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Acute myeloid leukemia

Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo

Leukemia volume 30, pages 1475–1484 (2016)Cite this article

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Abstract

The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high-affinity T-cell receptor-like murine monoclonal antibody, 8F4, that binds to the PR1/HLA-A2 complex, mediates lysis of AML and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, coincubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG (NOD scid IL-2 receptor γ-chain knockout) mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting the possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML.

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Acknowledgements

This study was supported by research funding from NCI CA100632 (to JJM); NCI P01 CA148600-05 (to JJM); Leukemia and Lymphoma Society 6030-12 (to JJM); Leukemia and Lymphoma Society 7262-08 (to JJM); Gillson Longenbaugh Foundation (to JJM), NCI CA16672 Core Grant (Monoclonal Antibody Core Facility; Flow Cytometry and Cellular Imaging Facility; Research Animal Support Facility; Histopathology Facility); NCI CA164346 (to MJY), Developmental Research Awards in Leukemia SPORE CA100632 (to MJY); and Ladies Leukemia League (to MJY), Center for Inflammation and Cancer, Center for Genetics and Genomics, IRG, Sister Institution Network fund of UT MD Anderson Cancer Center (to MJY). In particular, we wish to acknowledge Dr Long Vien in the Monoclonal Antibody Core Facility for providing purified 8F4. We acknowledge Dr Gregory Lizee for critical reading of manuscript.

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Author notes

  1. A Sergeeva and H He: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, Section of Transplantation Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Sergeeva, H He, K Ruisaard, L St John, G Alatrash, K Clise-Dwyer, D Li, R Patenia, R Hong, P Sukhumalchandra, Q Ma & J J Molldrem

  2. Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M J You

  3. Department of Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Gagea

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  1. A Sergeeva
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Correspondence to J J Molldrem.

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Dr Molldrem and Dr Sergeeva are inventors on a related patent and they receive royalty payments. The other authors declare no conflict of interest.

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Sergeeva, A., He, H., Ruisaard, K. et al. Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo. Leukemia 30, 1475–1484 (2016). https://doi.org/10.1038/leu.2016.57

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