Abstract 4515: The anti-CD47 antibody SRF231 increases anti-tumor activity of standard of care chemotherapy in platinum-resistant PDX models of ovarian cancer
Authors: Liu Joyce F. , Doshi Kshama A. , Lee Benjamin H. , Peluso Marisa O. , Zhang Li , Zhou Shan , Zeng Qing , Wang Stephen , Kirschmeier Paul T. , Tran Cam A. , Paweletz Cloud , Rausch Matthew , Paterson Alison M. , Gokhale Prafulla C. , Matulonis Ursula A. 
Published: September 2020

Abstract
Background: CD47 is a type I integral membrane protein expressed on multiple human tumors, including ovarian cancer, and modulates cell processes such as cell migration, adhesion, T-cell function, and cell death via interaction with multiple ligands. Interaction of CD47 with SIRPα expressed on myeloid cells results in an inhibitory “don't eat me” signal that prevents phagocytosis of CD47-expressing cancer cells. Enhancement of the anti-tumor activity of chemotherapy has also been reported with CD47 antagonists. We investigated the effects of combining SRF231, an investigational fully human IgG4 antibody, with chemotherapy in models of human ovarian cancer.
Methods: Expression of CD47 in 8 established platinum-resistant PDX models of ovarian cancer was measured by immunohistochemistry with the anti-CD47 antibody SP279. SRF231-mediated phagocytosis of ovarian cancer cell lines was assessed using a macrophage coculture system. Cell death from combining SRF231 with either doxorubicin or platinum in vitro was assessed by Annexin V assay. The activity of SRF231 combined with doxorubicin in vivo was compared to isotype control, SRF231, or doxorubicin monotherapy in an ovarian cancer subcutaneous xenograft model, OVCAR3. Additionally, the activity of SRF231 combined with platinum was compared to isotype control, SRF231, or platinum monotherapy in two luciferase-expressing intraperitoneal PDX ovarian cancer models, as measured by bioluminescent imaging.
Results: CD47 expression was high across all 8 PDX models. SRF231 induced phagocytosis of ovarian cancer cell lines by human monocyte-derived macrophages. SRF231 potentiated doxorubicin- or oxaliplatin-mediated cell death in Jurkat cells in Annexin V assays. In the OVCAR3 xenograft model, the combination of SRF231 and doxorubicin resulted in significant tumor growth inhibition and improved survival compared to isotype control, SRF231 monotherapy, or doxorubicin monotherapy. In the PDX model DF216, which demonstrates no evidence of monotherapy response to SRF231, combination of SRF231 and carboplatin resulted in tumor regression with significantly enhanced anti-tumor activity compared to carboplatin or SRF231 monotherapy, as well as to isotype control. Similarly, in the PDX model DF86, where SRF231 demonstrates modest monotherapy activity, combination SRF231 and carboplatin resulted in tumor regression and significant increase in anti-tumor activity compared to carboplatin or SRF231 monotherapies.
Conclusion: Anti-CD47 directed therapy with SRF231, a fully human antibody, demonstrated the ability to significantly increase the anti-tumor activity of standard chemotherapies in xenograft and platinum-resistant PDX models of ovarian cancer. Further exploration of combining anti-CD47 and platinum regimens in ovarian cancer is warranted.
Citation Format: Joyce F. Liu, Kshama A. Doshi, Benjamin H. Lee, Marisa O. Peluso, Li Zhang, Shan Zhou, Qing Zeng, Stephen Wang, Paul T. Kirschmeier, Cam A. Tran, Cloud Paweletz, Matthew Rausch, Alison M. Paterson, Prafulla C. Gokhale, Ursula A. Matulonis. The anti-CD47 antibody SRF231 increases anti-tumor activity of standard of care chemotherapy in platinum-resistant PDX models of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4515.