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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3813428?pdf=render |
| _version_ | 1819077546508025856 |
|---|---|
| author | Akiko Sano Hiroaki Matsushita Hua Wu Jin-An Jiao Poothappillai Kasinathan Eddie J Sullivan Zhongde Wang Yoshimi Kuroiwa |
| author_facet | Akiko Sano Hiroaki Matsushita Hua Wu Jin-An Jiao Poothappillai Kasinathan Eddie J Sullivan Zhongde Wang Yoshimi Kuroiwa |
| author_sort | Akiko Sano |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T18:58:55Z |
| format | Article |
| id | doaj.art-03a301bc1e7f41da96c18bb7eafeb96e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T18:58:55Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-03a301bc1e7f41da96c18bb7eafeb96e2022-12-21T18:53:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7811910.1371/journal.pone.0078119Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle.Akiko SanoHiroaki MatsushitaHua WuJin-An JiaoPoothappillai KasinathanEddie J SullivanZhongde WangYoshimi KuroiwaTherapeutic 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.http://europepmc.org/articles/PMC3813428?pdf=render |
| spellingShingle | Akiko Sano Hiroaki Matsushita Hua Wu Jin-An Jiao Poothappillai Kasinathan Eddie J Sullivan Zhongde Wang Yoshimi Kuroiwa Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. PLoS ONE |
| title | Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. |
| title_full | Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. |
| title_fullStr | Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. |
| title_full_unstemmed | Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. |
| title_short | Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. |
| title_sort | physiological level production of antigen specific human immunoglobulin in cloned transchromosomic cattle |
| url | http://europepmc.org/articles/PMC3813428?pdf=render |
| work_keys_str_mv | AT akikosano physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT hiroakimatsushita physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT huawu physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT jinanjiao physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT poothappillaikasinathan physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT eddiejsullivan physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT zhongdewang physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle AT yoshimikuroiwa physiologicallevelproductionofantigenspecifichumanimmunoglobulininclonedtranschromosomiccattle |