Potent in vitro and in vivo effects of polyclonal anti-human-myeloma globulins
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Aneta Schieferdecker1,2, Ofer Shoshani3,4, Benedikt Westner5,6, Dov Zipori3, Boris Fehse1, Nicolaus Kröger1, Francis Ayuk1
1Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Current Affiliation: Department of Oncology and Hematology with Section Pneumology, Hubertus Wald Tumorzentrum/ UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
4Current Affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA, USA
5Neovii (formerly Fresenius) Biotech GmbH, Gräfelfing, Germany
6Current Affiliation: Acino AG, Miesbach, Germany
Francis Ayuk, email: [email protected]
Keywords: myeloma, anti-human-myeloma globulins, AMG, polyclonal antibodies, ATG
Received: March 25, 2016 Accepted: August 10, 2016 Published: August 22, 2016
Introduction: Multiple myeloma is still incurable in most cases. Polyclonal anti T lymphocyte globulins (ATG) have been reported to kill human myeloma cells in vitro and in mouse models.
Methods: Anti-human-myeloma globulins (AMG) were produced by immunizing rabbits with human myeloma cell lines RPMI-8226 (AMG-8226) or KMS-12-BM (AMG-12-BM). Cytotoxicity of the polyclonal antibodies was analyzed in vitro and in a xenograft NOD-SCID mouse model.
Results: Both AMG had stronger cytotoxicity against myeloma cells compared to ATG. In primary T cells, AMG-8226 showed greater complement-dependent cytotoxicity (CDC) than ATG, whereas complement-independent cytotoxicity did not differ. Effects on non-hematopoietic cell lines were also similar. Competitive blocking assays revealed fourfold more antibodies against CD38 in AMG-8226 compared to ATG. Low concentrations of AMG-8226 and ATG increased ADCC. At higher concentrations, ATG inhibited ADCC more potently than AMG-8226. Combinations of ATG and AMG-8226 with melphalan or bortezomib showed additive to synergistic cytotoxicity on myeloma cells. The cytotoxic effects of AMG and ATG were confirmed in the xenograft NOD-SCID mouse model.
Conclusion: Our data show more potent antimyeloma effects of AMG compared to ATG. These results lay the ground for the development of polyclonal antibodies for the treatment of multiple myeloma.
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