{
  "abstract": "Background Multiple myeloma (MM) is the second most prevalent hematological malignancy and remains incurable despite recent therapeutic advancements. The primary aim of MM treatment is to prolong survival and enhance quality of life by effectively managing disease-related complications through sustained suppression of malignant plasma cells. Until recently, standard first-line therapy comprised a multi-agent regimen incorporating proteasome inhibitors, immunomodulatory agents, glucocorticoids, and anti-CD38 monoclonal antibodies such as daratumumab and isatuximab. CD38 is expressed at high levels in the hematopoietic system, including lymphoid and myeloid cells, red blood cells, and platelets. Given its elevated expression on plasma cells, CD38 has emerged as an attractive therapeutic target in MM immunotherapy. Recently, bispecific antibodies (bsAbs) such as teclistamab, elranatamab (targeting BCMA), and talquetamab (targeting GPRC5D) have been approved as T cell-redirecting therapies for MM. To date, no CD38-targeting bsAb has received clinical approval.Methods Nine CD38xCD3 bsAbs were generated using three distinct CD38 binders derived from daratumumab, isatuximab, and a high-affinity CD38 binder, described by Sanofi, 1 combined with three distinct anti-CD3/anti-TCR single-chains: the anti-CD3 clone UCHT1 (CD3high), the UCHT-1 derived low-affinity anti-CD3 clone M18 (CD3low),2 and a humanized, intermediate-affinity version of the TCR agonist BMA (TCRintermediate). These CD38xCD3 bsAbs were evaluated in various functional assays, including analyses of T cell activation and proliferation, cytokine release, and tumor cell lysis.Results The CD38 binder derived from isatuximab and the binder described by Sanofi showed a higher affinity to CD38 than the daratumumab-derived clone. All constructs induced antitumor effects, although the bsAbs including UCHT-1 and M18 showed the strongest and the bsAbs including BMA the weakest effects using low concentrations (<0.2 nM). At higher concentrations (>0.2 nM), the BMA-based bsAbs combined with the isatuximab- or Sanofi-derived CD38 binders achieved comparable T cell activation, proliferation and tumor cell killing to UCHT-1-based bsAbs, whereas cytokine release was significantly lower.Conclusions Our findings indicate that CD38xCD3 bsAbs hold therapeutic potential for the treatment of MM. Moreover, using an intermediate-affinity version of the TCR agonist BMA enables substantial reduction in cytokine release while maintaining strong antitumor efficacy.References Wu L, Seung E, Xu L, Rao E, Lord DM, Wei RR, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer. 2020;1(1):86–98. doi:10.1038/s43018-019-0004-z.Zekri L, Lutz M, Prakash N, Manz T, Klimovich B, Mueller S, et al. An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers. Mol Ther. 2023;31(4):1033–45. doi:10.1016/j.ymthe.2023.02.010.Ethics Approval The study was approved by IRB (ethics committee of the Faculty of Medicine of the Eberhard Karls Universitaet Tübingen) at the University Hospital Tübingen and was conducted in accordance with the Declaration of Helsinki; reference number13/2007 V.",
  "authors": [
    {
      "affiliations": [
        "Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, Germany",
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Ilona Hagelstein"
    },
    {
      "affiliations": [
        "Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, Germany",
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Kevin Wang"
    },
    {
      "affiliations": [
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Jan Van Ermingen"
    },
    {
      "affiliations": [
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Stefanie Müller"
    },
    {
      "affiliations": [
        "Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, Germany",
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Helmut R Salih"
    },
    {
      "affiliations": [
        "Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, Germany",
        "German Cancer Consortium (DKTK), Tübingen, Baden-Württemberg, Germany",
        "University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany"
      ],
      "name": "Martina S Lutz"
    }
  ],
  "title": "1187 Optimizing CD38xCD3 bispecific antibodies for the treatment of multiple myeloma with minimized cytokine release",
  "uid": "4ac6658d-108d-5c5f-a3be-9e3ca2461b32"
}