RRC ID |
38234
|
著者 |
Uchiyama S, Suzuki Y, Otake K, Yokoyama M, Ohta M, Aikawa S, Komatsu M, Sawada T, Kagami Y, Morishima Y, Fukui K.
|
タイトル |
Development of novel humanized anti-CD20 antibodies based on affinity constant and epitope.
|
ジャーナル |
Cancer Sci
|
Abstract |
We describe novel humanized anti-CD20 monoclonal antibodies (mAbs) developed for therapeutic use on the basis of their physicochemical properties and cellular cytotoxicity. A distinct correlation between apparent dissociation constants (K(d)) and apoptotic activity for eight murine anti-CD20 mAbs (OUBM1-OUBM8) and previously-developed murine anti-CD20 mAbs enabled us to categorize anti-CD20 mAbs into two groups. Group A mAbs had lower K(d) values and did not induce definite apoptosis, while Group B mAbs had greater K(d) values and did induce definite apoptosis. A murine version mAb of rituximab, 2B8, belongs to Group B. An epitope analysis showed that the epitope of two murine mAbs, OUBM3 and OUBM6, differed from that of 2B8 or 2F2 (ofatumumab). Two mAbs, OUBM3 from Group A and OUBM6 from Group B, were selected and humanized. As expected, the humanized OUBM3 with the lower K(d) did not induce apoptosis, while the humanized OUBM6 (hOUBM6) with the greater K(d) did. Both hOUBM3 and hOUBM6 induced highly-effective, complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity against Burkitt's and follicular lymphomas. Importantly, hOUBM6 exhibited cellular cytotoxicity against diffuse, large B cells that are less effectively depleted by rituximab and also exhibited effective cytotoxicity against tumor cells from human CD20(+) leukemia and lymphoma patients. These results suggest the potential impact of the further development of our anti-CD20 mAbs. Our study shows that the selection of mAbs based on their physicochemical parameters, followed by the biological activity assessment for the selected mAbs, is a rational and efficient approach for pharmaceutical mAb development.
|
巻・号 |
101(1)
|
ページ |
201-9
|
公開日 |
2010-1-1
|
DOI |
10.1111/j.1349-7006.2009.01392.x
|
PII |
CAS1392
|
PMID |
19930155
|
MeSH |
Animals
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / pharmacology
Antibody Affinity*
Antigens, CD20 / immunology*
Apoptosis
Cell Line, Tumor
Complement System Proteins / physiology
Cytotoxicity, Immunologic
Epitopes*
Humans
Mice
|
IF |
4.966
|
引用数 |
29
|
WOS 分野
|
ONCOLOGY
|
リソース情報 |
ヒト・動物細胞 |
RAJI(RCB1647) |