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Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Peiyin Wang, Liping L Sun, Robyn Clark

    Molecular Cancer Therapeutics
    |April 1, 2022
    PubMed

    Insights

    A new bispecific antibody targeting LY6G6D shows promise for treating colorectal cancer, especially in microsatellite-stable (MSS) or microsatellite instability-low (MSI-L) patients. Combination therapy with PD-1 blockade further enhances its antitumor efficacy.

    Area of Science:

    • Oncology
    • Immunotherapy
    • Antibody Engineering

    Background:

    • Colorectal cancer (CRC) treatment has improved, but outcomes for microsatellite-stable (MSS) or microsatellite instability-low (MSI-L) metastatic CRC (mCRC) remain poor.
    • Immune checkpoint inhibitors are effective for mismatch-repair-deficient or MSI-high mCRC, but not for MSS/MSI-L subtypes.
    • There is a critical need for novel therapeutics targeting MSS/MSI-L mCRC.

    Purpose of the Study:

    • To discover and characterize a novel T-cell-dependent bispecific antibody (TDB) targeting the tumor-associated antigen LY6G6D for CRC treatment.
    • To evaluate the therapeutic potential of LY6G6D-TDB in preclinical models of colorectal cancer, including MSS/MSI-L subtypes.

    Main Methods:

    • RNA sequencing and immunohistochemistry (IHC) were used to assess LY6G6D expression in colorectal tumors and normal tissues.
    • A novel TDB (LY6G6D-TDB) targeting LY6G6D and CD3 was engineered and optimized.
    • In vitro functional assays assessed T-cell activation and cytotoxicity. In vivo efficacy was evaluated in mouse xenograft tumor models, with and without PD-1 blockade.

    Main Results:

    • LY6G6D is differentially expressed in colorectal cancer, with high prevalence in MSS/MSI-L subsets and limited expression in normal tissues.
    • The optimized LY6G6D-TDB demonstrated potent, target-dependent T-cell activation and cytotoxicity in vitro.
    • LY6G6D-TDB showed significant antitumor activity as a single agent in mouse xenograft models and enhanced efficacy when combined with PD-1 blockade.

    Conclusions:

    • LY6G6D is a promising therapeutic target for colorectal cancer, particularly in MSS/MSI-L patient populations.
    • LY6G6D-TDB is a novel T-cell-dependent bispecific antibody with potent preclinical antitumor activity against colorectal cancer.
    • LY6G6D-TDB represents a potential new treatment option for colorectal cancer, especially when used in combination with PD-1 inhibitors.

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