Jie Liu

All Publications

• MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS). Clinical lymphoma, myeloma & leukemia Chen, J., Johnson, L., McKenna, K., Choi, T., Duan, J., Feng, D., Tsai, J., Garcia-Martin, N., Sompalli, K., Maute, R., Vyas, P., Majeti, R., Takimoto, C., Liu, J., Ramsingh, G., Chao, M., Volkmer, J., Weissman, I. 2022; 22 Suppl 2: S317-S318

  Abstract

  CONTEXT: Magrolimab is an antibody blocking CD47, a "don't eat me" signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Preclinical studies found that CD47 is critical to RBC homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD47 agents. Several clinical trials demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower "priming" dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at higher maintenance doses. However, the underlying mechanism has not been fully defined.OBJECTIVE: To describe manageable anemia in magrolimab-treated patients and further investigate the underlying mechanisms in preclinical models.DESIGN: Prospective analysis from a ph1 trial of magrolimab+azacitidine (NCT03248479). Complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected from patients at prespecified time points. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for CD47 expression on RBCs and white blood cells (WBCs). Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice.PATIENTS: 57 patients with HR MDS.INTERVENTIONS: Magrolimab IV 1 mg/kg (priming) then 30 mg/kg QW, then Q2W (maintenance). Azacitidine 75 mg/m2 days 1-7 (each 28-day cycle).RESULTS: Treatment with magrolimab+azacitidine resulted in tolerable anemia that correlated with rapid, near-complete loss of CD47 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for CD47 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab+rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 cross-linking between RBCs and non-RBCs.CONCLUSIONS: These results support the idea that on-target magrolimab-mediated anemia is mitigated by a near-complete loss of RBC CD47. Patients with HR MDS treated with magrolimab+azacitidine had tolerable anemia with priming and maintenance doses.

  View details for DOI 10.1016/S2152-2650(22)01421-5

  View details for PubMedID 36163968

• Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS) Chen, J., Johnson, L., McKenna, K., Choi, T., Duan, J., Feng, D., Tsai, J., Garcia-Martin, N., Sompalli, K., Maute, R., Vyas, P., Majeti, R., Takimoto, C., Liu, J., Ramsingh, G., Chao, M., Volkmer, J., Weissman, I. CIG MEDIA GROUP, LP. 2022: S317-S318

  View details for Web of Science ID 000897948100300

• Impact of magrolimab treatment in combination with azacitidine on red blood cells in patients with higher-risk myelodysplastic syndrome (HR-MDS). Chen, J., Johnson, L., McKenna, K., Choi, T. S., Duan, J., Feng, D., Tsai, J. M., Garcia-Martin, N., Sompalli, K., Maute, R., Vyas, P., Majeti, R., Takimoto, C. M., Liu, J., Ramsingh, G., Chao, M., Volkmer, J., Weissman, I. L. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301955

• NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity. Blood cancer discovery Richards, R. M., Zhao, F., Freitas, K. A., Parker, K. R., Xu, P., Fan, A., Sotillo, E., Daugaard, M., Oo, H. Z., Liu, J., Hong, W. J., Sorensen, P. H., Chang, H. Y., Satpathy, A. T., Majzner, R. G., Majeti, R., Mackall, C. L. 2021; 2 (6): 648-665

  Abstract

  Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines.CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.See related commentary by Velasquez and Gottschalk, p. 559. This article is highlighted in the In This Issue feature, p. 549.

  View details for DOI 10.1158/2643-3230.BCD-20-0208

  View details for PubMedID 34778803

  View details for PubMedCentralID PMC8580619

• Targeting macrophage checkpoint inhibitor SIRPa for anticancer therapy. JCI insight Liu, J. n., Xavy, S. n., Mihardja, S. n., Chen, S. n., Sompalli, K. n., Feng, D. n., Choi, T. S., Agoram, B. n., Majeti, R. n., Weissman, I. L., Volkmer, J. P. 2020

