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1166 Preclinical evaluation of lintuzumab-Ac225, a CD33 antibody radioconjugate targeting myeloid-derived suppressor cells
  1. Amanda Chin1,
  2. Mary Chen1,
  3. Debbie Lewis1,
  4. Sumit Mukherjee2,
  5. Jason Li1,
  6. Le-Cun Xu1,
  7. Monideepa Roy1,
  8. Patrik Brodin1,
  9. William van der Touw1,
  10. Denis Beckford-Vera1 and
  11. Helen Kotanides1
  1. 1Actinium Pharmaceuticals, Inc., New York, NY, USA
  2. 2National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Myeloid-derived suppressor cells (MDSCs) are immunosuppressive myeloid lineage cells enriched in cancer patients. There is growing interest in the development of novel interventions to disrupt tumor immune evasion that results from crosstalk between MDSCs and the tumor microenvironment. Despite the heterogeneity of MDSCs, the cell surface CD33 myeloid marker is expressed by both monocytic-MDSC (M-MDSC) and granulocytic-MDSC (G-MDSC) subpopulations. Actimab-A (lintuzumab-Ac225) is composed of the anti-CD33 antibody lintuzumab armed with the alpha-particle emitter actinium-225 (Ac-225) as payload, and is currently being evaluated in relapsed/refractory acute myeloid leukemia (R/R AML) and has demonstrated significant anti-leukemic activity in Phase 1/2 clinical trials. The Ac-225 radionuclide payload can deliver high cytotoxic energy within a short distance, thereby providing potent and precise targeted cell killing. We hypothesized that targeting CD33 on solid tumor MDSCs with lintuzumab-Ac225 would be an effective therapeutic strategy. Here, we characterize the therapeutic potential of lintuzumab-Ac225 to alleviate MDSC-mediated immunosuppressive effects through preclinical studies in vitro and in vivo with a humanized mouse model.

Methods Lintuzumab-Ac225 was generated by conjugating lintuzumab with p-SCN-Bn-DOTA and subsequently radiolabeled with Ac-225. Primary MDSCs and T cells were isolated from cancer patient peripheral blood or healthy donor PBMCs. Lintuzumab-Ac225 targeting of MDSCs was examined in vitro in viability and cell growth suppression assays. Human CD34 reconstituted humanized NOG-EXL mice were used to evaluate MDSC response to lintuzumab-Ac225 treatment in peripheral blood by flow cytometry and in tumor tissues through molecular imaging using zirconium-89 (Zr-89) Positron Emission Tomography (PET) imaging.

Results Lintuzumab-Ac225 treatment of human MDSCs induced a reduction in MDSC viability compared to non-radiolabeled lintuzumab control. In the humanized NOG-EXL mouse model, lintuzumab-Ac225 therapy showed significant depletion of human MDSCs in the peripheral blood. Furthermore, PET imaging with Zr-89 radiolabeled CD33 antibody lintuzumab, revealed specific uptake of lintuzumab-Zr89 within NCI-H1975 lung tumor xenografts.

Conclusions In this study, we demonstrated lintuzumab-Ac225 radiotherapy can deplete human CD33 positive immune suppressing MDSCs and through PET imaging illustrated the intra-tumoral targeting capabilities of alpha-emitting radiotherapy. Continued evaluation of lintuzumab-Ac225 as an MDSC targeting agent is highly warranted, including the potential to combine with immune checkpoint therapy, to further enhance antitumor immunity in cancer patients.

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