{
  "abstract": "Background An ADC typically consists of a monoclonal antibody (mAb) covalently linked to a payload via a chemical linker. A critical aspect of ADC development is identifying a unique target antigen. The ideal target should exhibit high specificity to tumor cells, with minimal or no expression in healthy tissues. It should also be present on the surface of tumor cells for optimal accessibility and capable of internalizing upon antibody binding to enable intracellular delivery of the payload. Our ADC PB-vcMMAE-5 consists of the mAb PB-223 conjugated via the mc-vc-PABc linker to the microtubule-inhibitor MMAE. PB-223 was created through affinity maturation of NEO-102, a chimeric human IgG1 mAb that targets tumor specific truncated core-2 O-glycans. PB-223 exhibits 4-fold improvement in binding affinity (KD) compared to NEO-102 and recognizes a boarder range of tumor tissues while sparing normal tissues. The drug-to antibody ratio (DAR) of PB-vcMMAE-5 is 3.92. PB-vcMMAE-5 is stable in human plasma. This study aimed to evaluate its therapeutic efficacy in vitro and in vivo.Methods The in vitro cytotoxicity of PB-vc-MMAE-5 was evaluated in 9 human cancer cell lines, including prostate (PC-3, LnCAP), triple negative breast (HCC1937, MDA-MB-231), ER+,PR+,HER2+ breast (BT474), squamous non-small cell lung (NCI-H226), ovarian (OV-90), colorectal (SW403), pancreatic (CFPAC-1).. Cells were treated with various ADC concentrations for 5 days, and cytotoxicity was measured via luminescence. In vivo efficacy was tested in NOD-SCID mice bearing OV-90 xenografts, treated weekly for 5 weeks with PBS, payload alone or PB-vcMMAE-5 (1 and 3 mg/kg). Tumor growth inhibition (TGI), body weight, hematology and clinical chemistry parameters were monitored.Results PB-vcMMAE-5 induced significant cytotoxicity across all tested cell lines, whereas naked PB-223 showed no cytotoxicity. In vivo, PB-vcMMAE-5, at 3 mg/kg, showed significant TGI (72.3%) and tumor response to treatment (T/C) (33.79%) compared to control group (PBS). Groups treated with payload alone or PB-vcMMAE-5 1mg/kg showed no significant differences in average tumor volume compared to the PBS control group. Body weight, hematology, and chemistry parameters indicated the animals tolerated the treatment well, with no significant pathological changes observed in the heart, liver, spleen or brain tissues at the 3mg/kg dose.Conclusions PB-vcMMAE-5 demonstrated potent in vitro and in vivo anti-tumor activity and is well tolerated. A dose escalation study of 1,3,6, and 9 mg/kg is ongoing. These findings support its potential as broad-spectrum therapeutic agent against tumors expressing truncated core 2 O-glycans.",
  "authors": [
    {
      "affiliations": [
        "Precision Biologics, Inc., Bethesda, MD, USA"
      ],
      "name": "Kwong Y Tsang"
    },
    {
      "affiliations": [
        "Precision Biologics, Inc., Bethesda, MD, USA"
      ],
      "name": "Massimo Fantini"
    },
    {
      "affiliations": [
        "Precision Biologics, Inc., Bethesda, MD, USA"
      ],
      "name": "Anjum Zaki"
    },
    {
      "affiliations": [
        "Precision Biologics, Inc., Bethesda, MD, USA"
      ],
      "name": "Sharon Mavroukakis"
    },
    {
      "affiliations": [
        "Precision Biologics, Inc., Bethesda, MD, USA"
      ],
      "name": "Philip M Arlen"
    }
  ],
  "title": "949 In vitro and in vivo efficacy of the antibody-drug-conjugate (ADC) PB-vcMMAE-5 against human carcinoma expressing truncated core 2 O-glycans",
  "uid": "83eeaca8-4c30-5419-b7b2-c6ed5580b89e"
}