Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers.
Benjamin P M LakeRyan G WylieCyril BarinkaAnthony F RulloPublished in: Angewandte Chemie (International ed. in English) (2023)
Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs - bivalent small molecules containing an antibody-binding domain (ABD) and a target-binding domain (TBD)) direct immune-mediated clearance of diseased cells. Anti-cancer ARM function relies on high tumor antigen valency, limiting function against lower antigen expressing tumors. To address this limitation, we report a tunable multivalent immune recruitment (MIR) platform to amplify/stabilize antibody recruitment to cells with lower antigen valencies. An initial set of polymeric ARMs (pARMs) were synthesized and screened to evaluate ABD/TBD copy number, ratio, and steric occlusion on specific immune induction. Most pARMs demonstrated simultaneous high avidity binding to anti-dinitrophenyl antibodies and prostate-specific membrane antigens on prostate cancer. Optimized pARMs mediated enhanced anti-cancer immune function against lower antigen expressing target cells compared to an analogous ARM.
Keyphrases
- prostate cancer
- induced apoptosis
- copy number
- cell cycle arrest
- mitochondrial dna
- endoplasmic reticulum stress
- cell proliferation
- long non coding rna
- oxidative stress
- drug delivery
- genome wide
- high throughput
- gene expression
- radical prostatectomy
- dna methylation
- immune response
- binding protein
- dna binding
- young adults
- energy transfer
- childhood cancer