Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL. Issue 4 (18th May 2016)

• Record Type: Journal Article
• Authors: Chang, De-Kuan; Kurella, Vinodh B.; Biswas, Subhabrata; Avnir, Yuval; Sui, Jianhua; Wang, Xueqian; Sun, Jiusong; Wang, Yanyan; Panditrao, Madhura; Peterson, Eric; Tallarico, Aimee; Fernandes, Stacey; Goodall, Margaret; Zhu, Quan; Brown, Jennifer R.; Jefferis, Roy; Marasco, Wayne A
• Is Part Of: MAbs. Volume 8:Issue 4(2016)
• Page Start: 787
• Page End: 798
• Publication Date: 2016-05-18
• Subjects: B-cell chronic lymphocytic leukemia -- cytotoxicity -- GTL mice -- humanization -- immunotherapy -- monoclonal antibody -- precision medicine; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2016.1159365
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: 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 ∼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.