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Evaluation of a novel CD20-targeted IL-15 immunotherapeutic with potent activity against B cell lymphoma

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Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P122

https://doi.org/10.1186/2051-1426-2-S3-P122

  • Published:

Keywords

  • Cynomolgus Monkey
  • Immune Effector Cell
  • Systemic Immune Activation
  • Daudi Cell
  • Eliminate Tumor Cell

IL-15 exhibits potent antitumor efficacy in mouse models through its ability to promote proliferation and activation of NK cells and memory CD8+ T cells. Recently, targeting approaches have been developed to direct these activities against tumor cells and minimize potential toxicities related to systemic immune activation. IL-15 and its receptor α (IL-15Rα) are co-expressed in antigen presenting cells allowing trans-presentation of IL-15 to immune effector cells. We previously reported that the high-affinity interactions between an IL-15 superagonist (IL-15N72D) and the extracellular IL-15Rα sushi domain (IL-15RαSu) could be exploited to create a functional scaffold for the design of multivalent disease-targeted protein complexes. Extending these findings to relevant tumor antigens, a tetravalent complex (2B8T2M) was generated comprising the single-chain anti-human CD20 Fv domain of Rituximab linked to the N-termini of the IL-15N72D and IL-15RαSu-Fc fusion proteins. As designed, this complex was found to retained IL-15 activity to induce proliferative and effector responses of CD8+ T cells and NK cells as well as CD20- and Fc receptor-binding activity necessary to mediate ADCC and CDC against CD20-positive B cell lymphoma. Surprisingly, 2B8T2M (≥1 nM) was also capable of inducing significant apoptosis of B cell lymphoma cells, which was not observed following incubation with Rituximab (Daudi cell death: 2B8T2M; 36.5 ± 0.5% vs. Rituximab; 8.5 ± 0.3%). Moreover, treatment of tumor-bearing SCID mice with 2B8T2M (12.5 mg/kg, day 15, 18 post-tumor injection) was more effective than Rituximab (10 mg/kg equivalent to 12.5 mg/kg 2B8T2M) in reducing levels of CD20-positive Daudi lymphoma cells in the bone marrow (% BM Daudi cells at day 22: 2B8T2M, 1.4 ± 1.3% vs. Rituximab, 28.1 ± 6.2%; vs. PBS, 42.1 ± 8.0%; both p < 0.01). This antitumor activity was dependent on each of the three binding domains of 2B8T2M. In addition, 5 mg/kg 2B8T2M treatment of Daudi tumor-bearing SCID mice significantly prolonged survival compared to PBS control- and 10 mg/kg Rituximab-treatment groups (median survival: 2B8T2M, 42 days vs. Rituximab, 35 days; vs. PBS, 27 days; both p < 0.01). In cynomolgus monkeys, 2B8T2M administration (5 mg/kg, day 0, 3) also exhibited greater activity than Rituximab (10 mg/kg) for depleting B cells in the blood and lymph nodes (p < 0.05). 2B8T2M treatment was well tolerated in each of these models. Together, these finding demonstrate that tumor antigen-targeted IL-15 complexes can stimulate and direct immune responses to more effectively eliminate tumor cells than related therapeutic antibodies. Thus, these molecules represent novel and promising targeted immunotherapeutics for treating cancer.

Acknowledgements

NIH/NCI grant CA174091 (Wong).

Authors’ Affiliations

(1)
Altor BioScience Corporation, Miramar, FL, USA

Copyright

© Liu et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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