{
  "abstract": "Background T-cell engagers (TCEs), which can simultaneously target T-cell surface marker CD3 and a tumor-associated antigen (TAA) on cancer cells, have demonstrated great potential in tumor treatment. Due to the complex mechanism of TCE molecules, advanced models are required to better evaluate the performance of TCEs at the preclinical stage.Methods We established several medium to high-throughput in vitro assays to quickly screen TCE molecules. Candidate molecules were selected based on their ability of target binding, T cells activation, and tumor killing. Selected molecules were subjected to in vivo efficacy testing using either xenograft and syngeneic models.For xenograft models we used NCG-MHC-dKO mice, which were established by knocking out murine MHC class I and class II molecules in immunodeficient NCG mice. This model can reduce the graft-versus-host-disease (GvHD) response, prolonging the experimental window following engraftment with human PBMCs. Tarlatamab (DLL3 TCE) and Talquetamab (GPRC5D TCE) were evaluated in NCG-MHC-dKO mice inoculated with human small-cell lung cancer cells and human multiple myeloma cells, respectively.For syngeneic models, we generated BALB/c-hCD3EDG mice by replacing the mouse endogenous CD3e, CD3d and CD3g genes with human CD3E, CD3D and CD3G. We evaluated the efficacy of CD3/CD20 bispecific-antibody using BALB/c-hCD3EDG mouse inoculated with the humanized mouse lymphoma A20-hCD20 cell lines.Results Both Talquetamab and Tarlatamab effectively inhibited tumor growth in huPBMC-NCG-MHC-dKO mice, with animals demonstrating good health conditions throughout the study. Mice bearing SHP-77 and NCI-H929 tumors demonstrated a complete response to Tarlatamab and Talquetamab following two weeks of treatment.In the BALB/c-hCD3EDG mice model, the CD3/CD20 bispecific antibody suppressed tumor growth, with tumor inhibition at 81.46% was following 18 days of treatment.Conclusions GemPharmatech’s integrated in vitro and in vivo platforms, including our NGC-MHC-dKO and CD3-humanized mouse models provide a powerful, scalable framework for the rapid and comprehensive evaluation of T-cell engagers.",
  "authors": [
    {
      "affiliations": [
        "GePharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Xinjie Lian"
    },
    {
      "affiliations": [
        "GePharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Shiying Guo"
    },
    {
      "affiliations": [
        "GePharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Hongyan Sun"
    },
    {
      "affiliations": [
        "GePharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Jianming Xu"
    },
    {
      "affiliations": [
        "GePharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Xiang Gao"
    }
  ],
  "title": "1237 Integrated platforms for the preclinical evaluation of T-cell engagers",
  "uid": "4fa35489-ff73-5636-a351-84d97279d2e6"
}