{
  "abstract": "Background ISB 2001 is a trispecific T-cell engager antibody that targets BCMA and CD38 on myeloma cells, with binder affinity tuning and distal positioning of the CD38 vs CD3 to drive potent tumor killing while minimizing CD38-related off-tumor adverse events. We report PK/PD results from the dose escalation part of the FIH Phase 1 study of ISB 2001.Methods ISB 2001 was administered weekly by subcutaneous injection, with step-up doses on days 1 and 4 followed by target dose from day 8. ISB 2001 and 28 biomarkers were measured in serum, and T-cell activation markers in whole blood, to characterize PK/PD properties of ISB 2001.Results As of 8 May, 2025, 42 patients received ISB 2001 across 9 dose levels between 5-2700 μg/kg with no dose-limiting toxicity observed. ORR across effective dose levels (50–2700 µg/kg) was 79% (n=33), and 73% in the 15 patients treated with prior BCMA-directed therapies. PK was dose proportional with a median half-life of approximately 17 days, supporting the potential for less frequent dosing of ISB 2001. Serum soluble BCMA levels and circulating B-cell counts were reduced by ISB 2001 ( figure 1), an effect that was rapid and sustained, and there were gradual increases in BCMA ligands APRIL and BAFF (figure 2). These effects are consistent with strong cytotoxicity from co-targeting BCMA and CD38 on MM and normal plasma cells, whereas CD38+BCMA- NK cells and monocytes demonstrated relatively limited and/or transient reductions or increases, respectively. Transient increases in serum levels of soluble biomarkers were observed in some patients following initial doses of ISB 2001, including most frequently IL-6, IL-8, IL-10, IL-2RA, CXCL11, CCL17, MCP-1 and MIP-3β. These effects generally coincided with CRS events which were grade 1 (n=20) or 2 (n=4), and generally occurred following the first or second doses of ISB 2001. Transient increases in cell surface expression of multiple T-cell activation/proliferation markers were also observed following initial doses of ISB 2001, including Ki-67, PD-1, CD25, HLA-DR, CD137, TIM-3 and LAG-3.Conclusions ISB 2001 demonstrated dose proportional PK, a high ORR and acceptable safety profile across a wide range of dose levels (50-2700 μg/kg) in patients with heavily pre-treated RRMM. Biomarker changes at these dose levels were consistent with T-cell engaging activity and reduced tumor burden, while sparing CD38 +BCMA- normal immune cells. PK/PD data support the exploration of multiple doses and schedules in the ongoing dose expansion part of the study.Trial Registration NCT05862012Ethics Approval The study was approved by the institutional review board at each site and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonization. All patients provided written informed consent.Abstract 554 Figure 1Reduced serum soluble BCMA and peripheral blood B-cell counts following ISB 2001 treatment. Serum soluble BCMA (sBCMA) was determined by immunocapture-mass spectrometry (left); peripheral blood B-cell counts were determined by flow cytometry prior to ISB 2001 (right). Plots represent data from patients who achieved an objective responseAbstract 554 Figure 2Increased BCMA ligands APRIL and BAFF following ISB 2001 treatment. Serum levels of APRIL (left) and BAFF (right) were determined by bead-based immunoassay; Tmax data represents the highest measured value for each patient. Plots represent data from patients who achieved an objective response",
  "authors": [
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Andrew Garton"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Vinu Menon"
    },
    {
      "affiliations": [
        "St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia"
      ],
      "name": "Hang Quach"
    },
    {
      "affiliations": [
        "Peter MacCallum Cancer Center, Melbourne, VIC, Australia"
      ],
      "name": "Amit Khot"
    },
    {
      "affiliations": [
        "Sir Charles Gairdner Hospital and Linear Clinical Research, Perth, Western Australia, Australia"
      ],
      "name": "Bradley Augustson"
    },
    {
      "affiliations": [
        "Pindara Private Hospital, Benowa, QLD, Australia"
      ],
      "name": "Hanlon Sia"
    },
    {
      "affiliations": [
        "Concord Hospital, Concord, NSW, Australia"
      ],
      "name": "Nicole Wong Doo"
    },
    {
      "affiliations": [
        "Montefiore Einstein Comprehensive Cancer Center, New York, NY, USA"
      ],
      "name": "David Levitz"
    },
    {
      "affiliations": [
        "University of North Carolina School of Medicine, Chapel Hill, NC, USA"
      ],
      "name": "Eben Lichtman"
    },
    {
      "affiliations": [
        "Stanford University, Palo Alto, CA, USA"
      ],
      "name": "Michaela Liedtke"
    },
    {
      "affiliations": [
        "Medqualis, Montreal, QC, Canada"
      ],
      "name": "Camille Martinet"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Beata Holkova"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Harjeet Sembhi"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Lida Pacaud"
    },
    {
      "affiliations": [
        "Glenmark Pharmaceuticals Ltd., Mumbai, Maharashtra, India"
      ],
      "name": "Sunitha Gn"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Maria Pihlgren"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Mario Perro"
    },
    {
      "affiliations": [
        "IGI Inc., New York, NY, USA"
      ],
      "name": "Cyril Konto"
    }
  ],
  "title": "554 Pharmacokinetics (PK) and pharmacodynamics (PD) of ISB 2001, a BCMAxCD38xCD3 trispecific antibody, in TRIgnite-1, the first-in-human (FIH) phase 1 study in relapsed/refractory multiple myeloma (RRMM)",
  "uid": "d8b41ce3-6d08-5e5b-8c48-ab1b82d36e9d"
}