Broadening and Enhancing Functions of Antibodies by Self-Assembling Multimerization at Cell Surface

Area of Science:

• Immunology
• Biotechnology
• Molecular Biology

Background:

• Monoclonal antibody therapy shows promise but often lacks efficacy due to monovalent binding.
• Antibody monovalency limits receptor engagement and subsequent cellular responses.

Purpose of the Study:

• To develop a pretargeting-postassembly strategy for enhanced antibody-mediated cellular responses.
• To improve antibody efficacy by promoting receptor clustering and multivalency.

Main Methods:

• Utilized Watson-Crick base pairing of oligonucleotides for antibody pretargeting and postassembly.
• Modified anti-CD20 obinutuzumab with morpholino oligonucleotides (OBN-MORF1).
• Introduced albumin grafted with complementary morpholino oligonucleotides (HSA-(MORF2)) for multivalent tethering.

Main Results:

• OBN-MORF1 binding induced actin redistribution, homotypic adhesion, and lysosome-mediated cell death.
• HSA-(MORF2) treatment promoted CD20 clustering, calcium influx, and caspase-related apoptosis.
• The combined approach significantly extended survival in mice with disseminated B-cell lymphomas.

Conclusions:

• The pretargeting-postassembly strategy effectively enhances antibody functions through sequential receptor binding and clustering.
• This novel approach offers a promising avenue for improving antibody-based cancer therapies.
• The dual-mechanism system demonstrated significant therapeutic benefits in a preclinical lymphoma model.