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Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers

Benjamin P M Lake1,2, Ryan G Wylie2,3, Cyril Bařinka4

  • 1Department of Medicine, Center for Discovery in Cancer Research, McMaster University, Hamilton, Ontario, L8S 4K1, Canada.

Angewandte Chemie (International Ed. in English)
|December 28, 2022
PubMed

Insights

New polymeric Antibody Recruiting Molecules (pARMs) enhance immune response against cancer cells with low antigen expression. This tunable multivalent immune recruitment (MIR) platform improves immunotherapy efficacy for challenging tumors.

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.
Keywords:
AntibodiesCell RecognitionDrug DesignImmunochemistryPolymers

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