| RRC ID |
57003
|
| Author |
Aoyama M, Tada M, Tatematsu KI, Hashii N, Sezutsu H, Ishii-Watabe A.
|
| Title |
Effects of amino acid substitutions on the biological activity of anti-CD20 monoclonal antibody produced by transgenic silkworms (Bombyx mori).
|
| Journal |
Biochem Biophys Res Commun
|
| Abstract |
Recombinant monoclonal antibodies (mAbs) have been used in various therapeutic applications including cancer therapy. Fc-mediated effector functions play a pivotal role in the tumor-killing activities of some tumor-targeting mAbs, and Fc-engineering technologies with glyco-engineering or amino acid substitutions at the antibody Fc region have been used to enhance cytotoxic activities including antibody-dependent cellular cytotoxicity (ADCC). We previously reported that the mAbs produced using transgenic silkworms showed stronger ADCC activity and lower complement-dependent cytotoxicity (CDC) activity than mAbs derived from Chinese hamster ovary (CHO) cells due to their unique N-glycan structure (lack of core-fucose and non-reducing terminal galactose). In this study, we generated anti-CD20 mAbs with amino acid substitutions using transgenic silkworms and analyzed their biological activities to assess the effect of the combination of glyco-engineering and amino acid substitutions on the Fc-mediated function of mAbs. Three types of amino acid substitutions at the Fc region (G236A/S239D/I332E, L234A/L235A, and K326W/E333S) modified the Fc-mediated biological activities of silkworm-derived mAbs as in the case of CHO-derived mAbs, resulting in the generation of Fc-engineered mAbs with characteristic Fc-mediated functions. The combination of amino acid substitutions at the Fc region and glyco-engineering using transgenic silkworm made it possible to generate Fc-engineered mAbs with suitable Fc-mediated biological functions depending on the pharmacological mechanism of their actions. Transgenic silkworms were shown to be a promising system for the production of Fc-engineered mAbs.
|
| Volume |
503(4)
|
| Pages |
2633-2638
|
| Published |
2018-9-18
|
| DOI |
10.1016/j.bbrc.2018.08.015
|
| PII |
S0006-291X(18)31688-7
|
| PMID |
30119885
|
| MeSH |
Amino Acid Substitution
Animals
Animals, Genetically Modified
Antibodies, Monoclonal, Humanized / biosynthesis
Antibodies, Monoclonal, Humanized / chemistry*
Antibodies, Monoclonal, Humanized / genetics
Antibody-Dependent Cell Cytotoxicity*
Antigens, CD20 / genetics
Antigens, CD20 / immunology*
Bombyx / genetics*
Carbohydrate Sequence
Cell Line, Tumor
Fucose / chemistry
Fucose / immunology
Galactose / chemistry
Galactose / immunology
Gene Expression
Humans
Immunoglobulin Fc Fragments / biosynthesis
Immunoglobulin Fc Fragments / chemistry*
Immunoglobulin Fc Fragments / genetics
Jurkat Cells
Lymphocytes / cytology
Lymphocytes / immunology*
Polysaccharides / chemistry
Polysaccharides / immunology
Protein Engineering
|
| IF |
2.705
|
| Times Cited |
2
|
| Resource |
| Silkworms |
|
