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

  • Denise Garcia
  • Patrick Nasarre
  • Ingrid V. Bonilla
  • Eleanor Hilliard
  • Yuri K. Peterson
  • Laura Spruill
  • Anne-Marie Broome
  • Elizabeth G. Hill
  • Jason T. Yustein
  • Shikhar Mehrotra
  • Nancy Klauber-DeMoreEmail author
Translational Research and Biomarkers
  • 28 Downloads

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.

Notes

Funding

This work was supported by funding from the Department of Defense (W81XWH-18-1-0007) to NKD and AMB; the Sarcoma Foundation of American (NKD); R21CA137725, R01CA138930 to SM; The Cancer Prevention and Research Institute of Texas (CPRIT), WWWW Foundation, Inc. (QuadW), The St. Baldrick’s Foundation to JTY, and NIH T32 Grant CA193201. Support from the Hollings Cancer Center and Biostatistics Shared Resources (partly supported by P30 CA138313) at the Medical University of South Carolina is also acknowledged.

Disclosure

Novel Targets for Regulation of Angiogenesis, US Patent No. 8,734,789. Inventor: Nancy Klauber-DeMore, MD. Combination therapy of a humanized antibody to secreted frizzled-related 2 with PD-1 inhibition for the treatment of cancer. US Provisional App. No. 62/737,155. Inventor: Nancy Klauber-DeMore, MD. Dr. Klauber-DeMore is co-founder, shareholder, Chief Scientific Officer, and Board Member of Enci Therapeutics, Inc.

Supplementary material

10434_2019_7800_MOESM1_ESM.pdf (133 kb)
Supplementary material 1 (PDF 133 kb)
10434_2019_7800_MOESM2_ESM.pdf (6.9 mb)
Supplementary material 2 (PDF 7088 kb)

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Denise Garcia
    • 1
  • Patrick Nasarre
    • 1
  • Ingrid V. Bonilla
    • 1
  • Eleanor Hilliard
    • 1
  • Yuri K. Peterson
    • 2
  • Laura Spruill
    • 3
  • Anne-Marie Broome
    • 4
  • Elizabeth G. Hill
    • 5
  • Jason T. Yustein
    • 6
  • Shikhar Mehrotra
    • 1
  • Nancy Klauber-DeMore
    • 1
    Email author
  1. 1.Department of SurgeryMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Drug Discovery and Biomedical Sciences, College of PharmacyMedical University of South CarolinaCharlestonUSA
  3. 3.Department of PathologyMedical University of South CarolinaCharlestonUSA
  4. 4.Department of Cell and Molecular PharmacologyMedical University of South CarolinaCharlestonUSA
  5. 5.Department of Public Health SciencesMedical University of South CarolinaCharlestonUSA
  6. 6.Department of Pediatrics, Texas Children’s Cancer and Hematology CentersBaylor College of MedicineHoustonUSA

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