Development of Apoptotic-Cell-Inspired Antibody-Drug Conjugate for Effective Immune Modulation.

Background: Apoptotic cells' phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4 cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody-drug conjugates (ADCs) in a targeted anti-inflammatory approach.

Aim: We conducted this research to introduce an apoptotic-cell-inspired antibody-drug conjugate for effective immunomodulation.

Method: Poly(2-hydroxyethyl methacrylate--2-methacryloyloxyethyl phosphorylserine) (p(HEMA--MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA--MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated.

Results: We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody-polymer ratio to achieve the highest antibody-binding affinity.

Conclusion: We successfully introduced p(HEMA--MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody-polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.