Therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein Journal Article


Authors: Veomett, N.; Dao, T.; Liu, H.; Xiang, J.; Pankov, D.; Dubrovsky, L.; Whitten, J. A.; Park, S. M.; Korontsvit, T.; Zakhaleva, V.; Casey, E.; Curcio, M.; Kharas, M. G.; O'Reilly, R. J.; Liu, C.; Scheinberg, D. A.
Article Title: Therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein
Abstract: Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)-derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell-based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines. Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibodydependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice. Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A* 02:01+ transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage. Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein. © 2014 American Association for Cancer Research.
Keywords: cancer survival; controlled study; treatment response; unclassified drug; acute granulocytic leukemia; human cell; drug efficacy; nonhuman; antineoplastic agent; binding affinity; animal cell; mouse; tumor volume; protein depletion; animal experiment; animal model; drug potency; acute lymphoblastic leukemia; t lymphocyte receptor; drug distribution; mesothelioma; drug clearance; fc receptor; drug cytotoxicity; wt1 protein; drug half life; tumor growth; fc receptor iib; antigen binding; drug protein binding; antibody dependent cellular cytotoxicity; immunoglobulin receptor; monoclonal antibody esk1; human; male; priority journal; article; monoclonal antibody eskm; fc gamma receptor 4; fc receptor iia; fc receptor iiia; mesothelioma cell line
Journal Title: Clinical Cancer Research
Volume: 20
Issue: 15
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2014-08-01
Start Page: 4036
End Page: 4046
Language: English
DOI: 10.1158/1078-0432.ccr-13-2756
PROVIDER: scopus
PMCID: PMC4119489
PUBMED: 24850840
DOI/URL:
Notes: Export Date: 2 September 2014 -- CODEN: CCREF -- Source: Scopus
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MSK Authors
  1. Tao Dao
    57 Dao
  2. Dmitry D. Pankov
    18 Pankov
  3. Richard O'Reilly
    476 O'Reilly
  4. Emily Catherine Casey
    9 Casey
  5. Michael Kharas
    45 Kharas
  6. Sun Mi Park
    13 Park
  7. Michael J Curcio
    27 Curcio
  8. Nicholas J Veomett
    10 Veomett