Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers

Area of Science:

• Immunology
• Oncology
• Materials Science

Background:

• Chemical immunotherapies like Antibody Recruiting Molecules (ARMs) leverage immune-mediated clearance of diseased cells.
• Current ARMs require high tumor antigen valency for effective anti-cancer function, limiting efficacy against tumors with low antigen expression.
• A need exists for immunotherapeutic strategies that can overcome low antigen expression hurdles.

Purpose of the Study:

• To develop and evaluate a tunable multivalent immune recruitment (MIR) platform to enhance antibody recruitment to cells with low antigen valencies.
• To design and synthesize polymeric ARMs (pARMs) with varying Antibody-Binding Domain (ABD) and Target-Binding Domain (TBD) characteristics.
• To assess the impact of pARM design on immune induction and anti-cancer efficacy.

Main Methods:

• Synthesis of a series of polymeric ARMs (pARMs) with controlled ABD/TBD copy numbers and ratios.
• Screening of pARMs for high avidity binding to anti-dinitrophenyl antibodies and prostate-specific membrane antigens (PSMA) on prostate cancer cells.
• Evaluation of pARM-mediated immune induction and anti-cancer immune function in vitro.
• Comparison of optimized pARMs against analogous ARMs in low-antigen-expressing target cells.

Main Results:

• pARMs were successfully synthesized, demonstrating tunable multivalent immune recruitment capabilities.
• Most pARMs exhibited simultaneous high avidity binding to both antibodies and prostate cancer cells expressing PSMA.
• Optimized pARMs significantly enhanced anti-cancer immune function compared to conventional ARMs.
• The pARM platform demonstrated improved efficacy against target cells with lower antigen expression levels.

Conclusions:

• The tunable multivalent immune recruitment (MIR) platform, utilizing polymeric ARMs (pARMs), effectively overcomes the limitation of low tumor antigen valency in immunotherapies.
• Optimized pARMs show promise for enhancing immune-mediated cancer cell clearance in a broader range of tumors, including those with heterogeneous or low antigen expression.
• This approach represents a significant advancement in the design of targeted immunotherapies for improved clinical outcomes.