Immunocompromised ungulates

Inventors

AYARES, DAVID L. • Mendicino, Michael • Wells, Kevin • Dandro, Amy S.

Assignees

Revivicor Inc

Abstract

Porcine animals, tissue and organs as well as cells and cell lines derived from such animals are provided that lack functional endogenous immunoglobulin loci and are deficient in immunoglobulin expression and B-cells. These animals are useful as model systems for research and for development of new pharmaceutical and biological agents. In addition, methods are provided to prepare such animals.

Core Innovation

The invention provides genetically modified porcine animals that lack expression of functional porcine heavy chain immunoglobulin. In particular, the porcine heavy chain (Hc) gene is targeted for disruption in both alleles, so that functional heavy chain immunoglobulin expression is absent and B-cell production is lacking. This design produces a large-animal model characterized by lack of endogenous antibody expression, including lack of serum Ig and lack of IgM+ B-cell populations.

The genetically modified pigs are used to characterize cellular immune responses and the course of infection to an antigen or infectious agent. By removing functional porcine heavy chain immunoglobulin expression and B-cell production, the model is described as lacking humoral immunity for infectious disease and immunology research. The document further describes use of such models for vaccines and prophylactic or therapeutic testing in the setting of antigen exposure and subsequent immune response characterization.

The document also describes additional genetic and functional extensions to further impair or modulate immune function, including optional T-cell impairment, expression of human or xenogenous immunoglobulins using artificial chromosome approaches, and enhanced antibody pharmacokinetics by deletion of glycosyltransferase genes such as α(1,3)galactosyltransferase. Supporting characterization is described showing impaired lymphoid follicle and germinal center development in Hc−/− pigs, and robust CTLA4-Ig expression with decreased IgG/IgM consistent with immunocompromise.

Claims Coverage

The document includes two independent claims. Both claims center on genetically modified porcine animals lacking functional porcine heavy chain immunoglobulin due to targeted disruption in both alleles of the Hc gene, producing lack of B-cell production, and each independent claim uses this porcine genotype to characterize a cellular immune response in the context of antigen or infectious agent exposure, respectively.

Across the independent claims, the key inventive concept is use of a genetically modified porcine animal lacking functional porcine heavy chain immunoglobulin (via targeted disruption in both Hc alleles) to characterize cellular immune responses, including cellular immune response characterization and course-of-infection assessment for medicament effectiveness.

Stated Advantages

Documented Applications