Reversible Chemical Modification of Antibody Effector Function Mitigates Unwanted Systemic Immune Activation.

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Antibody effector functions like ADCC and ADCP rely on Fc region interactions with Fcγ receptors on immune cells.
• Current methods to enhance Fc-Fcγ engagement for antitumor responses can cause systemic cytokine release and infusion reactions.
• Balancing potent antitumor activity with reduced systemic immune activation is a key challenge in antibody therapeutics.

Purpose of the Study:

• To develop a method for reversible chemical modulation of antibody-Fcγ interactions.
• To create a system that temporarily mutes Fcγ engagement, restoring it in vivo over time.
• To apply this technology to an enhanced CD40 antibody (SEA-CD40) and assess its safety and efficacy.

Main Methods:

• Utilized poly(ethylene glycol) (PEG) linkers conjugated to antibody interchain disulfides via maleimide attachments.
• Developed a reversible chemical modulation strategy for antibody Fc-Fcγ interactions.
• Tested the technology on an effector function-enhanced agonist CD40 antibody (SEA-CD40) in vitro and in vivo.

Main Results:

• Demonstrated significant reductions in Fc-induced immune activation in vitro and in preclinical models (mice, nonhuman primates).
• Showcased retained therapeutic efficacy of the modulated antibody compared to the parent antibody.
• Observed improved pharmacokinetic profiles for the modulated antibody.

Conclusions:

• The described reversible chemical modulation system effectively reduces systemic immune activation caused by Fc-FcγR binding.
• This technology offers a modular approach to mitigate dose-limiting toxicities associated with Fc-enhanced antibodies.
• The method holds promise for broad application in immuno-oncology to improve the therapeutic index of antibody-based drugs.