  Abstract

  The SIRPα-CD47 interaction provides a macrophage immune checkpoint pathway that plays a critical role in cancer immune evasion across multiple cancers. Here, we report the engineering of a humanized anti-SIRPα monoclonal antibody (1H9) for antibody target cancer therapy. 1H9 has broad activity across a wide range of SIRPα variants. Binding of 1H9 to SIRPα blocks its interaction with CD47, thereby promoting macrophage-mediated phagocytosis of cancer cells. Pre-clinical studies in vitro and in vivo demonstrate that 1H9 synergizes with other therapeutic antibodies to promote phagocytosis of tumor cells and inhibit tumor growth in both syngeneic and xenograft tumor models, leading to survival benefit. Thus, 1H9 can potentially act as a universal agent to enhance therapeutic efficacy when used in combination with most tumor-targeting antibodies. We report for the first time, a comparison of anti-SIRPα and anti-CD47 antibodies in CD47/SIRPα double humanized mice, and found that 1H9 exhibits a substantially reduced antigen-sink effect due to the limited tissue distribution of SIRPα expression. Toxicokinetic studies in non-human primates show that 1H9 is well tolerated with no treatment-related adverse effects noted. These data highlight the clinical potential of 1H9 as a pan-therapeutic with the desired properties when used in combination with tumor-targeting antibodies.

  View details for DOI 10.1172/jci.insight.134728

  View details for PubMedID 32427583

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers JOURNAL OF CLINICAL ONCOLOGY Sikic, B., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019; 37 (12): 946-+

  View details for DOI 10.1200/JCO.18.02018

  View details for Web of Science ID 000466717700002

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A. D., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019: JCO1802018

  Abstract

  PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

  View details for PubMedID 30811285

• Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies. Frontiers in oncology Chao, M. P., Takimoto, C. H., Feng, D. D., McKenna, K., Gip, P., Liu, J., Volkmer, J., Weissman, I. L., Majeti, R. 2019; 9: 1380

  Abstract

  In recent years, immunotherapies have been clinically investigated in AML and other myeloid malignancies. While most of these are focused on stimulating the adaptive immune system (including T cell checkpoint inhibitors), several key approaches targeting the innate immune system have been identified. Macrophages are a key cell type in the innate immune response with CD47 being identified as a dominant macrophage checkpoint. CD47 is a "do not eat me" signal, overexpressed in myeloid malignancies that leads to tumor evasion of phagocytosis by macrophages. Blockade of CD47 leads to engulfment of leukemic cells and therapeutic elimination. Pre-clinical data has demonstrated robust anti-cancer activity in multiple hematologic malignancies including AML and myelodysplastic syndrome (MDS). In addition, clinical studies have been underway with CD47 targeting agents in both AML and MDS as monotherapy and in combination. This review will describe the role of CD47 in myeloid malignancies and pre-clinical data supporting CD47 targeting. In addition, initial clinical data of CD47 targeting in AML/MDS will be reviewed, and including the first-in-class anti-CD47 antibody magrolimab.

  View details for DOI 10.3389/fonc.2019.01380

  View details for PubMedID 32038992

• RBC-Specific CD47 Pruning Confers Protection and Underlies the Transient Anemia in Patients Treated with Anti-CD47 Antibody 5F9 Chen, J. Y., McKenna, K., Choi, T. S., Duan, J., Brown, L., Stewart, J. J., Sompalli, K., Vyas, P., Schrier, S., Majeti, R., Weissman, I. L., Elrod, K., Chao, M., Takimoto, C. H., Liu, J., Volkmer, J. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115674

  View details for Web of Science ID 000454837606298

• Combination Treatment with 5F9 and Azacitidine Enhances Phagocytic Elimination of Acute Myeloid Leukemia Feng, D., Gip, P., McKenna, K., Zhao, F., Mata, O., Choi, T. S., Duan, J., Sompalli, K., Majeti, R., Weissman, I. L., Takimoto, C. H., Chao, M., Chen, J. Y., Liu, J., Volkmer, J. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-120170

  View details for Web of Science ID 000454837607335

• Programmed cell removal by calreticulin in tissue homeostasis and cancer NATURE COMMUNICATIONS Feng, M., Marjon, K. D., Zhu, F., Weissman-Tsukamoto, R., Levett, A., Sullivan, K., Kao, K. S., Markovic, M., Bump, P. A., Jackson, H. M., Choi, T. S., Chen, J., Banuelos, A. M., Liu, J., Gip, P., Cheng, L., Wang, D., Weissman, I. L. 2018; 9

  View details for DOI 10.1038/s41467-018-05211-7

  View details for Web of Science ID 000441306000001

• Programmed cell removal by calreticulin in tissue homeostasis and cancer. Nature communications Feng, M. n., Marjon, K. D., Zhu, F. n., Weissman-Tsukamoto, R. n., Levett, A. n., Sullivan, K. n., Kao, K. S., Markovic, M. n., Bump, P. A., Jackson, H. M., Choi, T. S., Chen, J. n., Banuelos, A. M., Liu, J. n., Gip, P. n., Cheng, L. n., Wang, D. n., Weissman, I. L. 2018; 9 (1): 3194

  Abstract

  Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.

