{
  "abstract": "Background Therapeutic antibodies modulating the immune response are frequently specific for human proteins but fail to cross-react with the corresponding rodent homologs. Hence, their preclinical development requires suitable ‘humanized’ mouse models, i.e. mice bearing a human immune system, so that immunotherapies can be evaluated in a more relevant immune context in vivo.Methods Such ‘humanized’ mice are developed by reconstituting the immune system of immunodeficient animals with human immune cells from 2 possible origins: CD34 + hematopoietic stem cells (huCD34+ mice) isolated from cord blood, or mature peripheral blood mononuclear cells prepared from buffy coats (huPBMC mice). According to the compound to be tested and the goal of the research, one model may be preferred over the other.Results HuCD34 + mice exhibit multilineage immune populations allowing the evaluation of immune checkpoint inhibitors. We developed the human A375 melanoma model in huCD34+ NCG mice to evaluate the combination strategy of relatlimab (anti-LAG-3 antibody) and nivolumab (anti-PD-1 antibody) approved at the beginning of 2024 as a first-line treatment for specific melanoma indications. Anti-PD-1 single treatment tended to, albeit without statistical significance, decrease tumor growth compared to isotype control group while anti-LAG-3 alone had no impact on tumor growth. The combination strategy induced a significant decrease in tumor growth compared to single agents in line with the data observed in the RELATIVITY-047 clinical trial (Tawbi H., NEJM, 2022). We also developed huPBMC mice that exhibit exclusively T-cell lineage and are suitable option to evaluate T-cell engagers like the CD3xEpCAM bispecific antibody, solitomab. We observed a dose-dependency between the dose of PBMC injected and the obtained level of human immune cell reconstitution. We observed that the level of reconstitution did not impact engraftment or tumor progression of the A375 melanoma or the BT474-clone5 breast cancer model, and conversely, that the tumor growth did not impact T-cell reconstitution. Finally, in the BT474-Clone5 model, we confirmed a dose-dependent efficacy of solitomab in controlling tumor growth. Moreover, solitomab efficacy was further potentiated by combination treatment with an Evotec proprietary co-stimulatory bispecific antibody.Conclusions Mice humanized for the immune system exhibiting either multiple lineages (CD34+ huNCG) or just T-cell lineage (huPBMC) proved themselves suitable tools to assess non-mouse cross-reactive anti-tumor immunotherapy assets. Expertise in handling such models and deep knowledge in their benefits and limitations are required to selecting the most valuable model to perform preclinical studies predictive of human therapeutic response.",
  "authors": [
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Lise Pasquet"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Sulayman Benmerzoug"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Alice Marchand"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Marion Mars"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Thibault Angles"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Sophie Chabot"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Frederique Dol-Gleizes"
    },
    {
      "affiliations": [
        "TransCure bioServices, Archamps, France"
      ],
      "name": "Sebastien Tabruyn"
    },
    {
      "affiliations": [
        "TransCure bioServices, Archamps, France"
      ],
      "name": "Dan Georgess"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Melanie Pichery"
    },
    {
      "affiliations": [
        "Evotec SE, Hamburg, Germany"
      ],
      "name": "Thomas Eden"
    },
    {
      "affiliations": [
        "Evotec International GmbH, Hamburg, Germany"
      ],
      "name": "Welbeck Danquah"
    },
    {
      "affiliations": [
        "Evotec International GmbH, Göttingen, Germany"
      ],
      "name": "Gerhard Niederfellner"
    },
    {
      "affiliations": [
        "Evotec France SAS, Toulouse, France"
      ],
      "name": "Pascale Lejeune"
    }
  ],
  "title": "731 Mice humanized for the immune system as validated tool for therapeutic antibody development",
  "uid": "b0f7c315-6284-5dd6-8e34-36fffaf12021"
}