Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL

被引：6

作者：

Chang, De-Kuan ^{[1
,2
,5
]}

Kurella, Vinodh B. ^{[1
,2
,6
]}

Biswas, Subhabrata ^{[1
,2
]}

Avnir, Yuval ^{[1
,2
]}

Sui, Jianhua ^{[1
,2
,7
]}

Wang, Xueqian ^{[1
,2
]}

Sun, Jiusong ^{[1
,2
]}

Wang, Yanyan ^{[1
]}

Panditrao, Madhura ^{[1
]}

Peterson, Eric ^{[1
]}

Tallarico, Aimee ^{[1
,2
]}

Fernandes, Stacey ^{[3
]}

Goodall, Margaret ^{[4
]}

Zhu, Quan ^{[1
,2
]}

Brown, Jennifer R. ^{[3
]}

Jefferis, Roy ^{[4
]}

Marasco, Wayne A. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Univ Birmingham, Sch Med, Div Immun & Infect, Birmingham, W Midlands, England

[5] AbVitro Inc, Boston, MA 02210 USA

[6] Intrexon Corp, Immunooncol Div, Germantown, MD 20876 USA

[7] Natl Inst Biol Sci, Beijing, Peoples R China

来源：

MABS | 2016年 / 8卷 / 04期

关键词：

B-cell chronic lymphocytic leukemia; cytotoxicity; GTL mice; humanization; immunotherapy; monoclonal antibody; precision medicine; CHRONIC LYMPHOCYTIC-LEUKEMIA; SOMATIC HYPERMUTATION; CELL LYMPHOMA; PATHOGENETIC IMPLICATIONS; IMMUNE-RESPONSES; XENOGRAFT MODELS; T-CELLS; ANTIGEN; VIRUS; EXPRESSION;

D O I：

10.1080/19420862.2016.1159365

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

In 10-20% of the cases of chronic lymphocytic leukemia of B-cell phenotype (B-CLL), the IGHV1-69 germline is utilized as VH gene of the B cell receptor (BCR). Mouse G6 (MuG6) is an anti-idiotypic monoclonal antibody discovered in a screen against rheumatoid factors (RFs) that binds with high affinity to an idiotope expressed on the 51p1 alleles of IGHV1-69 germline gene encoded antibodies (G6-id(+)). The finding that unmutated IGHV1-69 encoded BCRs are frequently expressed on B-CLL cells provides an opportunity for anti-idiotype monoclonal antibody immunotherapy. In this study, we first showed that MuG6 can deplete B cells encoding IGHV1-69 BCRs using a novel humanized GTL mouse model. Next, we humanized MuG6 and demonstrated that the humanized antibodies (HuG6s), especially HuG6.3, displayed similar to 2-fold higher binding affinity for G6-id(+) antibody compared to the parental MuG6. Additional studies showed that HuG6.3 was able to kill G6-id(+) BCR expressing cells and patient B-CLL cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, both MuG6 and HuG6.3 mediate in vivo depletion of B-CLL cells in NSG mice. These data suggest that HuG6.3 may provide a new precision medicine to selectively kill IGHV1-69-encoding G6-id(+) B-CLL cells.

引用

页码：787 / 798

页数：12

共 1 条

[1] Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope
Avnir, Yuval
Prachanronarong, Kristina L.
Zhang, Zhen
Hou, Shurong
Peterson, Eric C.
Sui, Jianhua
Zayed, Hatem
Kurella, Vinodh B.
McGuire, Andrew T.
Stamatatos, Leonidas
Hilbert, Brendan J.
Bohn, Markus-Frederik
Kowalik, Timothy F.
Jensen, Jeffrey D.
Finberg, Robert W.
Wang, Jennifer P.
Goodall, Margaret
Jefferis, Roy
Zhu, Quan
Yilmaz, Nese Kurt
Schiffer, Celia A.
Marasco, Wayne A.
CELL REPORTS, 2017, 21 (11): : 3243 - 3255

← 1 →