biostudies-literatureTian LV Foundation for Cancer Research V Scholar AwardNIAID NIH HHSBreast Cancer AllianceNCI NIH HHSNINDS NIH HHSMarkel Friedman Accelerator FundCalifornia Institute for Regenerative MedicineLeukemia &amp; Lymphoma SocietyNIH201-214https://www.ebi.ac.uk/biostudies/studies/S-EPMC8963132biostudies-literatureUnknown28(1)<h4>Purpose</h4>mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the "don't eat me" pathway. However, this strategy is associated with severe toxicity.<h4>Experimental design</h4>To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4).<h4>Results</h4>Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47-SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. <i>In vivo</i>, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection.<h4>Conclusions</h4>Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.Clinical cancer research : an official journal of the American Association for Cancer ResearchTargeting Fc Receptor-Mediated Effects and the "Don't Eat Me" Signal with an Oncolytic Virus Expressing an Anti-CD47 Antibody to Treat Metastatic Ovarian Cancer.PMC8963132CA255250CA210087R01 NS106170NS106170P01 CA163205P30 CA033572R01 CA265095CA20175R35 CA210087CA223400AI129582R21 CA201757R21 CA223400CA163205CA247550DISC2COVID19–11947R01 CA247550T32 CA221709R01 CA2552501364–19R01 AI129582CA265095Rodriguez LTian LZhu ZZhang JTeng KYYu JWang JSong MFeng MXu BChen YKaur BCaligiuri MAfalseTargeting Fc Receptor-Mediated Effects and the "Don't Eat Me" Signal with an Oncolytic Virus Expressing an Anti-CD47 Antibody to Treat Metastatic Ovarian Cancer.<h4>Purpose</h4>mAbs blocking immune checkpoints have emerged as important cancer therapeutics, as exemplified by systemic administration of the IgG1 anti-CD47 mAb that blocks the "don't eat me" pathway. However, this strategy is associated with severe toxicity.<h4>Experimental design</h4>To improve therapeutic efficacy while reducing toxicities for ovarian cancer, we engineered an oncolytic herpesvirus (oHSV) to express a full-length, soluble anti-CD47 mAb with a human IgG1 scaffold (OV-αCD47-G1) or IgG4 scaffold (OV-αCD47-G4).<h4>Results</h4>Both IgG1 and IgG4 anti-CD47 mAbs secreted by oHSV-infected tumor cells blocked the CD47-SIRPα signal pathway, enhancing macrophage phagocytosis against ovarian tumor cells. OV-αCD47-G1, but not OV-αCD47-G4, activated human NK-cell cytotoxicity and macrophage phagocytosis by binding to the Fc receptors of these cells. <i>In vivo</i>, these multifaceted functions of OV-αCD47-G1 improved mouse survival in xenograft and immunocompetent mouse models of ovarian cancer when compared with OV-αCD47-G4 and a parental oHSV. The murine counterpart of OV-αCD47-G1, OV-αmCD47-G2b, also enhanced mouse NK-cell cytotoxicity and macrophage phagocytosis and prolonged survival of mice bearing ovarian tumors compared with OV-αmCD47-G3. OV-αmCD47-G2b was also superior to αmCD47-G2b and showed a significantly better effect when combined with an antibody against PD-L1 that was upregulated by oHSV infection.<h4>Conclusions</h4>Our data demonstrate that an oHSV encoding a full-length human IgG1 anti-CD47 mAb, when used as a single agent or combined with another agent, is a promising approach for improving ovarian cancer treatment via enhancing innate immunity, as well as performing its known oncolytic function and modulation of immune cells.2022-01-01T00:00:00Z2022 Jan2024-11-09T04:33:14.667Z2022-07-10T06:45:33.18ZS-EPMC89631323464564710.1158/1078-0432.CCR-21-124810.1158/1078-0432.ccr-21-1248