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

MAbs. May-Jun 2016;8(4):787-98. doi: 10.1080/19420862.2016.1159365. Epub 2016 Mar 10.

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.

Keywords: B-cell chronic lymphocytic leukemia; GTL mice; cytotoxicity; humanization; immunotherapy; monoclonal antibody; precision medicine.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / biosynthesis
  • Antibodies, Anti-Idiotypic / pharmacology*
  • Antibodies, Monoclonal, Humanized / biosynthesis
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Mice
  • Receptors, Antigen, B-Cell / immunology*

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • IGHV1-69 B-cell receptor, human
  • Receptors, Antigen, B-Cell