Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle

Therapeutic human polyclonal antibodies (hpAbs) derived from pooled plasma from human donors are Food and Drug Administration approved biologics used in the treatment of a variety of human diseases. Powered by the natural diversity of immune response, hpAbs are effective in treating diseases caused...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e78119-e78119
Main Authors: Sano, Akiko, Matsushita, Hiroaki, Wu, Hua, Jiao, Jin-An, Kasinathan, Poothappillai, Sullivan, Eddie J, Wang, Zhongde, Kuroiwa, Yoshimi
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antigens
Artificial chromosomes
B-cell receptor
B-Lymphocytes - metabolism
Bovidae
Cattle
Cell activation
Cell growth
Cell Proliferation
Chains
Chromosomes, Artificial, Human - genetics
Chromosomes, Artificial, Human - immunology
Chromosomes, Artificial, Human - metabolism
Cloning
Epidemics
Humans
Immune response
Immune system
Immunization
Immunoglobulin G
Immunoglobulin G - genetics
Immunoglobulin G - immunology
Immunoglobulin G - metabolism
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Heavy Chains - immunology
Immunoglobulin Heavy Chains - metabolism
Immunoglobulin M
Immunoglobulin M - genetics
Immunoglobulin M - immunology
Immunoglobulin M - metabolism
Immunoglobulin mu-Chains - genetics
Immunoglobulin mu-Chains - immunology
Immunoglobulin mu-Chains - metabolism
Immunoglobulins
Immunoglobulins - genetics
Immunoglobulins - immunology
Immunoglobulins - metabolism
Incompatibility
Loci
Lymphocytes B
Medical treatment
Physiology
Polyclonal antibodies
Proteins
T cell receptors
Viruses
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Therapeutic human polyclonal antibodies (hpAbs) derived from pooled plasma from human donors are Food and Drug Administration approved biologics used in the treatment of a variety of human diseases. Powered by the natural diversity of immune response, hpAbs are effective in treating diseases caused by complex or quickly-evolving antigens such as viruses. We previously showed that transchromosomic (Tc) cattle carrying a human artificial chromosome (HAC) comprising the entire unrearranged human immunoglobulin heavy-chain (hIGH) and kappa-chain (hIGK) germline loci (named as κHAC) are capable of producing functional hpAbs when both of the bovine immunoglobulin mu heavy-chains, bIGHM and bIGHML1, are homozygously inactivated (double knockouts or DKO). However, B lymphocyte development in these Tc cattle is compromised, and the overall production of hpAbs is low. Here, we report the construction of an improved HAC, designated as cKSL-HACΔ, by incorporating all of the human immunoglobulin germline loci into the HAC. Furthermore, for avoiding the possible human-bovine interspecies incompatibility between the human immunoglobulin mu chain protein (hIgM) and bovine transmembrane α and β immunoglobulins (bIgα and bIgβ) in the pre-B cell receptor (pre-BCR) complex, we partially replaced (bovinized) the hIgM constant domain with the counterpart of bovine IgM (bIgM) that is involved in the interaction between bIgM and bIgα/Igβ; human IgM bovinization would also improve the functionality of hIgM in supporting B cell activation and proliferation. We also report the successful production of DKO Tc cattle carrying the cKSL-HACΔ (cKSL-HACΔ/DKO), the dramatic improvement of B cell development in these cattle and the high level production of hpAbs (as measured for the human IgG isotype) in the plasma. We further demonstrate that, upon immunization by tumor immunogens, high titer tumor immunogen-specific human IgG (hIgG) can be produced from such Tc cattle.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0078119