Article Text

Download PDFPDF

1076 Discovery and evaluation of an anti-IL18BP antibody to enhance anti-tumor immunity
  1. Deborah A Witherden,
  2. Eric K Elliott,
  3. Christine M Chidester,
  4. Maggie S Willen,
  5. Bryan R Peguero,
  6. Merrick Chai,
  7. Robert A Horlick,
  8. David J King and
  9. H Toni Jun
  1. Lassen Therapeutics, San Diego, CA, USA


Background Interleukin-18 (IL-18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses and induces high levels of interferon-γ.1 Although recombinant IL-18 has demonstrated efficacy in mouse tumor models,2 recombinant human IL-18 has not been efficacious in clinical studies,3 likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of the IL-18 signaling axis. IL-18BP is induced 10 – 100-fold after IL-18 administration, binds to IL-18 with high affinity, and prevents IL-18 binding to the IL-18 receptor.4 Inhibition of IL-18/IL-18BP binding, and especially the ability to release IL-18 from pre-formed complex, may therefore release IL-18 in situ, leading to IL-18-mediated proinflammatory effects and enhanced anti-tumor immunity.

Methods Here we analyze IL-18 and IL-18BP expression in tumors and describe the discovery of a high affinity monoclonal antibody that recognizes IL-18BP. Using in vitro and in vivo assays we analyze the ability of the antibody to disrupt IL-18/IL-18BP complex and activate IL-18-mediated responses.

Results Analysis of expression data from the TCGA database and archived patient samples from select indications reveals that both IL-18 and IL-18BP are co-expressed in multiple tumor types, suggesting there is a preexisting pool of IL-18/IL-18BP complex at the site of the tumor in some patients. Although the interaction of IL-18 with IL-18BP is a high affinity interaction (KD 700 pM), we have been able to identify very high affinity antibodies with KD values more than ten-fold lower for both human and mouse IL-18BP. These antibodies can both inhibit complex formation and importantly, disrupt existing IL-18/IL-18BP complexes, liberating endogenous IL-18 at the tumor site. These antibodies are active in cell-based functional assays, resulting in potent stimulation of interferon-γ production from both NK and T cells, including when IL-18/IL-18BP is present as a preexisting complex. In vivo, we observe efficacy in a syngeneic tumor model using an anti-mouse IL-18BP antibody and demonstrate that interferon-γ is upregulated at the tumor site but not in the serum. Combination therapy with anti-PD1 leads to significantly increased efficacy compared to anti PD-1 alone and results in complete responses in more than half of the animals. RNA and protein analysis demonstrates expression of both IL-18BP and IL-18 within the tumors. Additionally, we observe an increase in NK cells and granzyme B expression in response to combination therapy.

Conclusions These data suggest that inhibition of IL-18/IL-18BP binding may prove efficacious in the treatment of cancers where IL-18BP prevents an IL-18-mediated proinflammatory response.


  1. Nakamura K, Okamura H, Nagata K, Komatsu T, Tamura T. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immun. 1993;61:64–70.

  2. Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97:665–75.

  3. Tarhini AA, Millward M, Mainwaring P, Kefford R, Logan T, Pavlick A, Kathman SJ, Laubscher KH, Dar MM, Kirkwood JM. A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer. 2009;115:859–68.

  4. Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol. 2013;4:289.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.