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12.09.2019 | Translational Research and Biomarkers | Ausgabe 13/2019

Annals of Surgical Oncology 13/2019

Development of a Novel Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein-2 That Inhibits Triple-Negative Breast Cancer and Angiosarcoma Growth In Vivo

Zeitschrift:
Annals of Surgical Oncology > Ausgabe 13/2019
Autoren:
MD Denise Garcia, PhD Patrick Nasarre, BS Ingrid V. Bonilla, BS Eleanor Hilliard, PhD Yuri K. Peterson, MD, PhD Laura Spruill, PhD Anne-Marie Broome, PhD Elizabeth G. Hill, MD, PhD Jason T. Yustein, PhD Shikhar Mehrotra, MD, FACS Nancy Klauber-DeMore
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1245/​s10434-019-07800-2) contains supplementary material, which is available to authorized users.
Denise Garcia and Patrick Nasarre contributed equally to this work.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Background

We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth.

Methods

The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4 mg/kg intravenously every 3 days for 3 weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40 days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis.

Results

Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy.

Conclusion

We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.

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