Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity
ISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blockin...
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| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2025.2457471 |
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| author | Jeremy Loyau Thierry Monney Marco Montefiori Fedir Bokhovchuk Jeremy Streuli Matthew Blackburn Arnaud Goepfert Lydia N. Caro Samitabh Chakraborti Stefania De Angelis Camille Grandclément Stanislas Blein M. Lamine Mbow Ankita Srivastava Mario Perro Stefano Sammicheli Eugene A. Zhukovsky Michael Dyson Cyrille Dreyfus |
| author_facet | Jeremy Loyau Thierry Monney Marco Montefiori Fedir Bokhovchuk Jeremy Streuli Matthew Blackburn Arnaud Goepfert Lydia N. Caro Samitabh Chakraborti Stefania De Angelis Camille Grandclément Stanislas Blein M. Lamine Mbow Ankita Srivastava Mario Perro Stefano Sammicheli Eugene A. Zhukovsky Michael Dyson Cyrille Dreyfus |
| author_sort | Jeremy Loyau |
| collection | DOAJ |
| description | ISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blocking of proximal CD47 receptors. We previously reported the pharmacology of ISB 1442, designed to reestablish synthetic immunity in CD38+ hematological malignancies. Here, we describe the discovery, optimization and characterization of the ISB 1442 antigen binding fragment (Fab) arms, their assembly to 2 + 1 format, and present the high-resolution co-crystal structures of the two anti-CD38 Fabs, in complex with CD38. This, with biophysical and functional assays, elucidated the underlying mechanism of action of ISB 1442. In solution phase, ISB 1442 forms a 2:2 complex with CD38 as determined by size-exclusion chromatography with multi-angle light scattering and electron microscopy. The predicted antibody-antigen stoichiometries at different CD38 surface densities were experimentally validated by surface plasmon resonance and cell binding assays. The specific design and structural features of ISB 1442 enable: 1) enhanced trans binding to adjacent CD38 molecules to increase Fc density at the cancer cell surface; 2) prevention of avid cis binding to monomeric CD38 to minimize blockade by soluble shed CD38; and 3) greater binding avidity, with a slower off-rate at high CD38 density, for increased specificity. The superior CD38 targeting of ISB 1442, at both high and low receptor densities, by its biparatopic design, will enhance proximal CD47 blockade and thus counteract a major tumor escape mechanism in multiple myeloma patients. |
| format | Article |
| id | doaj-art-7607cc8116594207bd3ea9eb8ab2d672 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-7607cc8116594207bd3ea9eb8ab2d6722025-01-30T12:19:54ZengTaylor & Francis GroupmAbs1942-08621942-08702025-12-0117110.1080/19420862.2025.2457471Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidityJeremy Loyau0Thierry Monney1Marco Montefiori2Fedir Bokhovchuk3Jeremy Streuli4Matthew Blackburn5Arnaud Goepfert6Lydia N. Caro7Samitabh Chakraborti8Stefania De Angelis9Camille Grandclément10Stanislas Blein11M. Lamine Mbow12Ankita Srivastava13Mario Perro14Stefano Sammicheli15Eugene A. Zhukovsky16Michael Dyson17Cyrille Dreyfus18Ichnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAIchnos Glenmark Innovation, New York, NY, USAISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blocking of proximal CD47 receptors. We previously reported the pharmacology of ISB 1442, designed to reestablish synthetic immunity in CD38+ hematological malignancies. Here, we describe the discovery, optimization and characterization of the ISB 1442 antigen binding fragment (Fab) arms, their assembly to 2 + 1 format, and present the high-resolution co-crystal structures of the two anti-CD38 Fabs, in complex with CD38. This, with biophysical and functional assays, elucidated the underlying mechanism of action of ISB 1442. In solution phase, ISB 1442 forms a 2:2 complex with CD38 as determined by size-exclusion chromatography with multi-angle light scattering and electron microscopy. The predicted antibody-antigen stoichiometries at different CD38 surface densities were experimentally validated by surface plasmon resonance and cell binding assays. The specific design and structural features of ISB 1442 enable: 1) enhanced trans binding to adjacent CD38 molecules to increase Fc density at the cancer cell surface; 2) prevention of avid cis binding to monomeric CD38 to minimize blockade by soluble shed CD38; and 3) greater binding avidity, with a slower off-rate at high CD38 density, for increased specificity. The superior CD38 targeting of ISB 1442, at both high and low receptor densities, by its biparatopic design, will enhance proximal CD47 blockade and thus counteract a major tumor escape mechanism in multiple myeloma patients.https://www.tandfonline.com/doi/10.1080/19420862.2025.2457471Biparatopic bispecific antibodyCD38CD47CDCco-crystal structuresinnate cell modulator |
| spellingShingle | Jeremy Loyau Thierry Monney Marco Montefiori Fedir Bokhovchuk Jeremy Streuli Matthew Blackburn Arnaud Goepfert Lydia N. Caro Samitabh Chakraborti Stefania De Angelis Camille Grandclément Stanislas Blein M. Lamine Mbow Ankita Srivastava Mario Perro Stefano Sammicheli Eugene A. Zhukovsky Michael Dyson Cyrille Dreyfus Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity mAbs Biparatopic bispecific antibody CD38 CD47 CDC co-crystal structures innate cell modulator |
| title | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity |
| title_full | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity |
| title_fullStr | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity |
| title_full_unstemmed | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity |
| title_short | Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity |
| title_sort | biparatopic binding of isb 1442 to cd38 in trans enables increased cell antibody density and increased avidity |
| topic | Biparatopic bispecific antibody CD38 CD47 CDC co-crystal structures innate cell modulator |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2025.2457471 |
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