CB307 : A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
©2024 The Authors; Published by the American Association for Cancer Research..
PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease.
EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques.
RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration.
CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 8 vom: 15. Apr., Seite 1595-1606 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Archer, Sophie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.04.2024 Date Revised 25.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-3052 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370825705 |
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| 100 | 1 | |a Archer, Sophie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CB307 |b A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors |
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| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2024 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease | ||
| 520 | |a EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques | ||
| 520 | |a RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration | ||
| 520 | |a CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Brailey, Phillip M |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Minjung |e verfasserin |4 aut | |
| 700 | 1 | |a Bartlett, Phillip D |e verfasserin |4 aut | |
| 700 | 1 | |a Figueiredo, Ines |e verfasserin |4 aut | |
| 700 | 1 | |a Gurel, Bora |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Brucklacher-Waldert, Verena |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, H Lorraine |e verfasserin |4 aut | |
| 700 | 1 | |a Akinwale, Jude |e verfasserin |4 aut | |
| 700 | 1 | |a Boyle, Samantha E |e verfasserin |4 aut | |
| 700 | 1 | |a Rossant, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Birkett, Neil R |e verfasserin |4 aut | |
| 700 | 1 | |a Pizzey, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Maginn, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Legg, James |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Johnston, Colette M |e verfasserin |4 aut | |
| 700 | 1 | |a Bland-Ward, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a de Bono, Johann S |e verfasserin |4 aut | |
| 700 | 1 | |a Pierce, Andrew J |e verfasserin |4 aut | |
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