SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models
Background SGN-B7H4V is a novel investigational vedotin antibody–drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin link...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/10/e007572.full |
| _version_ | 1797642270528241664 |
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| author | Elizabeth Gray Kelly Hensley Sean Allred Robert Thurman Katie Snead Michelle Ulrich Dannah Miller Serena Wo Angela Epp Disha Sahetya Julie Hahn Chris Frantz Natalya Nazarenko Kellie Spahr Patrick Younan Li-Ya Huang Kristen Gahnberg Piper M Treuting Esther S Trueblood John J Gosink Evgenia Jane Haass Mary Padilla Alyson J Smith Jason P Schrum Shyra J Gardai |
| author_facet | Elizabeth Gray Kelly Hensley Sean Allred Robert Thurman Katie Snead Michelle Ulrich Dannah Miller Serena Wo Angela Epp Disha Sahetya Julie Hahn Chris Frantz Natalya Nazarenko Kellie Spahr Patrick Younan Li-Ya Huang Kristen Gahnberg Piper M Treuting Esther S Trueblood John J Gosink Evgenia Jane Haass Mary Padilla Alyson J Smith Jason P Schrum Shyra J Gardai |
| author_sort | Elizabeth Gray |
| collection | DOAJ |
| description | Background SGN-B7H4V is a novel investigational vedotin antibody–drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.Methods B7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.Results Immunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.Conclusion The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies. |
| first_indexed | 2024-03-11T13:57:43Z |
| format | Article |
| id | doaj.art-f885976e5e104e04a8016c6dbb713fb4 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-11T13:57:43Z |
| publishDate | 2023-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-f885976e5e104e04a8016c6dbb713fb42023-11-02T06:20:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-10-01111010.1136/jitc-2023-007572SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical modelsElizabeth Gray0Kelly Hensley1Sean Allred2Robert Thurman3Katie Snead4Michelle Ulrich5Dannah Miller6Serena Wo7Angela Epp8Disha Sahetya9Julie Hahn10Chris Frantz11Natalya Nazarenko12Kellie Spahr13Patrick Younan14Li-Ya Huang15Kristen Gahnberg16Piper M Treuting17Esther S Trueblood18John J Gosink19Evgenia Jane Haass20Mary Padilla21Alyson J Smith22Jason P Schrum23Shyra J Gardai24Seagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USASeagen Inc, Bothell, Washington, USABackground SGN-B7H4V is a novel investigational vedotin antibody–drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.Methods B7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.Results Immunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.Conclusion The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.https://jitc.bmj.com/content/11/10/e007572.full |
| spellingShingle | Elizabeth Gray Kelly Hensley Sean Allred Robert Thurman Katie Snead Michelle Ulrich Dannah Miller Serena Wo Angela Epp Disha Sahetya Julie Hahn Chris Frantz Natalya Nazarenko Kellie Spahr Patrick Younan Li-Ya Huang Kristen Gahnberg Piper M Treuting Esther S Trueblood John J Gosink Evgenia Jane Haass Mary Padilla Alyson J Smith Jason P Schrum Shyra J Gardai SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models Journal for ImmunoTherapy of Cancer |
| title | SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models |
| title_full | SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models |
| title_fullStr | SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models |
| title_full_unstemmed | SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models |
| title_short | SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models |
| title_sort | sgn b7h4v an investigational vedotin adc directed to the immune checkpoint ligand b7 h4 shows promising activity in preclinical models |
| url | https://jitc.bmj.com/content/11/10/e007572.full |
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