Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL
| Autor: | Eric C. Peterson, Yuval Avnir, Aimee St. Clair Tallarico, Margaret Goodall, Subhabrata Biswas, Jennifer R. Brown, Quan Zhu, Vinodh B. Kurella, Stacey M. Fernandes, Madhura M. Panditrao, Jianhua Sui, Yanyan Wang, Wayne A. Marasco, De-Kuan Chang, Xueqian Wang, Jiusong Sun, Roy Jefferis |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.drug_class Immunology B-cell receptor Receptors Antigen B-Cell Antineoplastic Agents Monoclonal antibody Antibodies Monoclonal Humanized 03 medical and health sciences Mice 0302 clinical medicine hemic and lymphatic diseases Report medicine Immunology and Allergy Animals Humans Antibody-dependent cell-mediated cytotoxicity biology breakpoint cluster region Idiotopes Molecular biology Leukemia Lymphocytic Chronic B-Cell Antibodies Anti-Idiotypic 030104 developmental biology Humanized mouse Monoclonal biology.protein Antibody 030215 immunology |
| Zdroj: | mAbs |
| ISSN: | 1942-0870 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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