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A Chimeric Antigen Coreceptor System For Optimized Antigen Targeting

Interests: Immunotherapy, Oncology
Published:
Lead Inventor: Jun Huang
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SUMMARY

A novel chimeric antigen coreceptor system mimicking the CD4/CD8 and TCR interaction to enhance signaling for increased antigen sensitivity to treat B cell malignancies.

 

The unmet need: Solutions for CAR therapy insufficient efficacy and clinical non-response/relapse

  • CAR-T cells are T cells genetically engineered to express a scFv against a target antigen coupled to intracellular signaling domains borrowed from the endogenous TCR pathway. Since CARs recognize a chosen epitope, they provide an alternative, pMHC-independent pathway of T cell activation.

  • Decreased expression of target antigen is a critical barrier for CAR-T clinical efficacy. It is especially problematic for FDA-approved CAR designs, as they are limited by up to 1,000-fold reduced sensitivity for antigen relative to T-cell receptors (TCRs), in part due to poor recruitment of downstream signaling molecules to facilitate T-cell signaling. As most clinically used CARs use similar intracellular signaling domains and differ mainly by choice of scFv, low sensitivity is common across designs.

The proposed solution: Dual chimeric antigen coreceptors with increased antigen sensitivity

  • The faculty inventor developed a CAR system inspired by the interactions between CD4 or CD8 coreceptor and the TCR. The systems consists of co-expressed molecules: a novel chimeric CD8 or CD4 coreceptor (i.e., CoCAR, mimicking CD8 or CD4) to enhance signaling and a 42BB-CD3 CAR( mimicking TCR).

  • The system induces CAR signaling that more closely mimics TCR signaling and will improve CAR-T efficacy in cases of downregulation of target antigen. By increasing CAR sensitivity, the occurrences of relapse due to low antigen expression can be reduced leading to better patient outcomes.

ADVANTAGES

ADVANTAGES

  • Increased antigen sensitivity

  • Preserves endogenous TCR function

  • Simultaneous targeting of two distinct CD22 epitopes

APPLICATIONS

  • B cell leukemias and lymphomas
  • CAR platform for solid tumors