capra aegagrus hircus) system to produce hIgG in smaller ungulates. Because large numbers of Tc goats can be quickly produced, plasma from sufficient numbers of animals can be included in plasma pooling strategies to ensure a greater lot to lot consistency
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