  View details for PubMedID 30097573

• Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors SCIENCE TRANSLATIONAL MEDICINE Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 2017; 9 (381)

  Abstract

  Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

  View details for DOI 10.1126/scitranslmed.aaf2968

  View details for PubMedID 28298418

• The CD47 Macrophage Checkpoint as a New Immunotherapy Target Sikic, B. I., Padda, S. K., Shah, S. A., Colevas, D., Narayanan, S., Fisher, G. A., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Villalobos, V. M., Liu, J., Takimoto, C., Chao, M. P., Volkmer, J. P., Majeti, R., Weissman, I. L. ELSEVIER SCIENCE INC. 2017: S108–S109

  View details for Web of Science ID 000413055800089

• SIRP alpha-Antibody Fusion Proteins Selectively Bind and Eliminate Dual Antigen-Expressing Tumor Cells CLINICAL CANCER RESEARCH Piccione, E. C., Juarez, S., Tseng, S., Liu, J., Stafford, M., Narayanan, C., Wang, L., Weiskopf, K., Majeti, R. 2016; 22 (20): 5109-5119

  Abstract

  CD47 is highly expressed on a variety of tumor cells. The interaction of CD47 with signal regulatory protein alpha (SIRPα), a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. CD47-SIRPα antagonists enable phagocytosis by disrupting the inhibitory signal and can synergize with Fc-mediated pro-phagocytic signals for potent elimination of tumor cells. A potential limitation of therapeutic CD47-SIRPα antagonists is that expression of CD47 on normal cells may create sites of toxicity or an "antigen sink." To overcome these limitations and address selective tumor targeting, we developed SIRPabodies to improve the therapeutic benefits of CD47-SIRPα blockade specifically toward tumor.SIRPabodies were generated by grafting the wild-type SIRPα either to the N-terminus or to the C-terminus of the heavy chain of rituximab. Selective tumor binding was tested using CFSE-labeled human primary CLL cells in the presence of 20-fold excess of human RBCs. NSG mice were transplanted with Raji-luciferase cells and were assigned to controls versus SIRPabody treatment. Cynomolgus nonhuman primates were administered a single intravenous infusion of SIRPabody at 3, 10, or 30 mg/kg.SIRPabodies selectively bound to dual antigen-expressing tumor cells in the presence of a large antigen sink. SIRPabody reduced tumor burden and extended survival in mouse xenograft lymphoma models. SIRPabody caused no significant toxicity in nonhuman primates.These findings establish SIRPabodies as a promising approach to deliver the therapeutic benefit of CD47-SIRPα blockade specifically toward tumor cells. SIRPabodies may be applied to additional cancer types by grafting SIRPα onto other tumor-specific therapeutic antibodies. Clin Cancer Res; 22(20); 5109-19. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-15-2503

  View details for Web of Science ID 000385632700019

  View details for PubMedID 27126995

• CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer JOURNAL OF CLINICAL INVESTIGATION Weiskopf, K., Jahchan, N. S., Schnorr, P. J., Cristea, S., Ring, A. M., Maute, R. L., Volkmer, A. K., Volkmer, J., Liu, J., Lim, J. S., Yang, D., Seitz, G., Thuyen Nguyen, T., Wu, D., Jude, K., Guerston, H., Barkal, A., Trapani, F., George, J., Poirier, J. T., Gardner, E. E., Miles, L. A., de Stanchina, E., Lofgren, S. M., Vogel, H., Winslow, M. M., Dive, C., Thomas, R. K., Rudin, C. M., van de Rijn, M., Majeti, R., Garcia, K. C., Weissman, I. L., Sage, J. 2016; 126 (7): 2610-2620

  Abstract

  Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. Antibodies to these targets, including CD56/neural cell adhesion molecule (NCAM), promoted phagocytosis in human SCLC cell lines that was enhanced when combined with CD47-blocking therapies. In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRPα axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.

