Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma
Abstract Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematologic...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46310-y |
| _version_ | 1797266721142210560 |
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| author | C. Grandclément C. Estoppey E. Dheilly M. Panagopoulou T. Monney C. Dreyfus J. Loyau V. Labanca A. Drake S. De Angelis A. Rubod J. Frei L. N. Caro S. Blein E. Martini M. Chimen T. Matthes Z. Kaya C. M. Edwards J. R. Edwards E. Menoret C. Kervoelen C. Pellat-Deceunynck P. Moreau M. L. Mbow A. Srivastava M. R. Dyson E. A. Zhukovsky M. Perro S. Sammicheli |
| author_facet | C. Grandclément C. Estoppey E. Dheilly M. Panagopoulou T. Monney C. Dreyfus J. Loyau V. Labanca A. Drake S. De Angelis A. Rubod J. Frei L. N. Caro S. Blein E. Martini M. Chimen T. Matthes Z. Kaya C. M. Edwards J. R. Edwards E. Menoret C. Kervoelen C. Pellat-Deceunynck P. Moreau M. L. Mbow A. Srivastava M. R. Dyson E. A. Zhukovsky M. Perro S. Sammicheli |
| author_sort | C. Grandclément |
| collection | DOAJ |
| description | Abstract Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma. |
| first_indexed | 2024-04-25T01:05:11Z |
| format | Article |
| id | doaj.art-ae64b6350d9447b3aeaa07c8f647d23b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-25T01:05:11Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ae64b6350d9447b3aeaa07c8f647d23b2024-03-10T12:17:37ZengNature PortfolioNature Communications2041-17232024-03-0115111610.1038/s41467-024-46310-yDevelopment of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myelomaC. Grandclément0C. Estoppey1E. Dheilly2M. Panagopoulou3T. Monney4C. Dreyfus5J. Loyau6V. Labanca7A. Drake8S. De Angelis9A. Rubod10J. Frei11L. N. Caro12S. Blein13E. Martini14M. Chimen15T. Matthes16Z. Kaya17C. M. Edwards18J. R. Edwards19E. Menoret20C. Kervoelen21C. Pellat-Deceunynck22P. Moreau23M. L. Mbow24A. Srivastava25M. R. Dyson26E. A. Zhukovsky27M. Perro28S. Sammicheli29Ichnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationHaematology Service, Department of Oncology and Clinical Pathology Service, Department of Diagnostics, University Hospital GenevaNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of OxfordNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of OxfordNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of OxfordNantes Université, Inserm, CNRS, Université d’AngersNantes Université, Inserm, CNRS, Université d’AngersNantes Université, Inserm, CNRS, Université d’AngersNantes Université, Inserm, CNRS, Université d’AngersIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationIchnos Glenmark InnovationAbstract Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.https://doi.org/10.1038/s41467-024-46310-y |
| spellingShingle | C. Grandclément C. Estoppey E. Dheilly M. Panagopoulou T. Monney C. Dreyfus J. Loyau V. Labanca A. Drake S. De Angelis A. Rubod J. Frei L. N. Caro S. Blein E. Martini M. Chimen T. Matthes Z. Kaya C. M. Edwards J. R. Edwards E. Menoret C. Kervoelen C. Pellat-Deceunynck P. Moreau M. L. Mbow A. Srivastava M. R. Dyson E. A. Zhukovsky M. Perro S. Sammicheli Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma Nature Communications |
| title | Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| title_full | Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| title_fullStr | Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| title_full_unstemmed | Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| title_short | Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| title_sort | development of isb 1442 a cd38 and cd47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma |
| url | https://doi.org/10.1038/s41467-024-46310-y |
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