Engineered humanized dimeric forms of IgG are more effective antibodies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Humanized IgG1 M195 (HuG1-M195) is a recombinant monoclonal antibody targeting CD33, an antigen on myelogenous leukemia cells, currently in clinical trials for acute myelogenous leukemia therapy.
• The biological activity of immunoglobulin G (IgG) may be influenced by multimeric clustering of its Fab and Fc regions.

Purpose of the Study:

• To investigate the impact of IgG homodimerization on the therapeutic efficacy of HuG1-M195 against leukemia cells.
• To explore the potential advantages of genetically engineered multimeric antibody constructs over naturally occurring forms.

Main Methods:

• Construction of homodimeric HuG1-M195 by introducing a CH3 region mutation (serine to cysteine) for interchain disulfide bond formation.
• Comparison of homodimeric and non-multimeric HuG1-M195 in terms of radioisotope internalization, retention in leukemia cells, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity.

Main Results:

• Homodimeric HuG1-M195 exhibited significantly improved internalization and radioisotope retention in target leukemia cells compared to its non-multimeric counterpart, despite similar avidity.
• Homodimers demonstrated a 100-fold increase in potency for complement-mediated leukemia cell killing and antibody-dependent cellular cytotoxicity using human effectors.

Conclusions:

• Genetically engineered homodimeric IgG constructs, such as HuG1-M195, offer enhanced therapeutic potential compared to naturally occurring monomeric forms.
• Multimeric IgG engineering represents a promising strategy for improving antibody-based cancer therapies, particularly for acute myelogenous leukemia.