  View details for DOI 10.1172/JCI81603

  View details for Web of Science ID 000379094800024

  View details for PubMedID 27294525

  View details for PubMedCentralID PMC4922696

• A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.3019

  View details for Web of Science ID 000404665404058

• Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo PLOS ONE Zhang, M., Hutter, G., Kahn, S. A., Azad, T. D., Gholamin, S., Xu, C. Y., Liu, J., Achrol, A. S., Richard, C., Sommerkamp, P., Schoen, M. K., McCracken, M. N., Majeti, R., Weissman, I., Mitra, S. S., Cheshier, S. H. 2016; 11 (4)

  Abstract

  Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

  View details for DOI 10.1371/journal.pone.0153550

  View details for Web of Science ID 000374541200027

  View details for PubMedID 27092773

  View details for PubMedCentralID PMC4836698

• A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells MABS Piccione, E. C., Juarez, S., Liu, J., Tseng, S., Ryan, C. E., Narayanan, C., Wang, L., Weiskopf, K., Majeti, R. 2015; 7 (5): 946-956

  Abstract

  Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.

  View details for DOI 10.1080/19420862.2015.1062192

  View details for Web of Science ID 000360218900015

• Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PloS one Liu, J., Wang, L., Zhao, F., Tseng, S., Narayanan, C., Shura, L., Willingham, S., Howard, M., Prohaska, S., Volkmer, J., Chao, M., Weissman, I. L., Majeti, R. 2015; 10 (9)

  View details for DOI 10.1371/journal.pone.0137345

  View details for PubMedID 26390038

• OVERCOMING IMMUNE EVASION IN PEDIATRIC BRAIN TUMORS: A PRE-CLINICAL DEVELOPMENT STUDY USING A HUMANIZED ANTI-CD47 ANTIBODY Gholamin, S., Mitra, S., Feroze, A., Zhang, M., Esparza, R., Kahn, S., Richard, C., Achrol, A., Volkmer, A., Liu, J., Volkmer, J., Majeti, R., Weissman, I., Cheshier, S. OXFORD UNIV PRESS INC. 2014: 138

  View details for Web of Science ID 000337924200531

• Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Edris, B., Weiskopf, K., Volkmer, A. K., Volkmer, J., Willingham, S. B., Contreras-Trujillo, H., Liu, J., Majeti, R., West, R. B., Fletcher, J. A., Beck, A. H., Weissman, I. L., van de Rijn, M. 2012; 109 (17): 6656-6661

  Abstract

  Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-α, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells. Leiomyosarcoma (LMS) is a tumor of smooth muscle that can express varying levels of colony-stimulating factor-1 (CSF1), the expression of which correlates with the numbers of tumor-associated macrophages (TAMs) that are found in these tumors. We have previously shown that the presence of TAMs in LMS is associated with poor clinical outcome and the overall effect of TAMs in LMS therefore appears to be protumorigenic. However, the use of inhibitory antibodies against CD47 offers an opportunity to turn TAMs against LMS cells by allowing the phagocytic behavior of resident macrophages to predominate. Here we show that interference with CD47 increases phagocytosis of two human LMS cell lines, LMS04 and LMS05, in vitro. In addition, treatment of mice bearing subcutaneous LMS04 and LMS05 tumors with a novel, humanized anti-CD47 antibody resulted in significant reductions in tumor size. Mice bearing LMS04 tumors develop large numbers of lymph node and lung metastases. In a unique model for neoadjuvant treatment, mice were treated with anti-CD47 antibody starting 1 wk before resection of established primary tumors and subsequently showed a striking decrease in the size and number of metastases. These data suggest that treatment with anti-CD47 antibodies not only reduces primary tumor size but can also be used to inhibit the development of, or to eliminate, metastatic disease.

  View details for DOI 10.1073/pnas.1121629109

  View details for PubMedID 22451919

• Effect of nanoparticle size on the aqueous solubility of polymer-coated silver nanoparticles as predicted by the modified Kelvin's equation Ma, R., Levard, C., Marinakos, S., Cheng, Y., Liu, J., Michel, F., Brown, G. E., Lowry, G. V. AMER CHEMICAL SOC. 2012

  View details for Web of Science ID 000324475103506