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      Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

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          Abstract

          Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 MAb. The studies reported here demonstrate (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFNγ can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.

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          Author and article information

          Journal
          101614637
          41946
          Cancer Immunol Res
          Cancer Immunol Res
          Cancer immunology research
          2326-6066
          2326-6074
          15 June 2015
          26 May 2015
          October 2015
          01 October 2016
          : 3
          : 10
          : 1148-1157
          Affiliations
          [1 ]Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
          [2 ]Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
          Author notes
          [†]

          Contributed equally.

          [* ]Corresponding author: Jeffrey Schlom, Ph.D., Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD, USA. Tel: 301-496-4343; Fax: 301-496-2756; js141c@ 123456nih.gov
          Article
          PMC4739754 PMC4739754 4739754 nihpa694860
          10.1158/2326-6066.CIR-15-0059
          4739754
          26014098
          bdcc812d-877a-455a-95af-b7bdffd99ba8
          History
          Categories
          Article

          checkpoint inhibitor,antibody-dependent cellular cytotoxicity,anti-PD-L1

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