{
  "abstract": "Background Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, comprising ~15% of all lung cancers, with a 5-year survival rate under 4%. Over 80% of patients present with brain metastases and extensive-stage disease. Despite the approval of tarlatamab and ongoing development of DLL3- or B7-H3-targeted ADCs, tumor relapse and heterogeneity in target expression continue to pose challenges. Delta-like ligand 3 (DLL3), B7-H3, and seizure-related homolog 6 (SEZ6) have been validated targets for SCLC.Methods We designed two bispecific ADCs (bsADCs) targeting DLL3×B7-H3 and DLL3×SEZ6, respectively. Each bsADC was constructed in a 1+1 IgG format and conjugated with a novel topoisomerase I (TOP1) inhibitor payload using a highly hydrophilic, enzyme-cleavable linker (DAR 8), capable of inducing potent bystander effects. We used in vitro internalization activity, in vivo anti-tumor efficacy in SCLC CDX or PDX models, and developability screening as primary selection criteria.Results The DLL3×B7-H3 bsAb showed stronger internalization in double positive cell lines than the parental monovalent arms and outperformed the naked antibodies of DS-7300 and rovalpituzumab (Rova). The DLL3×B7-H3 bsADC demonstrated robust anti-tumor efficacy that was superior to DS-7300 ADC when all antibodies were conjugated to BLD-1102 and tested in SCLC CDX models. The bsADC outperformed DS-7300 with original payload in SCLC PDX model. The B7-H3 arm can work independently in the absence of DLL3 expression, allowing single-targeting of B7-H3 single positive tumor cells.The DLL3×SEZ6 bsAb exhibited a stronger trend of internalization activity than benchmarks and parental monovalent antibodies in SCLC cell lines. The DLL3×SEZ6 bsADC demonstrated comparable efficacy to benchmark with same payload and showed more potent anti-tumor efficacy than parental monovalent ADCs in SCLC CDX models.DLL3×B7-H3 and DLL3×SEZ6 bsAbs exhibited excellent stability under stress conditions, suggesting them as promising candidates for CMC development.Conclusions DLL3×B7-H3 and DLL3×SEZ6 bsADCs represent two novel and complementary strategies for addressing tumor heterogeneity and limited treatment options in SCLC. Their dual-targeting mechanisms enhanced specificity, broadened patient coverage, and resulted in robust preclinical efficacy, supporting further development toward clinical translation.",
  "authors": [
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Liu Yang"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Kunying Hao"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Peiran Li"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Yu Qi"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Gao An"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Chengzhang Shang"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Yanan Guo"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Yi Yang"
    },
    {
      "affiliations": [
        "Biocytogen, Waltham, MA, USA"
      ],
      "name": "Frank An"
    }
  ],
  "title": "955 Bispecific antibody-drug conjugates targeting DLL3×B7-H3 and DLL3×SEZ6 demonstrate potent anti-tumor activity in preclinical models of small-cell lung cancer",
  "uid": "b9b63c42-b376-511d-9ffc-c04281f44740"
}