Covalent Immune Proximity-Induction Strategy Using SuFEx-Engineered Bifunctional Viral Peptides

Area of Science:

• Immunology
• Organic Chemistry
• Chemical Biology

Background:

• Covalent antibody recruiting molecules (cARMs) use small molecules to link antibodies to tumor antigens.
• Existing cARMs are limited to recruiting antibodies specific for small molecule haptens.
• Most immune effector mechanisms recognize protein epitopes, necessitating broader recruitment strategies.

Purpose of the Study:

• To develop a new covalent immune proximity-inducing strategy using synthetic electrophilic peptides.
• To enable the recruitment of protein-specific antibodies, such as anti-viral antibodies, to cancer cells.
• To enhance anti-tumor immunotherapeutic efficacy by leveraging a broader range of immune machinery.

Main Methods:

• Engineered synthetic bifunctional electrophilic peptides containing tumor-targeting moieties and sulfonyl (VI) fluoride exchange (SuFEx) electrophiles.
• Synthesized peptides derived from herpes simplex virus glycoprotein D (gD) to target prostate-specific membrane antigen (PSMA)-expressing cancer cells.
• Utilized human serum containing anti-HSV antibodies for recruitment and assessed targeting selectivity and reaction kinetics via SuFEx chemistry.

Main Results:

• Demonstrated selective and irreversible targeting of anti-HSV antibodies by the electrophilic peptides.
• Showcased enhanced reaction rates by tuning SuFEx chemistry without compromising selectivity.
• Observed improved anti-tumor immunotherapeutic efficacy in cellular assays compared to non-electrophilic peptide controls.
• Confirmed enhanced efficacy with natural human anti-HSV antibodies and against tumor cells with lower PSMA expression.

Conclusions:

• Introduced a novel covalent peptide-based approach for immune proximity induction.
• Established the potential of using anti-viral antibodies in synthetic tumor immunotherapy.
• Highlighted the versatility of SuFEx chemistry in designing targeted immunotherapies.