BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells
Background Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates fun...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e006567.full |
| _version_ | 1797845422351319040 |
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| author | Timo K van den Berg Hugo Olsman Hanke L Matlung Katka Franke Imke Lodewijks Lilian Driessen-Engels Mary J van Helden Seline A Zwarthoff Roel J Arends Inge M J Reinieren-Beeren Marc C B C Paradé Karin de Laat-Arts Désirée Damming Ellen W H Santegoeds-Lenssen Daphne W J van Kuppeveld Ellen Mattaar-Hepp Marloes E M Stokman Benny de Wit Dirk H R F Glaudemans Daniëlle E J W van Wijk Lonnie Joosten-Stoffels Jan Schouten Paul J Boersema Monique van der Vleuten Jorien W H Sanderink Wendela A Kappers Diels van den Dobbelsteen Marco Timmers Ruud Ubink Gerard J A Rouwendal Gijs Verheijden Miranda M C van der Lee Wim H A Dokter |
| author_facet | Timo K van den Berg Hugo Olsman Hanke L Matlung Katka Franke Imke Lodewijks Lilian Driessen-Engels Mary J van Helden Seline A Zwarthoff Roel J Arends Inge M J Reinieren-Beeren Marc C B C Paradé Karin de Laat-Arts Désirée Damming Ellen W H Santegoeds-Lenssen Daphne W J van Kuppeveld Ellen Mattaar-Hepp Marloes E M Stokman Benny de Wit Dirk H R F Glaudemans Daniëlle E J W van Wijk Lonnie Joosten-Stoffels Jan Schouten Paul J Boersema Monique van der Vleuten Jorien W H Sanderink Wendela A Kappers Diels van den Dobbelsteen Marco Timmers Ruud Ubink Gerard J A Rouwendal Gijs Verheijden Miranda M C van der Lee Wim H A Dokter |
| author_sort | Timo K van den Berg |
| collection | DOAJ |
| description | Background Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.Method We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.Results BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPαBIT transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.Conclusions Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023. |
| first_indexed | 2024-04-09T17:38:46Z |
| format | Article |
| id | doaj.art-b070a5b304cf452fb3bfdad0492340e0 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-09T17:38:46Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-b070a5b304cf452fb3bfdad0492340e02023-04-17T09:30:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-006567BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cellsTimo K van den Berg0Hugo Olsman1Hanke L Matlung2Katka Franke3Imke Lodewijks4Lilian Driessen-Engels5Mary J van Helden6Seline A Zwarthoff7Roel J Arends8Inge M J Reinieren-Beeren9Marc C B C Paradé10Karin de Laat-Arts11Désirée Damming12Ellen W H Santegoeds-Lenssen13Daphne W J van Kuppeveld14Ellen Mattaar-Hepp15Marloes E M Stokman16Benny de Wit17Dirk H R F Glaudemans18Daniëlle E J W van Wijk19Lonnie Joosten-Stoffels20Jan Schouten21Paul J Boersema22Monique van der Vleuten23Jorien W H Sanderink24Wendela A Kappers25Diels van den Dobbelsteen26Marco Timmers27Ruud Ubink28Gerard J A Rouwendal29Gijs Verheijden30Miranda M C van der Lee31Wim H A Dokter32Department of Molecular Cell Biology and Immunology, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsLaboratory for Immunotherapy, Sanquin Research, Amsterdam, The NetherlandsDepartment of Blood Cell Research, Sanquin Research, Amsterdam, The NetherlandsSanquin Research, Amsterdam, The NetherlandsBioNovion/Aduro Biotech Europe, Oss, The NetherlandsBioNovion/Aduro Biotech Europe, Oss, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsByondis BV, Nijmegen, Gelderland, The NetherlandsBackground Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.Method We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.Results BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPαBIT transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.Conclusions Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.https://jitc.bmj.com/content/11/4/e006567.full |
| spellingShingle | Timo K van den Berg Hugo Olsman Hanke L Matlung Katka Franke Imke Lodewijks Lilian Driessen-Engels Mary J van Helden Seline A Zwarthoff Roel J Arends Inge M J Reinieren-Beeren Marc C B C Paradé Karin de Laat-Arts Désirée Damming Ellen W H Santegoeds-Lenssen Daphne W J van Kuppeveld Ellen Mattaar-Hepp Marloes E M Stokman Benny de Wit Dirk H R F Glaudemans Daniëlle E J W van Wijk Lonnie Joosten-Stoffels Jan Schouten Paul J Boersema Monique van der Vleuten Jorien W H Sanderink Wendela A Kappers Diels van den Dobbelsteen Marco Timmers Ruud Ubink Gerard J A Rouwendal Gijs Verheijden Miranda M C van der Lee Wim H A Dokter BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells Journal for ImmunoTherapy of Cancer |
| title | BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells |
| title_full | BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells |
| title_fullStr | BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells |
| title_full_unstemmed | BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells |
| title_short | BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells |
| title_sort | byon4228 is a pan allelic antagonistic sirpα antibody that potentiates destruction of antibody opsonized tumor cells and lacks binding to sirpγ on t cells |
| url | https://jitc.bmj.com/content/11/4/e006567.full |
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