CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.
Date
2024-04-15Author
Archer, S
Brailey, PM
Song, M
Bartlett, PD
Figueiredo, I
Gurel, B
Guo, C
Brucklacher-Waldert, V
Thompson, HL
Akinwale, J
Boyle, SE
Rossant, C
Birkett, NR
Pizzey, J
Maginn, M
Legg, J
Williams, R
Johnston, CM
Bland-Ward, P
de Bono, JS
Pierce, AJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Male
Humans
Mice
Animals
Prostatic Neoplasms, Castration-Resistant
Immunotherapy
Tumor Microenvironment
Research team
Cancer Biomarkers
PrCa Targeted Therapy
Language
eng
Date accepted
2024-02-05
License start date
2024-04-15
Citation
Clinical Cancer Research, 2024, 30 (8), pp. 1595 - 1606
Publisher
AMER ASSOC CANCER RESEARCH