dc.contributor.author | Archer, S | |
dc.contributor.author | Brailey, PM | |
dc.contributor.author | Song, M | |
dc.contributor.author | Bartlett, PD | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Guo, C | |
dc.contributor.author | Brucklacher-Waldert, V | |
dc.contributor.author | Thompson, HL | |
dc.contributor.author | Akinwale, J | |
dc.contributor.author | Boyle, SE | |
dc.contributor.author | Rossant, C | |
dc.contributor.author | Birkett, NR | |
dc.contributor.author | Pizzey, J | |
dc.contributor.author | Maginn, M | |
dc.contributor.author | Legg, J | |
dc.contributor.author | Williams, R | |
dc.contributor.author | Johnston, CM | |
dc.contributor.author | Bland-Ward, P | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Pierce, AJ | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-07-03T12:27:55Z | |
dc.date.available | 2024-07-03T12:27:55Z | |
dc.date.issued | 2024-04-15 | |
dc.identifier | 741911 | |
dc.identifier.citation | Clinical Cancer Research, 2024, 30 (8), pp. 1595 - 1606 | en_US |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6276 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-23-3052 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-23-3052 | |
dc.description.abstract | 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. | |
dc.format | Print | |
dc.format.extent | 1595 - 1606 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER ASSOC CANCER RESEARCH | en_US |
dc.relation.ispartof | Clinical Cancer Research | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Male | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Animals | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Immunotherapy | |
dc.subject | Tumor Microenvironment | |
dc.title | CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-02-05 | |
dc.date.updated | 2024-07-03T12:27:14Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1158/1078-0432.CCR-23-3052 | en_US |
rioxxterms.licenseref.startdate | 2024-04-15 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38593226 | |
pubs.issue | 8 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/1078-0432.ccr-23-3052 | |
pubs.volume | 30 | |
icr.researchteam | Cancer Biomarkers | en_US |
icr.researchteam | PrCa Targeted Therapy | en_US |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Guo, Wei Yu | |
dc.contributor.icrauthor | De Bono, Johann | |
icr.provenance | Deposited by Mr Arek Surman on 2024-07-03. Deposit type is initial. No. of files: 1. Files: CB307 A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.pdf | |