| Literature DB >> 26963739 |
De-Kuan Chang1,2, Vinodh B Kurella1,2, Subhabrata Biswas1,2, Yuval Avnir1,2, Jianhua Sui1,2, Xueqian Wang1,2, Jiusong Sun1,2, Yanyan Wang1, Madhura Panditrao1, Eric Peterson1, Aimee Tallarico1,2, Stacey Fernandes3, Margaret Goodall4, Quan Zhu1,2, Jennifer R Brown3, Roy Jefferis4, Wayne A Marasco1,2.
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.Entities:
Keywords: B-cell chronic lymphocytic leukemia; GTL mice; cytotoxicity; humanization; immunotherapy; monoclonal antibody; precision medicine
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Year: 2016 PMID： 26963739 PMCID： PMC4966851 DOI： 10.1080/19420862.2016.1159365
Source DB: PubMed Journal: MAbs ISSN： 1942-0862 Impact factor: 5.857