Volume 2 Supplement 2

Abstracts from the 1st Immunotherapy of Cancer Conference (ITOC1)

Open Access

S41. Novel CEA-targeted IL2 variant immunocytokine for immunotherapy of cancer

  • C Klein1
Journal for ImmunoTherapy of Cancer20142(Suppl 2):I8

DOI: 10.1186/2051-1426-2-S2-I8

Published: 12 March 2014

Background

Here we describe a novel class of monomeric tumor-targeted immunocytokines that comprise a single IL-2 variant (IL2v) with abolished CD25 binding that is fused to the C-terminus of a tumor specific antibody with a heterodimeric Fc devoid of FcγR and C1q binding. For tumor targeting, human/humanized high affinity antibodies against CEA (GA504) or FAP (GA501) were selected.

Materials & methods

CEA- and FAP-IL2v activity was tested on effector cells by assessing the activation of P-STAT5, cell proliferation, sensitivity to Fas-induced apoptosis, expression of activation markers and cytokine release upon treatment. Safety, pharmacokinetics, pharmacodynamics and anti-tumor efficacy were analyzed in fully immunocompetent (CEA transgenic) C57Bl/6 mice as single agent and in combination with ADCC competent antibodies in SCID/hCD16 tg mice as well as Balb/neuT genetically engineered mice. Tumor targeting was investigated in the orthotopic syngeneic Renca RCC model in Balb/c mice.

Results

FAP- and CEA-IL2v completely lack binding to CD25, but retain IL-Rβγ binding, and show pM binding affinity to respective antigens, FAP or CEA. As a consequence of abolished binding to CD25 they do not preferentially activate Tregs, but IL-2Rβγ mediated activity is retained and FAP- and CEA-IL2v activate NK, CD4+ and CD8+ T cells as shown by induction of activation markers, cell proliferation and cytokine release. Furthermore, CEA-IL2v and FAP-IL2v enhance the cytotoxic activity of NK cells when combined with ADCC-competent antibodies. Mechanism of action studies in fully immunocompetent mice showed that the molecules strongly expand and activate NK, CD8+ T cells and gd T cells (up to 100-fold) and skew the CD4:CD8 ratio strongly towards CD8+ T cells in the peripheral blood, lymphoid tissues, and in the tumor. In C57Bl/6 mice. MicroSPECT/CT imaging with radioactively labeled FAP-IL2v reveal good FAP-mediated tumor targeting in the orthotopic syngeneic Renca model with low normal tissue uptake and low accumulation in lymphoid tissues, contrary to analogous IL-2 based immunocytokine that shows preferential targeting to lymphoid tissue. Studies in tumor-bearing mice show dose-dependent anti-tumor efficacy of CEA-IL2v in syngeneic MC38-CEA and PancO2-CEA models. Combination of a tumor-stroma targeted TNCA-IL2v with an ADCC-competent ratHER2 antibody in the Balb/neuT spontaneous breast cancer model results in enhanced antitumoral efficacy.

Conclusion

Compared to classical IL-2-based immunocytokines, CEA- and FAP-IL2v demonstrate superior safety, PK and tumor targeting due to abolished CD25 binding, monovalency and high-affinity to tumor antigens while failing to preferentially induce Tregs. CEA- and FAP-IL2v retain the capacity to activate and expand NK and CD8+ effector T cells both in the periphery and tumor microenvironment supporting their further nonclinical and clinical investigation for immunotherapy of cancer. Clinical trials with CEA-IL2v are foreseen in 2014.

Authors’ Affiliations

(1)
Roche Glycart AG

Copyright

© Klein; 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/2.0), 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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