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1. Video 1 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Video 1 shows the real time phagocytosis of cancer cells in presence of NI-1701

Published
2023
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2. Data from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal “don't eat me” signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701–induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20–targeted therapy. Mol Cancer Ther; 17(8); 1739–51. ©2018 AACR.

Published
2023
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3. Supplementary Table S3 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Table S3 shows the ratio of AUC0-inf low/high dose for the PK single dose study.

Published
2023
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4. Supplementary Materials and Methods from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary material and methods

Published
2023
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5. Supplementary Table S5 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Table S5 shows the hematological results of cynomolgus monkeys treated with vehicle (Ctr.) or NI-1701 (Treat.) at 30 and 100 mg/kg over 4 weeks.

Published
2023
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6. Supplementary Figure S1 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Figure S1 shows shows the percentage of in vitro phagocytosis of Raji cells by macrophages with NI-1701 or CD19/CD47hi biAb.

Published
2023
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7. Supplementary Table S2 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Table S2 shows the cell surface density (expressed as number of receptors per cell) for CD19, CD47, CD20 on different human tumor cell lines.

Published
2023
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8. Video 2 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Video 2 shows the real time phagocytosis of cancer cells in presence of hIgG1 control

Published
2023
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9. Supplementary Table S4 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Table S4 shows the mean Cmax values from the DRF and the single dose study.

Published
2023
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10. Supplementary Table S1 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Table S1 shows the cell surface density (expressed as number of receptors per cell) for CD19, CD47, CD20 on different subpopulations in human whole blood

Published
2023
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11. Supplementary Figure S2 from Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter G. Ferlin, Limin Shang, Nicolas Fischer, Krzysztof Masternak, Marie H. Kosco-Vilbois, John F. DiPersio, Michael Rettig, Julie Ritchey, Linda Eissenberg, Adele K. Fielding, Katharine Bailey, Aditi Dey, José María Ribera, Eulàlia Genescà Ferrer, Robert K. Clarke Hinojosa, Karin Tarte, Thierry Fest, Simon LeGallou, Thomas Matthes, Matilde D'Asaro, Lucile Broyer, Laura Cons, Bruno Daubeuf, Leticia Barba, Françoise Richard, Xavier Chauchet, Eric Hatterer, Anne Papaioannou, Susana Salgado-Pires, Zoë Johnson, and Vanessa Buatois

Abstract

Supplementary Figure S2 shows in vitro hemagglutination in human or cynomolgus monkeys whole blood, or platelet aggregation in human platelet rich-plasma (PRP)in presence of NI-1701

Published
2023
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12. Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Author

Walter Ferlin, Vanessa Buatois, Krzysztof Masternak, Leticia Barba, Françoise Richard, Aditi Dey, Michael P. Rettig, Zoë Johnson, Bruno Daubeuf, Julie Ritchey, Xavier Chauchet, Anne Papaioannou, Eric Hatterer, Robert K. Clarke Hinojosa, Thomas Matthes, Marie Kosco-Vilbois, Thierry Fest, Matilde D'Asaro, Eulàlia Genescà Ferrer, Laura Cons, Limin Shang, Simon LeGallou, Karin Tarte, Katharine Bailey, Nicolas Fischer, Jose Maria Ribera, Adele K. Fielding, Susana Salgado-Pires, Lucile Broyer, Linda Eissenberg, John F. DiPersio, Novimmune SA, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University College of London [London] (UCL), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), R50CA211466, National Cancer Institute, D'Asaro, Matilde, Matthes, Thomas, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Washington University in St Louis

Subjects
Cancer Research, Lymphoma, B-Cell, Antigens, CD19, CD47 Antigen, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD19, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, Antibodies, Bispecific, medicine, Animals, Humans, ddc:616, Innate immune system, Leukemia, biology, business.industry, CD47, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, Rituximab, Antibody, business, 030215 immunology, medicine.drug
Abstract

CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal “don't eat me” signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701–induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20–targeted therapy. Mol Cancer Ther; 17(8); 1739–51. ©2018 AACR.

Published
2018
Full Text
View/download PDF

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