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三重免疫球蛋白基因敲除易位牛：牛 λ 基因簇缺失及其对完全人源化多克隆抗体产生的影响。

Triple immunoglobulin gene knockout transchromosomic cattle: bovine lambda cluster deletion and its effect on fully human polyclonal antibody production.

机构信息

Sanford Applied Biosciences L.L.C., Sioux Falls, South Dakota, United States of America; Hematech, Inc., Sioux Falls, South Dakota, United States of America.

Kyowa Hakko Kirin, Co., Ltd., Chiyoda-ku, Tokyo, Japan; Hematech, Inc., Sioux Falls, South Dakota, United States of America.

出版信息

PLoS One. 2014 Mar 6;9(3):e90383. doi: 10.1371/journal.pone.0090383. eCollection 2014.

DOI:10.1371/journal.pone.0090383
PMID:24603704
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3946162/
Abstract

Towards the goal of producing fully human polyclonal antibodies (hpAbs or hIgGs) in transchromosomic (Tc) cattle, we previously reported that Tc cattle carrying a human artificial chromosome (HAC) comprising the entire unrearranged human immunoglobulin (Ig) heavy-chain (hIGH), kappa-chain (hIGK), and lambda-chain (hIGL) germline loci produced physiological levels of hIgGs when both of the bovine immunoglobulin mu heavy-chains, bIGHM and bIGHML1, were homozygously inactivated (bIGHM-/-, bIGHML1-/-; double knockouts or DKO). However, because endogenous bovine immunoglobulin light chain loci are still intact, the light chains are produced both from the hIGK and hIGL genomic loci on the HAC and from the endogenous bovine kappa-chain (bIGK) and lambda-chain (bIGL) genomic loci, resulting in the production of fully hIgGs (both Ig heavy-chains and light-chains are of human origin: hIgG/hIgκ or hIgG/hIgλ) and chimeric hIgGs (Ig heavy-chains are of human origin while the Ig light-chains are of bovine origin: hIgG/bIgκ or hIgG/bIgλ). To improve fully hIgG production in Tc cattle, we here report the deletion of the entire bIGL joining (J) and constant (C) gene cluster (bIGLJ1-IGLC1 to bIGLJ5-IGLC5) by employing Cre/loxP mediated site-specific chromosome recombination and the production of triple knockout (bIGHM-/-, bIGHML1-/- and bIGL-/-; TKO) Tc cattle. We further demonstrate that bIGL cluster deletion greatly improves fully hIgGs production in the sera of TKO Tc cattle, with 51.3% fully hIgGs (hIgG/hIgκ plus hIgG/hIgλ).

摘要

为了生产完全人源的多克隆抗体（hpAbs 或 hIgGs）的目标，我们之前报道过，携带包含整个未重排人免疫球蛋白（Ig）重链（hIGH）、κ链（hIGK）和 λ链（hIGL）种系基因座的人源染色体（HAC）的转染色体（Tc）牛，当两个牛免疫球蛋白 μ 重链，bIGHM 和 bIGHML1，都是纯合失活（bIGHM-/-, bIGHML1-/-；双敲除或 DKO）时，会产生生理水平的 hIgGs。然而，由于内源性牛免疫球蛋白轻链基因座仍然完整，轻链既来自 HAC 上的 hIGK 和 hIGL 基因组基因座，也来自内源性牛 κ 链（bIGK）和 λ 链（bIGL）基因组基因座，导致完全 hIgGs 的产生（重链和轻链均来自人源：hIgG/hIgκ 或 hIgG/hIgλ）和嵌合 hIgGs（重链来自人源，而轻链来自牛源：hIgG/bIgκ 或 hIgG/bIgλ）。为了提高 Tc 牛中完全 hIgG 的产量，我们在此报告通过 Cre/loxP 介导的定点染色体重组删除整个 bIGL 连接（J）和恒定（C）基因簇（bIGLJ1-IGLC1 到 bIGLJ5-IGLC5），并生产三重敲除（bIGHM-/-, bIGHML1-/- 和 bIGL-/-；TKO）的 Tc 牛。我们进一步证明，bIGL 簇缺失极大地提高了 TKO Tc 牛血清中完全 hIgGs 的产量，其中 51.3%是完全 hIgGs（hIgG/hIgκ 加 hIgG/hIgλ）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/e287b8167c5b/pone.0090383.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/b2c6f68bf5d1/pone.0090383.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/3aaa0e14ecd2/pone.0090383.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/7091a93f642b/pone.0090383.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/3f363d367795/pone.0090383.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/97323490dca1/pone.0090383.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/d17350d35c37/pone.0090383.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/e287b8167c5b/pone.0090383.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/b2c6f68bf5d1/pone.0090383.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/3aaa0e14ecd2/pone.0090383.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/7091a93f642b/pone.0090383.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/3f363d367795/pone.0090383.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/97323490dca1/pone.0090383.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/d17350d35c37/pone.0090383.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05b6/3946162/e287b8167c5b/pone.0090383.g007.jpg

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