Antigen-specific human polyclonal antibodies from hyperimmunized cattle.
Antigen-specific human polyclonal antibodies (hpAbs), produced by hyperimmunization, could be useful for treating many human diseases. However, yields from available transgenic mice and transchromosomic (Tc) cattle carrying human immunoglobulin loci are too low for therapeutic applications. We report a Tc bovine system that produces large yields of hpAbs. Tc cattle were generated by transferring a human artificial chromosome vector carrying the entire unrearranged, human immunoglobulin heavy (hIGH) and kappa-light (hIGK) chain loci to bovine fibroblasts in which two endogenous bovine IgH chain loci were inactivated. Plasma from the oldest animal contained >2 g/l of hIgG, paired with either human kappa-light chain (up to approximately 650 microg/ml, fully human) or with bovine kappa- or lambda-light chain (chimeric), with a normal hIgG subclass distribution. Hyperimmunization with anthrax protective antigen triggered a hIgG-mediated humoral immune response comprising a high proportion of antigen-specific hIgG. Purified, fully human and chimeric hIgGs were highly active in an in vitro toxin neutralization assay and protective in an in vivo mouse challenge assay.
Kuroiwa
Yoshimi
Y
Hematech, Inc, 4401 S. Technology Dr., Sioux Falls, South Dakota 57106, USA. ykuroiwa@hematech.com
Kasinathan
Poothappillai
P
Sathiyaseelan
Thillainayagen
T
Jiao
Jin-an
JA
Matsushita
Hiroaki
H
Sathiyaseelan
Janaki
J
Wu
Hua
H
Mellquist
Jenny
J
Hammitt
Melissa
M
Koster
Julie
J
Kamoda
Satoru
S
Tachibana
Katsumi
K
Ishida
Isao
I
Robl
James M
JM
D000818:Animals; D030801:Animals, Genetically Modified; D000942:Antigens, Bacterial / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D016466:CHO Cells; D002417:Cattle / Q000235:genetics; D022222:Chromosomes, Artificial, Human / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D055786:Gene Knockout Techniques; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D009500:Neutralization Tests; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin