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Immune Response Against Viral Pathogens01:29

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The immune system's response to viral infections is a complex and coordinated process involving natural killer (NK) cells, T cell-mediated responses, and antibody-mediated responses.
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Covalent Immune Proximity-Induction Strategy Using SuFEx-Engineered Bifunctional Viral Peptides.

Harrison M McCann1,2, Benjamin P M Lake1,2, Kyle S Hoffman3

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Researchers developed synthetic electrophilic peptides to bridge anti-viral antibodies to cancer cells, enhancing anti-tumor immunity. This novel covalent approach utilizes sulfonyl fluoride exchange chemistry for irreversible targeting and improved therapeutic efficacy, even against difficult-to-treat tumors.

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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.